Download REVIEW ARTICLE Viral Infections in Domestic Animals as Models

J. gen. Virol. (1986), 66, 1-25. Printed in Great Britain
Key words : immunology/pathogenesis/domestic/animal models
REVIEW
ARTICLE
Viral Infections in Domestic Animals as Models for Studies of Viral
Immunology and Pathogenesis
BY H. B I E L E F E L D T
OHMANN*t
AND L. A. B A B I U K
Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatchewan,
Canada S 7 N 0 WO
INTRODUCTION
The interactions between viruses and the host immune system involve a complex series of
events which often lead to activation of the immune response and clearance of the infectious
agent. Alternatively, viruses can adversely affect the immune system resulting in chronic or
persistent infections or immunopathology. The majority of information regarding viral infection
and the host response to such infections has been obtained from laboratory animal models.
Although these laboratory models have been very useful in helping us understand many virushost interactions, they do have some limitations which natural animal models may overcome.
The present review will attempt to focus on a few isolated animal models not often considered, as
well as to review the most recent information regarding some viral diseases of domestic animals
previously recognized as useful (Table 1). Using these models, we hope to locus on questions
pertinent to how viruses may evade the immune response, resulting in viral persistence and
immunopathology or cause immunosuppression, and demonstrate the value of these natural
animal models in aiding the elucidation of virus-host interactions. In each of the instances
attempts will be made at demonstrating the usefulness of these models for comparative studies.
Virus persistence
Congenital injection
A major challenge to the student of viral immunology and immunopathology is the disease
complex caused by pestiviruses. Even though only one similar human disease is caused by a nonarthropod-borne togavirus, i.e. congenital rubella, the complex appears to present so many
challenges to the general understanding of virus-cell and virus-host interact ions that it deserves
attention beyond the narrow field of veterinary medicine (Porter, 1971).
The genus Pestivirus comprises bovine viral diarrhoea virus (BVDV, also known as mucosal
disease virus), hog cholera virus (HCV, synonym: classical or European swine lever) and border
disease virus (BDV, synonym: hairy shaker disease virus), and constitute in conjunction with
rubella virus (RV), equine arteritis virus and lactic dehydrogenase-elevating virus the 'non-arbo'
togaviruses (Porterfield et al., 1978; Horzinek, 1981). A common feature of BVDV, BDV and
HCV is their ability to cause acute, chronic or clinically inapparent infections in their respective
hosts with similar clinical, pathological and immunological manifestations (Stober, 1984; van
Oirschot, 1980; Barlow et al., 1983; Bielefeldt Ohmann, 1981). All three viruses, like RV, are
capable of causing a wide variety of congenital abnormalities including abortion, stillbirth,
intrauterine growth retardation and selective organ stunting, cerebral and cerebellar
malformations (including hypoplasia, dysmyelination, skeletal defects and skin abnormalities;
for reviews, see van Oirschot, 1983; also Barlow et al., 1979; Bielefeldt Ohmann, 1984). In
addition, BVDV and RV can cause chorioretinopathy and cataracts (Bielefeldt Ohmann, 1984;
Forrest & Menser, 1975; Dudgeon, 1976). Generally, multiple defects are present, but clinically
t Present address: Department of Veterinary Virology and Immunology, The Royal Veterinary and
Agricultural University, 13 Bulowsvej, DK-1870 Copenhagen V, Denmark.
0000-6762 © 1986 SGM
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H. B I E L E F E L D T
O H M A N N A N D L. A. B A B I U K
Table 1. Examples of virus infections in domestic animals with potential as animal models for
understanding virus host interactions
Virus group
Togaviruses (non-arbo)
Iridoviridae
Virus
Borderdisease
Hog cholera
Bovine viral diarrhoea
African swine fever
Host
Sheep
Swine
Cattle
Swine
Coronavirus
Feline infectious peritonitis
Cat
Visna-maedi
Caprine arthritis-encephalitis
Equine infectious anaemia
Sheep
Goat
Horse
Bovine leukaemia
Feline leukaemia
Cattle
Cat
Aleutian disease
Mink
Canine parvovirus
Feline panleukopenia
Dog
Cat
Malignant catarrhal fever
Cattle
Infectious bovine
rhinotracheitis (bovine
herpesvirus type 1)
Marek's disease
Cattle
Retroviridae
Non-oncogenic
Oncogenic
Parvoviruses
Herpesviruses
Morbilliviruses
Canine distemper
Rinderpest
Orthomyxoviruses
Swine influenza
Comment
Immunotolerance.
Immunopathology: hypersensitivity reaction. No neutralizing antibody.
Immunopathology: hypersensitivity type
IIl reaction, immune complex disease,
and disseminated intravascular coagulation.
Slow virus disease, macrophage subpopu
lation is productive host cell.
Antigenic drift due to macrophage-virus
interaction and antibody response?
Immunosuppression.
Immunosuppression: decreased interleu
kin-2 production and suppressed response to lymphokines.
Virus persistence, hypergammaglobulin
aemia, immune complex disease.
Macrophage modulation of antigen.
Immunosuppression.
Atrophy of lymphoid tissues, immunosuppression ?
Benign lymphoproliferative disease; dearranged T cell control.
Immunosuppression; increased susceptibility to secondary bacterial infection.
Chicken Lymphoproliferative disease, "natural" resistance and defence genetically
determined.
Dog
Neurological diseases: demyelinating encephalitis or meningoencephalitis.
Immunosuppression. Cytotoxic T cell
response decisive for outcome.
Cattle
Initial immunosuppression: lymphoid
cells lytically infected. Later development of protective immunity.
Swine
Increased susceptibility to secondary bacterial infection.
inapparent persistently infected individuals may also be born. They may remain clinically
normal throughout life, or they may with time (weeks, months or years later) develop a clinical,
inevitably fatal syndrome (BVDV, HCV, BDV), or other long-term sequelae including
progressive panencephalitis (RV) (for review, see van Oirschot, 1983). Factors determining the
outcome of a congenital infection include (i) the stage of foetal development at the time of
infection, including both organogenetic and immunological aspects (Mims, 1968), (ii) virus
strain (McClurkin et al., 1984; Barlow et al., 1979; Vantsis et al., 1980; Done et al., 1980; Brown
et al., 1973, 1974; van Oirschot, 1980; Bielefeldt Ohmann, 1981) and (iii) host genotype (Barlow
et al., 1979, 1980). The latter phenomenon has also been inferred to influence the outcome of RV
infections in humans (Honeyman et al., 1975).
The teratological mechanisms involved in congenital infections with pestiviruses appear to be
a neglected field of research (Derbyshire & Barlow, 1976; Barlow & Storey, 1977). More
information is available for RV despite the necessary (for ethical reasons) limitations to in vitro
studies and studies on aborted foetuses (examples: Plotkin et al., 1965; Rawts & Melnick, 1966;
Tondury & Smith, 1966). Virus-induced congenital malformations and lesions are fraught with
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Review: 'Natural' animal models for viral diseases
3
pathogenic possibilities; thus, these naturally occurring infections in easily assessible species
lend themselves as obvious tools for studies in teratology that have immediate relevance to both
animal and human viral infections.
Of even greater interest are the disease manifestations encountered later on in postnatal life,
notably in persistently viraemic animals lacking evidence of a virus-specific humoral immune
response. In cattle, in which the relation between virus persistence and a clinical syndrome was
first noted (Liess et al., 1974), the disease has long been known as mucosal disease (MD)
(Ramsey & Chivers, 1953). Typically it is seen in animals 6 to 18 months old, often occurring in
isolated cases (1 to 5~) in herds which generally contain a high percentage of BVDVseropositive animals. Another characteristic feature is that within a particular affected herd,
clinically acute MD is often seen in the same age group of animals. The course is acute, usually
with a fatal outcome within 5 to 7 days. The animals show intercurrent fever and develop severe
ulcerative lesions of the mucosa of the entire digestive tract. This is associated with a profuse
watery diarrhoea, often mixed with blood and fibrin. Furthermore, dermatosis becomes evident
(Pritchard, 1963; Bielefeldt Ohmann, 1981). In addition to the gross and histopathological
lesions related to the above-mentioned signs, the most significant findings are severe atrophy of
the thymus, depletion of lymphocytes in T cell-dependent areas in the peripheral lymphoid
tissues, and fibroid replacement of cells in germinal centres (Bielefeldt Ohmann, 1981, 1983).
The virus can be isolated from blood and most tissues. The animals thus affected invariably lack
neutralizing antibodies to BVDV. In recent years another course of MD has been recognized.
The opinion has been that the disease might have changed over the years, towards a less classical
symptomatology; however, it is more likely that improved diagnostic procedures have led to the
aetiological identification of previously unrecognized conditions (Horzinek, 1981; Stober,
1984). It affects cattle from 0.5 to 3 years of age, with a low incidence in affected herds similar to
that seen with 'classical' acute MD. Animals become, over a course of weeks to months,
emaciated with intermittent, exacerbated diarrhoea. Gross necrotic erosive lesions of the
mucosa and dermatosis may be absent or insignificant, but histopathologically moderate
changes are usually present, as are changes in the lymphoid tissues (atrophy and cell depletion)
(Bietefeldt Ohmann, 1981). Virus can be isolated from blood and tissues before and during the
prolonged clinical course. Nevertheless, neutralizing BVDV-specific antibodies are not
detectable.
A syndrome very similar to the chronic 'atypical' MD has now also been recognized in pigs
(van Oirschot, 1980). This disease appears to be a consequence of an intrauterine infection of
pregnant pigs with low-virulent HCV in mid-gestation (natural or experimental). The piglets
born to these dams develop a runting-like syndrome at approximately 4 months of age. They
become emaciated, develop conjunctivitis, dermatitis and locomotory disturbances, eventually
leading to posterior lameness. Thymus atrophy and lymph node swelling are the most prominent
pathological findings (van Oirschot, 1980). The pigs are viraemic from birth and fail to respond
specifically to HCV after disappearance of maternal antibodies (van Oirschot, 1980, 1983).
Lambs that recover from typical congenital BD, i.e. hairy shaker disease in the postnatal
period, may later in life develop intractable diarrhoea or respiratory distress and die. The
clinical signs and pathological changes resemble those seen in MD-affected calves (Barlow et al.,
1983). Moreover, affected sheep remain persistent virus excreters from birth and only rarely
produce BD-specific neutralizing antibody (Barlow et al., 1983; Gardiner et al., 1983).
The common mechanism for viral persistence in cattle, sheep and pigs without development
of antibody to the virus, has been suggested to occur as a result of congenital infection early in
gestation, resulting in immunotolerance (Kendrick, 1971; Liess et al., 1974). However, the
events that precipitated the disease in these immunotolerant animals remain an enigma.
Recently, it was demonstrated that immunotolerant, persistently infected offspring could be
produced experimentally by infecting the bovine foetus between days 40 and 125 of gestation
(McClurkin et al., 1984). Similar results were obtained in sheep with BDV (Terpstra, 1981) and
in pigs with HCV (van Oirschot, 1980). One difference is that the persistently infected pigs
inevitably develop disease, whereas sheep and cattle can remain clinically normal throughout
life (Terpstra, 1981 ; Coria & McClurkin, 1978; McClurkin et al., 1984; Liess et al., 1983).
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H. BIELEFELDT OHMANN AND L. A. BABIUK
Several theories have been proposed to explain the events which may precipitate the disease
in some of these persistently infected animals. One possibility is that re-infection with the
homologous virus strain to which the animal is tolerant (Barlow et al., 1983; Gardiner et al.,
1983; Steck et al., 1980), a heterologous strain (Brownlie et al., 1984; Liess et al., 1983), or
hormonal changes associated with puberty (Roeder & Drew, 1984) can induce clinical disease.
However, several paradoxes have to be resolved. Persistently infected animals of all three
species are immunocompetent, as evidenced by the presence of normal humoral and cellular
responses to other microbial as well as inert antigens (Terpstra, 1981 ; van Oirschot, 1980; Steck
et al., 1980; Liess et al., 1983 ; McClurkin et al., 1984). Furthermore, persistently infected cattle
may develop a good antibody titre to a BVDV vaccine strain, but nevertheless die from acute or
chronic MD (Steck et al., 1980; Liess et al., 1983), suggesting that tolerance is restricted to
epitopes on the particular virus strain, or closely related strains, that caused in utero infection.
Likewise, BDV-infected sheep may respond to BVDV (cross-reacting antibodies) or to a
heterologous strain of BDV (Vantsis et al., 1980). Some sheep can, however, develop strainspecific antibodies later in life (Gardiner et al., 1983; Terpstra, 1981; Westbury et aL, 1979).
This suggests that the unresponsiveness of the immune system (tolerance) to specific epitopes is
neither absolute nor invariably permanent, and consequently not the result of a clonal deletion of
virus-reactive cells (Oldstone, 1979). However, until it is known which specific epitopes are
involved in immunotolerance and which are involved in protection, and whether these are
common epitopes among virus strains, it will not be possible to draw any major conclusions as to
how immunotolerance to specific epitopes is established.
Unfortunately, the difficulties encountered in the study of the molecular structure and biology
of pestiviruses may continue to hamper our efforts in this regard. Thus, they remain among the
least characterized of animal viruses. In cell cultures the yields of pestiviruses are usually low,
the macromolecular synthesis of the host cell is not shut off, and virus purification is difficult
since they appear to remain intimately associated with host cell membrane components. Host
cell-controlled modifications of the virion occur in cell culture systems, as demonstrated by
changes in virion densities (Laude, 1979), are also likely to take place in vivo. This latter aspect
will certainly hamper studies of serological similarity and diversity among strains of a particular
virus, and among BVDV, HCV and BDV (Horzinek, 1981). Thus, it seems unlikely that a
resolution of virus-host interactions can be obtained unless the biology of the pestiviruses is
better understood, and the first objective in pestivirus research should perhaps be in this area.
The development of specific monoclonal antibodies would be a definite asset with respect to
identification of the important epitopes on the virus and their relationships among different
isolates as well as the modifications caused by the host cell. This would help to establish whether
the strains that induce disease in immunotolerant animals are indeed different from the
persistent virus acquired in utero, as well as which epitopes are important in providing
protection. Thus, these virus infections provide a unique, challenging model for the
understanding of viral persistence following congenital infection and hopefully will allow us to
'break' tolerance to the appropriate epitopes and thereby lead to virus clearance.
Role of the macrophage in virus persistence
The mononuclear phagocytic system (MPS) (van Furth et al., 1972) is considered to be one of
the primary non-specific defence mechanisms against foreign agents, including viruses. In
addition, it is involved in induction, regulation and amplification of the immune system, thus
playing a central role in eliminating viruses. Extensive evidence supporting the importance of
the MPS in resistance to viral infections has recently been reviewed (Morahan et al., 1985) and
will not be reiterated here. However, in addition to playing a role in eliminating viruses from the
host, cells of the MPS can also play a major role in viral persistence.
A number of viral diseases of domestic animals have in common an established or conjectural
predilection for the MPS wherein virus replication, persistence and spread in the host occurs as a
consequence of infection of these cells. Viruses capable of MPS infection are found in several
different virus groups (Table 1).
Visna-maedi viruses (VMV) are the classical examples of conventional viruses capable of
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causing slow virus disease (Gudnadottir, 1974; Sigurdsson, 1954). In addition, lentiviruses
include progressive pneumonia virus (PPV) initially isolated from sheep in North America
(Kennedy et al., 1968) and caprine arthritis-encephalitis virus (CAEV) (Crawford et al., 1980).
The disease complex induced by these viruses includes progressive leukoencephalitis (visna),
progressive pneumonia (maedi), chronic arthritis and mastitis. The lesions induced by
PPV/VMV and CAEV have the same types of cellular infiltrates and progression although the
organ distribution is frequently different. Whether this is due to differences in tissue tropism of
the various virus strains or to host-related factors, or both, remains to be investigated.
Nevertheless, in both natural and experimental infections with PPV and CAEV, the lesions are
often indistinguishable (Oliver et al., 1981 a, b; Banks et al., 1983 ; Querat et aL, 1984). Caprine
arthritis has recently received much attention as a natural model for chronic connective tissue
disease and a possible correlate to rheumatoid arthritis in man (Cork & Narayan, 1980; Adams
et al., 1980; McGuire, 1984). Several excellent reviews regarding immunopathological aspects of
these infections as well as of equine infectious anaemia are available (Crawford et al., 1978;
Gudnadottir, 1974; Henson & McGuire, 1974; McGuire, 1984; McGuire & Crawford, 1979;
Stroop & Baringer, 1982; Thormar et al., 1974). Therefore, only a brief account of the diseases
will be given, highlighting some of the most recent findings and their implications with respect
to their potential use as models for helping understand a number of immunopathological events.
One central question is how these viruses persist in the host in the face of a very active immune
response. Another, and closely related, question concerns the identity of the host cell involved in
viral persistence. Not surprisingly the monocyte-macrophage (M~b) series has been implicated
in the pathogenesis of these retrovirus infections, because viral antigens and/or virus replication
can be detected in this population of cells in the infected animals and, furthermore, M~b readily
support viral replication in vitro (Adams et al., 1980; Anderson et al., 1983 ; Henson & McGuire,
1974; Klevjer-Anderson & Anderson, 1982; Narayan et al., 1982, 1983). However, neither the
exact role of the M~b in viral persistence nor the specific subpopulation of the MPS allowing
virus replication is well characterized in most instances. In blood, only a minor fraction of the
monocytes appear to be infected with CAEV or VMV, and the infection does not appear to be
productive until after the cells differentiate and mature (Narayan et al., 1983). In addition to
acting as a depot for virus replication M~b may also be important in inducing virus production in
other persistently infected, non-productive cells such as fibroblasts (Narayan et al., 1982),
possibly by releasing macrophage secretory products (enzymes), which are taken up by the
fibroblast and cleave virus precursor proteins required for virion assembly. This latter
mechanism could also conceivably be involved in equine infectious anaemia virus (EIAV)
disease, where M~b are the only cells identified which harbour the virus and support viral
replication (Stroop & Baringer, 1982) even though a persistent non-productive infection can be
established in fibroblasts in vitro (Crawford et al., 1978). These recent observations demonstrate
the various ways, both direct and indirect, in which M~b may aid viral replication and
persistence.
One mechanism whereby viruses can elude the antiviral immune response and persist is by
emergence of antigenically new virus strains in the infected host due to mutational changes of
the viral genome. EIAV is a highly mutable virus with point mutations occurring spontaneously,
perhaps even independently of the immune response (Payne et al., 1984), producing new stable
strains. These mutations occur most frequently in viral glycoproteins gp90 and gp45, which are
the primary immunogens during a persistent infection (Payne et al., 1984). Once these mutations
occur, the immune response acts as the selective force for the ensuing emergence of novel
antigenic strains of EIAV (Payne et al., 1984). Thus, it is conceivable that each clinical episode is
related to a M~b-mediated production of a new mutant that will also infect Mq~, thereby
amplifying virus production and spread. The ensuing antibody response will again cause
formation of immune complexes promoting vascular lesions and clinical disease. Moreover,
enhanced infection of M~b may occur due to Fc receptor-mediated uptake of infectious
complexes (Schlesinger & Brandriss, 1981). The viraemia is, however, eventually controlled and
the infection becomes quiescent until a new virus mutant emerges, perhaps as a result of an
intracellular event in the M~b virus interaction (Morahan et al., 1985).
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H. BIELEFELDT
OHMANN
AND
L. A. BABIUK
The phenomenon of antigenic drift has also been observed with VMV (Narayan et al., 1977)
but is not likely to play a major role in persistence of this virus group, as it does not occur until
several months after the appearance of neutralizing antibodies (Narayan et al., 1978). With
CAEV, antigenic drift does not seem to be important in persistence since no neutralizing
antibodies are induced by the virus (Klevjer-Anderson & McGuire, 1982). Instead, virus
characteristics such as the level of expression of particular viral components or the degree of
integration of viral DNA into the host cell genome may be implicated in establishment of virus
persistence and the fate of the host cell (Querat et al., 1984; Harris et al., 1984; Gonda et al.,
1985). In addition, host genetic factors may be decisive in the outcome of an infection with ovine
or caprine lentiviruses (Nathanson et al., 1976; Narayan et al., 1974, 1977).
Not only does CAEV fail to induce neutralizing antibodies in its natural host or in sheep
(Narayan et al., 1984), but only complement-dependent neutralizing antibodies are induced in a
heterologous host (Klevjer-Anderson & McGuire, 1982). CAEV is distinct from VMV/PPV as
measured by genome sequence homology (Roberson et al., 1982; Querat et al., 1984), but has
protein patterns similar to ovine lentiviruses (Johnson et al., 1983). In CAEV-infected goats
non-neutralizing antibodies are produced against four or five of the six major proteins, including
the high molecular weight glycoprotein (Johnson et al., 1983). The latter corresponds to the
VMV glycoprotein responsible for induction of neutralizing activity (Scott et al., 1979). Faced
with this fact, two possibilities for the apparent failure to neutralize the virus must be
considered. One is the lack of appropriate antigenic epitopes, either qualitatively or
quantitatively~ on the glycoprotein(s). The other concerns the host immune response, which may
either be constitutively deficient in presenting and responding to this antigen, or may somehow
be impaired due to the infection itself. These questions were approached by Narayan et al.
(1984), who found that CA EV infection of the M~b was not the only deciding factor in the failure
of induction of neutralizing antibodies, and that the ability of the host to produce neutralizing
antibodies to heterologous agents, including VMV, was not compromised by persistent infection
with CAEV. Interestingly, production of neutralizing antibodies to CAEV could be induced by
injecting the goats with large amounts of Mycobacteriurn tuberculosis at the time of virus
inoculation. Activation of Mth both in vivo and in vitro by M. tuberculosis is a well established
phenomenon (Edelson & Erbs, 1978; Lodwell & Ewalt, 1978). The indications are, however,
it was not merely an activation of the M~ normally present in the host, but induction of a totally
different M~b subpopulation with a novel or enhanced capacity for antigen processing (Narayan
et al., 1984). This possibility should be further investigated since it may yield useful information
with respect to other hyporesponsive states observed in viral infections, and may contribute to
the understanding of development and differentiation pathways within the MPS (Bursuker &
Goldman, 1983; Morahan et aL, 1985).
No coherent picture of lymphocyte reactivity and involvement in the pathobiology and
immunology of the non-oncogenic retrovirus infections has yet emerged. It is clear that infected
animals do not suffer from generalized immunosuppression, as they are fully immunocompetent
to other antigens, and produce virus-specific antibodies. Moreover, the pathological changes
characteristic of the diseases are those of non-malignant lymphoproliferation and cell
infiltrations. The occasional reports of transient depression of lectin-induced lymphocyte
proliferation and decreased interleukin-2 production (Ellis & DeMartini, 1985 a, b; Kono et al.,
1978) are difficult to reconcile in this context. Obviously, more research is needed to elucidate
the significance of such phenomena and their possible involvement in immunological imbalance
leading to unrestricted lymphoproliferation, in addition to what the continuous presence of viral
antigen or virus-induced changes in tissue antigens will induce. The recent findings that human
T-cell leukaemia virus type III (HTLV-III), the aetiological agent of the acquired immune
deficiency syndrome (AIDS), shares genomic and morphological features with VMV (Gonda et
al., 1985) and that HTLV-III can be detected in brain tissue of AIDS patients (Shaw et al., 1985),
and shows antigenic cross-reactivity with EIAV (Montagnier et al. as cited in Thiry et al., 1985)
and BLV (Thiry et al., 1985), may create an upsurge in research on the non-oncogenic
retroviruses to the benefit of both human and veterinary medicine, as well as stimulating basic
studies in virology, immunology and pathology.
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The disease caused by African swine fever virus (ASFV) in domestic pigs has attracted much
attention over the years, and its various aspects have been frequently reviewed in monographs
and textbooks (Hotchin, 1971 ; Coggins, 1974; Maurer, 1975; Hess, 1981 ; Wardley et al., 1983).
Therefore, we will only review aspects of the obscure immunological response that apply to
pathogenesis. ASF may appear as a peracute, acute, subacute or chronic disease. Lesions
encountered in peracute to subacute cases comprise haemorrhages in various organs, especially
peripheral lymph nodes and fluid accumulation in body cavities. Extensive cell necrosis is
usually present in lymphoid tissues (Maurer, 1975). Chronic ASF begins rather uncharacteristically with interstitial pneumonia, eventually progressing to lung necrosis (Moulton et al., 1975),
arthritis, skin ulcers and emaciation (Hess, 1981). Such animals remain viraemic for extended
periods. Neutralizing antibodies nevertheless fail to develop, even though high titres of
precipitating, complement-fixing and haemadsorptionoinhibiting antibodies develop. Chronically infected animals thus develop hypergammaglobulinaemia (Pan et al., 1970). The initial
virus replication is thought to take place in Mq~ in lymphoid tissues (tonsil) and from there to
spread to lymphocytes and endothelial cells. As this infection is lytic it may account for the
lesions in acute cases. However, as will be discussed later, a hypersensitivity reaction may also
be involved. Macrophages are also thought to be the primary site of virus persistence (Wardley
& Wilkinson, 1977). However, infection of M~b by ASFV appears to imply some inherent
contradictions, or alternatively to constitute a virus-cell interaction completely contrary to what
is known about virus-M~b relations in other virus infections (Allison, 1974). Thus, ASFV
attenuated by in vitro cultivation (i.e. avirulent for swine) appears to be much more cytopathic
for M~ than virus strains highly virulent for pigs, when the comparison is based on the initial
infection dose (multiplicity of infection). In addition, infection with this attenuated ASFV is
established much more easily and gives rise to comparatively higher virus yields (Wardley et al.,
1979), suggesting that factors other than the ease of infection of M~b are important in
determining the virulence of the virus for the animal host (Virelizier & Allison, 1976).
Following an acute infection with virulent ASFV, pigs develop lymphopenia. Conflicting
results have been reported with respect to the differential effect on lymphocyte populations.
Thus, Wardley & Wilkinson (1980) reported that B cells were predominantly affected.
Curiously, the changes in total and relative lymphocyte numbers did not result in significant
changes in lectin-stimulated lymphocyte proliferation. In contrast, Sanchez-Vizcaino et al.
(1981) found that the T cell population was depleted, that lectin-stimulated T cell proliferation
was correspondingly decreased, and that mitogenic responsiveness and antibody production
reflected the chances of the animal surviving the disease. Their findings seem to correlate better
with the finding that ASFV-infected animals can mount a normal humoral response to other
microbial antigens (DeBoer, 1967).
Chronic ASF is characterized by lymphocytosis accompanied by fluctuations in the numbers
of T and B cells in the blood; but the only significant changes appear to be a marked increase in
the number of'null' lymphocytes at various times during the course of the infection and a rise in
B cell numbers corresponding to the appearance of precipitating serum antibodies. The
significance of the 'null' cells is not known (Pan et al. as cited in Hess, 1981).
It has been suggested that the lesions seen in pigs with chronic ASF are caused by an autoimmune phenomenon (Pan et a l . , 1975; Wardley, 1982; Wardley et al., 1983). However, data
were not presented to substantiate this. The hypergammaglobulinaemia seen after infection in
vivo and in vitro with virulent ASFV strains (Wardley, 1982) may be due to a large extent to nonspecific activation of'bystander' cells (Ahmed & Oldstone, 1984). So far, there is no evidence for
production of auto-antibodies or activation of auto-aggressive cells. There seems to be more
support for the theory of a hypersensitivity reaction being central in the pathogenesis of lesions,
as proposed by Slauson & Sanchez-Vizcaino (1981). During ASFV infection virus-specific IgE is
produced, as is precipitating IgG. Blood basophils armed with this IgE then become activated
upon encounter with antigen (viraemia) and release platelet-activating factor, causing platelets
to aggregate and release vasoactive amines. This mechanism, designated the anaphylactic
trigger for immune complex (IC) deposition (Henson & Pinchard, 1977), provokes leakage of
circulating IC into the tissues. Upon deposition, the IC may bi~ld complement (Slauson &
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H. B I E L E F E L D T O H M A N N A N D L. A. B A B I U K
Sanchez-Vizcaino, 1981) and IC disease ensues. Whether the latter occurs depends on how long
the animal survives. Nevertheless, deposition can be detected in the kidneys of pigs in the acute
phase of the infection. It is not inconceivable that deposition also occurs in the lungs and
vascular bed of the skin, and can thus account for the lesions in chronic ASF. In agreement with
this proposal, it has also been found that eosinophils occur constantly in chronic lung lesions
(Moulton et aL, 1975). Eosinophils appear to be an important constituent of an anaphylactic
reaction. It remains to be shown that this mechanism, proposed by Slauson & Sanchez-Vizcaino
(1981), can eventually lead to the pathological lesions seen in chronic ASF. In the same context it
may be speculated whether the anaphylactic trigger is also involved in the substantial extravasation in acute ASF. In addition to its usefulness as a model for virus-induced IC disease, ASF
provides an opportunity for exploring how a virus may bypass the development of neutralizing
antibodies.
Immunopathological phenomena similar to those of ASF may prove central to another viral
disease, feline infectious peritonitis (FIP). The infection appears to occur worldwide in the cat
population (Horzinek & Osterhaus, 1979 a), but is usually subclinical or has transient mild and
uncharacteristic symptoms of an upper respiratory tract or gastrointestinal tract infection
(Pedersen, 1976a; Horzinek & Osterhaus, 1979b). In a small percentage of cats, a secondary
fatal disease occurs weeks to years later, characterized by fibrinous serositis (i.e. inflammation
of serosal membranes with fibrin deposited) and/or disseminated perivascular pyogranulomata
(i.e. focal, chronic inflammation of purulent character) (Pedersen, 1976a; Horzinek &
Osterhaus, 1979b). Experimentally, it has been found that seropositive cats develop cardinal
symptoms and die faster than seronegative cats (Hayashi et al., 1982a, b, 1983; Weiss & Scott,
1981 ; Weiss eta/., 1980a). Thus, a comparison has been drawn to the dengue shock syndrome in
humans (Horzinek & Osterhaus, 1979b; Weiss et al., 1980a). This may apply as far as the first
part of the immunological enhancement hypothesis (Halstead, 1980) is concerned, which
proposes that in the presence of virus-specific opsonizing, non-neutralizing antibodies, virus
uptake by mononuclear phagocytes is enhanced. This is followed by a rapid and upgraded
replication in these cells, and spread of the infection to various tissues, mainly intracellularly in
infected monocytes. A similar step in the pathogenesis has been proposed for FIP (Pedersen,
1976b; Jacobse-Geels et al., 1982; Weiss & Scott, 1981). The hypothesis further states that an
immune elimination response directed against virus-infected monocytes, probably involving Tkiller lymphocytes, is responsible for activating the monocytes to release various substances
such as C3b, thromboplastin and vascular permeability factor (Halstead, 1980). In contrast, an
Arthus-like reaction has been suggested as the basis for the lesions in classical FIP (Hayashi et
al., 1982a, 1983; Jacobse-Geels et al., 1980; Pedersen & Boyle, 1980). This was supported by the
observation that a decrease in total haemolytic activity (CHs0) and the third component of
complement (C3) occurred at the same time as an increase in anti-coronavirus antibodies and in
circulating immune complexes (Jacobse-Geels et al., 1982). However, appearance of clinical
FIP and pathological lesions, most notably disseminated intravascular coagulation, was
accompanied by increased quantities of fibrin-fibrinogen degradation products and decreased
quantities of various coagulation factors (Weiss et al., 1980 b). It was proposed that this occurred
as a consequence of systemic complex deposition (Weiss et al., 1980b; Jacobse-Geels et al.,
1982). In this context, it was suggested that the preclinical increase in CHs0 might be explained
by virus activation of MqS, which then releases complement factors (Brade & Bentley, 1980), or,
alternatively, release of such factors may be the result of leakage from virus-damaged M4~
(Jacobse-Geels et al., 1982). Apart from being a component of an inflammatory response in FIP,
especially in the pyogranulomatous lesions, polymorphonuclear neutrophils (PMNs) have also
been implicated as being virus carriers either passively or as infected cells (Hayashi et al., 1984;
Horzinek & Osterhaus, 1979b; Ward et al., 1971).
The initial event(s) precipitating development of clinical FIP still remain to be elucidated.
Epidemiological observations indicate that other immunosuppressive infections, such as feline
leukaemia (Olsen et al., 1984), may play a role. Alternatively, an acute secondary infection with
a different FIP virus serotype may induce non-neutralizing antibodies in an anamnaestic
response, and thereby initiate the pathogenic cascade (Weiss & Scott, 1981). Once the virus-host
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9
balance is disturbed, one may envisage a sequence of events wherein the virus replicates in the
intestinal (Hayashi et al., 1982b; Horzinek & Osterhaus, 1979b) and/or the respiratory tract
epithelium (Weiss & Scott, 1981) of the FIP virus-immune host. Subsequently, IC are formed
with non-neutralizing antibodies, and these are taken up by Mq~ (Jacobse-Geels et al., 1982;
Weiss & Scott, 1981). This is next followed by a replication phase in the Me, and simultaneously
the virus is transported intracellularly to local lymph nodes. Further spread to other monocytes
and development of a cell-associated viraemia results in virus spread to the spleen and liver
where local lesions may ensue. Concomitantly, renewed virus replication is likely to boost virusspecific immunoglobulin production, including that of IgE. Thereby, the scene is set for IC
deposition (Henson & Pinchard, 1977). Moreover ICs formed in antibody excess and in the
presence of complement will directly activate platelets, causing aggregation and release of
vasoactive amines. Extravasation and deposition of ICs attract inflammatory cells, especially
PMNs. The process now continues to escalate, with vascular lesions, complement activation,
activation of the coagulation cascade, deposition of further ICs, extravasation of plasma
constituents and cells (Jacobse-Geels et al., 1982). The Mq~ may contribute to this not only by
being the site of viral replication and viral dissemination, but also by producing and releasing
procoagulant (Rothenberger et al., 1977) and complement components, as well as taking part in
antibody-dependent cellular cytotoxicity against other virus-infected cells. Whether the
dominant feature of any particular case is polyserositis or pyogranulomata may depend on the
animal's initial immune status and general immunological responsiveness, the site of initial
virus replication, and perhaps its genotype (Virelizier & Allison, 1976) and the virus strain
(Taguchi et al., 1981). Thus, the picture emerging is that of a very complex and multifarious
pathogenesis, with obvious possibilities for studies of mechanisms involved in virus-induced
immunopathology.
Aleutian disease (AD), a naturally occurring virus infection in mink, is caused by a nondefective parvovirus, ADV (Bloom et al., 1982, 1983). The main features of the chronic,
progressive form of AD, caused by virulent virus strains, are virus persistence, hyperglobulinaemia, circulating infectious ICs, and fatal IC disease (for reviews, see Porter & Cho, 1980;
Stroop & Baringer, 1982). All types of mink become infected by ADV and virus may or may not
persist (Larsen & Porter, 1975; An & Ingram, 1977). However, development of clinical
progressive AD is strongly dependent on the genotype of the mink, and on the virus strain
(Lodwell & Portis, 1981: Stroop & Baringer, 1982). Although differences in the structural
proteins of virulent and non-virulent virus strains have been identified (Aasted et al., 1984) it is
unlikely that the mere size of the virion proteins accounts for the differences in virulence.
Breeding experiments show that no single gene is responsible for host resistance (An & Ingrain,
1977). Differences in the antibody response, qualitative and quantitative, may explain, at least
in part, differences in host susceptibility to virus persistence and development of IC disease.
Thus, only mink with a strong antibody response to the ADV-induced non-structural polypeptide, p71, succumb to ADV (Bloom et al., 1982). It remains to be determined at what cellular
level (M~b, T cells, B cells) of the immune response such differences are controlled and regulated
(Sherman et al., 1983; Howard & Paul, 1983; Singer & Hodes, 1983; Green et al., 1983).
Initially, it was suggested that ADV persisted and replicated in the M~b (Porter et al., 1969);
however, this has not been substantiated (Roth et al., 1984) and therefore the virus-producing
target cell(s) remains unknown. Recent findings suggest a new and rather different role of the
M~b in the pathogenesis of AD. ADV undergoes proteolytic degradation during an in vivo
infection (Aasted et al., 1984), and it was suggested that this may take place intracellularly in the
Mq~ after uptake of virus-antibody complexes (Aasted, 1980; Aasted et al., 1984). Moreover, the
degradation products, low molecular weight proteins, are highly antigenic and react with
antibody raised against ADV structural proteins (Aasted et al., 1984). The small immune
complexes (9S and 25S) previously demonstrated in the blood and tissue deposits (Porter et al.,
1965; Cochrane & Hawkins, 1968) may consist of these virus-specific low mol. wt. proteins and
ADV-specific antibody (Aasted et al., 1984; Race et al., 1983). The contribution of other types of
immune complexes such as p71 anti-P71 (Bloom et al., 1982) and DNA-anti-DNA antibody
complexes (Hahn & Kenyon, 1980) also cannot be excluded. Furthermore, the low mol. wt.
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H. BIELEFELDT OHMANN AND L. A. BABIUK
degradation products and/or the 'modified' virus may play an important role in development of
an ADV-specific T lymphocyte response. Thus, it was found that only mink developing
clinically progressive AD acquire an ADV-specific T cell response, and that this is temporally
correlated with development of IC lesions (Race et al., 1983). Therefore, not only may the M~b
degrade the ADV, but in addition they could also contribute to the lymphocyte response (T
and/or B cells) by presenting the stimulating antigen (i.e. low mol. wt. proteins or ADV) in
immunogenic complexes with major histocompatibility complex antigens (Sherman et al.,
1983). It remains to be elucidated whether the antiviral lymphocyte response represents a
normal antigen response or disordered immunoregulation in ADV infection. In this context it is
noteworthy that pastel mink inoculated with a low-virulent ADV strain, such as Pullman ADV,
develop a virus-specific humoral response and infectious virus persists. Nevertheless, they
remain clinically normal and do not develop an ADV-specific lymphocyte proliferative response
(Race et al., 1983). It might therefore be speculated that the lymphocytes specifically responding
to ADV in vitro represent a subpopulation of T cells with helper function or suppressor cells, that
in vivo deregulate normal immunoregulatory circuits, the consequence being unconstrained B
cell proliferation (Green et aL, 1983). As indicated above perhaps not all of the drastically
elevated antibody is specific for viral antigen, but also includes one or more auto-antibodies
(Hahn & Kenyon, 1980) which may add an autoimmunity aspect to the pathogenesis of ADVinduced lesions (Notkins et al., 1984).
Much still remains to be learned before the pathogenesis of AD is unravelled. Recent
developments clearly indicate that this will only be achieved by combined efforts from the areas
of molecular virology and all aspects of immunology (Aasted et al., 1984; Bloom et al., 1982;
Race et al., 1983). Thus, not only is A D a favourable model for persistent virus infections (Porter
& Cho, 1980), but these studies could also provide new insights into directions of research with
other virus diseases.
The recent availability of M~b cell lines from a number of the species discussed, the ability to
use primary M~b cultures as well as molecular biological techniques and monoclonal antibodies
to identify subpopulations of Mth capable of being infected with specific viruses should greatly
increase our understanding of virus-M~ interactions. If these in vitro studies are combined with
in vivo studies in the natural host, considerable progress will be possible in helping to elucidate
the role of Mqb in persistence as well as in induction of immunity to a wide variety of viral
infections.
Other virus infections characterized by immunopathology
Although the immune response evolved primarily to aid the host to ward off infections, in
many instances during recovery the immune system can over-respond and produce more
damage than is often caused by the virus itself. This is especially true in many persistent noncytopathic or poorly cytopathic virus infections. These immunopathological events may occur as
a result of direct killing of infected cells by cytotoxic T cells, natural killer (NK) cells or M e (for
reviews, see Doherty, 1985; Morahan et al., 1985; Rager-Zisman & Bloom, 1982; Sissons &
Borysiewicz, 1985). Alternatively, the immunopathology may occur as a result of virus infection
of certain subpopulations of lymphoid/Me cells which leads to altered functions of these cells.
These latter interactions are proving to be much more common than was previously thought.
Two excellent models for deciphering virus-lymphocyte interactions are malignant catarrhal
fever (MCF) and Marek's disease.
MCF is a benign lymphoproliferative disease of domestic cattle, deer and buffalo (Plowright,
1968; Reid et al., 1984) with a peracute to slightly protracted, but invariably fatal course. In
Africa the aetiological agent has been identified as alcelaphine herpesvirus type 1 (Plowright et
al., 1960; Reid et al., 1975), with the wildebeest (Connochaetes taurinus albojubatus) acting as the
reservoir of this virus. Outside Africa no aetiological agent has so far been identified, but it is
widely accepted that sheep are the natural host, hence the designation sheep-associated MCF
(Plowright, 1968). The clinical and pathological changes that follow natural or experimental
infection with either alcelaphine herpesvirus type 1 or the sheep-associated agent are very
similar, and do not provide a basis for differentiation (Reid et al., 1984). The clinical signs are
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those of generalized lymph node swelling, severe vasculitis, rhinotracheitis, eye inflammation,
pansystemic involvement of the gastrointestinal tract and exanthema (Plowright, 1968). The
most significant histopathological findings are widespread mononuclear cell infiltration and
proliferation, generalized lymphoid vasculitis and epithelial lesions (Liggitt et al., 1978;
Plowright, 1968; Selman et al., 1974). Both agents can be experimentally transmitted to rabbits,
causing both symptoms and pathological lesions which rather closely resemble those in cattle
(Buxton & Reid, 1980; Edington et al., 1979). The mononuclear cell infiltrates are dominated by
small, medium and blast-like lymphocytes (Edington et al., 1979; Liggitt & DeMartini, 1980a,
b), with variable numbers of monocytes and Mq~. Plasma cells and neutrophilic granulocytes are
rare (Liggitt et al., 1978; Liggitt & DeMartini, 1980a, b; Selman et al., 1974), although in one
report they seemed to occur more prominently, especially in relation to vessel involvement
(Rweyemamu et al., 1976). It is notable that the overall architecture of the lymphoid tissues
usually is largely preserved, but the thymus-dependent areas are markedly enlarged. In contrast,
follicles and germinal centres are absent or inconspicuous (Selman et al., 1974). The
pathogenesis remains unknown, but recent data open up new avenues for the use of this disease
as a model not only to explore mechanisms of viral immunopathology but also to gain insights
into some basic regulatory mechanisms of the immune system. Early suggestions that
hypersensitivity is involved in the pathogenesis (Plowright, 1968) were based on the detection of
viraemia in cattle with African MCF up to 10 days prior to the onset of clinical disease,
hyperglobulinaemia and vascular lesions with neutrophil infiltration and thrombosis
(Rweyemamu et al., 1976). Subsequent studies did not support this; rather, it was argued that
cell infiltrations as well as vascular and epithelial lesions bore resemblance to a graft-versus-host
reaction and other conditions with purported or established delayed hypersensitivity
involvement in the pathogenesis (Liggitt & DeMartini, 1980a, b; Liggitt et al., 1978).
Alternatively, it was suggested that viral infection of a lymphocyte subpopulation might cause
proliferation and activation of auto-aggressive T lymphocytes (Liggitt et al., 1978). Although the
agent is cell-associated and can be transferred with buffy coat cells (Plowright, 1968), negligible
numbers of blood lymphocytes or tissue-infiltrating cells appear to contain viral antigen
(Rossiter, 1980; Edington et al., 1979; Patel & Edington, 1980, 1981 ; Edington & Patel, 1981). It
remains to be seen whether some or all lymphocytes contain an integrated viral genome, such as
has now been demonstrated in Marek's disease (Reid et at., 1984; Sharma, 1977). The most
recent development in the studies of MCF pathogenesis is the isolation and propagation of a
lymphoid cell type derived from lymphoid or infiltrated tissues of rabbits, deer or cattle with
experimental sheep-associated MCF (Reid et al., 1983, 1984). The cells have been characterized
morphologically as large granular lymphocytes (LGL) with T lymphocyte surface antigens, and
possess cytotoxic activity against a range of normal and transformed cells (Reid et al., 1983).
They do not contain viral antigen detectable by conventional methods (Reid et al., 1983), and
they have so far not been identified within tissue by histological methods (Buxton et al., 1984).
The results nevertheless led the authors to propose that these LGL are the actual virus targets,
and that virus may persist as episomal DNA. The presence of viral DNA disrupts normal
cellular functions, i.e. T cell suppression (Herberman, 1982), resulting in a non-specific, benign
polyclonal proliferation of T lymphocytes. In addition, the infected LGL may now engage in
non-discriminatory natural killing, leading to tissue destruction (Buxton et al., 1984; Reid et al.,
1984). The proposal is highly conjectural, but both in the interest of resolving the enigmas of
MCF as well as learning more about the consequences of deranged control mechanisms in the
immune system, the proposal deserves to be pursued. This is not to say that the hypotheses for
autoimmunity and delayed hypersensitivity should therefore be completely ruled out.
Firmer progress has been made with another herpesvirus-induced lymphoproliferative
disease, Marek's disease in chickens. The virus (MDV) replicates only in epithelial cells of the
feather follicles (Purchase, 1974), but infects lymphocytes also. Here the viral genome either
becomes integrated or the virus undergoes an abortive replication cycle. The virus transforms
the lymphocytes and induces a tumour antigen, designated MATSA (Marek's disease turnoutassociated surface antigen; Witter et al., 1975). The transformed cells proliferate and infiltrate
most tissues, most notably peripheral nerves (Purchase, 1974). The latter feature may be the
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H. BIELEFELDT
OHMANN
AND
L. A. BABIUK
direct cause of clinical disease, i.e. paralysis and death, although direct viral infection of
Schwann cells and satellite cells with subsequent demyelination due to a specific immune
response probably also contributes to the disease (Pepose et al., 1981). The recognition of
MATSA as a marker for cellular transformation by MDV has generated interest in the possible
role this antigen may play in the pathogenesis of the disease. Thus, it was found that chickens
infected with MDV develop a cell-mediated immune response to MATSA as revealed by the
presence of antigen-specific cytotoxic cells in the spleen and peripheral blood, albeit in very low
numbers (Powell, 1976; Sharma & Coulson, 1977). Interestingly enough, the indications are that
it is T cells which become both transformed by MDV (Hudson & Payne, 1973; Rouse et al.,
1973; Sharma et al., 1977) and express anti-MATSA cytotoxicity (Sharma, 1977). Lymphomas
may thus consist of at least two different T cell subpopulations, i.e. target cells and effector cells.
This circumstance may account for the necrosis and atrophy in some lymphoid organs
(Purchase, 1974).
In contrast to T cell involvement in the specific immune response and pathogenesis of
Marek's disase, NK cells have been implicated in the resistance-susceptibility phenomenon of
the disease (Lain & Linna, 1980; Sharma, 1981). Susceptibility to MDV appears to be, in part,
genetically determined and is strongly correlated to the level of N K activity (Sharma, 1981). The
lower NK activity in susceptible chicks may be due either to induction of a suppressor
mechanism by MDV (Lee et al., 1978) or to a lack of responsiveness to natural NK cell
enhancers such as interferon (Sharma, 1981; Santoli & Koprowsky, 1979). Alternatively,
responsiveness to interferon induction may be absent. Thus, the interferon response appears
also to be genetically determined (DeMaeyer & DeMaeyer-Guignard, 1969). It is therefore
obvious that Marek's disease in chickens is a useful model for studies of'natural' resistance and
defence against tumour development and progression (Gorelik et al., 1979). Other aspects such
as the importance of antibody in the early pathogenesis of virus-induced oncogenesis (Calnek,
1972) also deserve further attention.
The possibility that the pathogenesis of MCF in cattle and Marek's disease in chickens are
similar deserves investigation, i.e. that transformation of a lymphocyte subpopulation and its
subsequent infiltration of various tissues is followed by recruitment of other, normal lymphoid
cells which react against the transformed cells, and perhaps against normal cells with crossreacting surface antigens or innocent bystanders. The outcome would be similar to an autoaggressive reaction, and could result in the animal's death before lymphomatous disease
develops. These models may help to clarify how disruption of one subset of lymphocytes alters
production of regulatory factors which can lead to immunopathology.
Virus-induced neurological disease
Virus infections that have as a prominent component neurological lesions in domestic
animals, include several examples already treated in other contexts in this review. These are
visna and caprine encephalitis-arthritis in sheep and goats respectively, and Marek's disease in
chickens (for reviews, see also Dal Canto & Rabinowitz, 1982; Pepose et al., 1981; Lampert,
1978; Johnson, 1982). They will not be discussed further. The questions and problems
surrounding rabies have recently been reviewed by Koprowski (1984). Here we shall restrict the
discussion to canine distemper virus (CDV)-induced encephalitides.
Demyelinating disease caused by CDV may develop weeks or months after the initial
systemic disease, or after several years in which case it is called chronic distemper
meningoencephalitis (CDE) (Appel & Gillespie, 1972; Koestner & Krakowka, 1977). In
addition, CDV has been implicated in old dog encephalitis (ODE), a demyelinating encephalitis
occurring in aged and CDV-immune dogs without any preceding clinical illness (Lincoln et al.,
1971; Imagawa et al., 1980). Because of the relatedness of CDV to measles virus, and its
involvement in central nervous system (CNS) lesions with a similarity to demyelinating diseases
in humans (Adams et al., 1975), CDV infections have on several occasions been considered as a
model for subacute sclerosing panencephalitis (SSPE) and multiple sclerosis (Dal Canto &
Rabinowitz, 1982; Lampert, 1978 ; Adams et al., 1975 ; Koestner & Krakowka, 1977). CDV has
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even been suggested to be the causative agent of the latter; however, this has since been
disproved (for review, see ter Meulen & Carter, 1982). The usefulness of this model has been
hampered by the difficulties in consistently reproducing demyelinating disease by CDV; there
also appear to be some essential differences in the virological aspect as well as humoral immune
responses during measles in man and distemper in dogs (Dal Canto & Rabinowitz, 1982; ter
Meulen & Carter, 1982). Despite these dissimilarities the two agents induce CNS disorders with
extensive similarities in clinical features and neuropathological changes (Adams et al., 1975; ter
Meulen & Carter, 1982). The recent finding that CDV strains more likely to cause persistent
infection and demyelinating disease can be distinguished by peptide mapping of the
nucleocapsid (NP) protein (Shapshak et al., 1982) may help overcome some of the difficulties in
establishing a reproducible animal model with CDV. It should then be possible to pursue studies
on the temporal relation between the virus-induced immunosuppression a n d immunological
recovery with the development of CNS lesions (Summers et al., 1979; Vandervelde et al., 1982a,
b; Cerruti-Sola et al., 1983; Appel et al., 1982).
Both humoral and cell-mediated immune responses appear to have a decisive role in the
outcome of a CDV infection (Krakowka et al., 1975, 1978; Appel et al., 1982). The time of onset
of a virus-specific cytotoxic T cell (Tc) response may be critical for clearance of virus from the
CNS. The temporal onset as well as the magnitude of this response appears to be determined at
the level of both the host and the virus. The degree of immunosuppression, the ability to mount a
virus-specific immune response, and subsequently to surmount viral invasion and prevent
establishment of persistent CNS infection may in part be determined by the susceptibility of
lymphocyte subpopulations to CDV infection (Casali et al., 1984; Appel et al., 1982; CerrutiSola et al., 1983). It appears that some CDV strains induce a delayed and low Tc response and
that these same strains cause persistent CDV infection with development of non-inflammatory
demyelinating encephalitis (Appel et al., 1982). Furthermore, the degreee of immunosuppression may determine the type of demyelination, i.e. without or with an inflammatory
component (Appel et al., 1982; Summers et al., 1979, 1984; Cerruti-Sola et al., 1983; Krakowka
et al., 1978). These findings and the indications that autoimmune reactions that occur during the
inflammatory stage of demyelination may be epiphenomena (Cerruti-Sola et al., 1983) should
make CDV infections in dogs an extremely useful model for studying virus~cell and virus-host
interactions in subacute and chronic demyelinating diseases, including the unresolved problems
surrounding 'bystander' and virus-induced autoimmune demyelination (Lampert & Rodriguez,
1984; ter Meulen & Carter, 1982; Waksman, 1984). Furthermore, this model may be useful for
determining how and why an infection becomes rekindled with the development of progressive
disease during adolescence (e.g. ODE and SSPE). With the application of monoclonal antibody
and molecular virology techniques it should now be possible to characterize viral epitopes that
elicit specific immune reactions (Buchmeier et al., 1984; Rammohan et al., 1981 ; Krakowka et
al., 1978) and determine virulence and persistence of the morbilliviruses (Seif et al., 1985;
Rozenblatt et al., 1985).
Virus-related immunosuppression and increased susceptibility to secondary microbial infections
A prominent feature of many virus infections is the virus-related immunosuppression of the
host. It is under this heading that the following naturally occurring virus diseases in 'nonconventional' laboratory animals will be described: feline and bovine leukaemia, swine
influenza, rinderpest, canine parvovirus disease, feline panleukopenia and infectious bovine
rhinotracheitis. Immunosuppression may also be seen in some virus infections mentioned above
in other contexts (e.g. Marek's disease, canine distemper, pestivirus infections) and will not be
further commented on here. Independent of the mechanism(s) involved in the virus-induced
immunosuppression, the most significant common feature of these diseases is the increased
susceptibility to secondary (bacterial, parasitic, viral) infections. The clinical symptoms and
lesions caused by the primary viral infection may be rather innocent, with virus clearance and
complete resolution of lesions within a short period of time, if secondary infection does not
occur. A secondary bacterial infection, however, will severely aggravate the condition; thus, it is
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H. BIELEFELDT OHMANN AND L. A. BABIUK
notable that in some diseases, e.g. canine distemper and the 'bovine respiratory disease
complex', many of the so-called cardinal clinical signs are attributable to the secondary bacterial
infections (McCullough et al., 1974; Yates, 1982).
Cats infected with feline leukaemia virus (FeLV) appear to be immunosuppressed as early as
the preneoplastic stage of leukaemogenesis as revealed by increased susceptibility to FIP virus,
haemobartonella and various bacterial infections, by a prominent leukopenia, as well as
reduction in various lymphocyte functions in vitro (Olsen et al., 1981). The mechanism(s)
whereby FeLV induces suppression in the preneoplastic stage is not completely elucidated, but
seems to be independent of FeLV-induced T cell transformation (for review, see Olsen et al.,
198 l ; also Wainberg et al., 1983 ; Orosz et al., 1985). Rather, the suppression may be an effect of
FeLV products or structural components causing metabolic, rather than sensu stricto
immunological defects (Olsen et al., 1976; Mathes et al., 1979; Orosz et al., 1985). One
component specifically, a 15 000 mol. wt. protein, has strong immunosuppressive effects both in
vitro and in vivo (Mathes et al., 1979). This protein inhibits lymphocyte surface receptor mobility,
probably by inducing microtubule polymerization (Nichols et aL, 1979), and may also cause
decreased interleukin-2 production (Wainberg et al., 1983), suppressed responsiveness to
lymphokines (Orosz et al., 1985) and suppression of interferon-gamma production (Lin et al.,
1984; Engelman et al., 1985). This may evidently interfere with cell-antigen and cell-cell
interactions, thereby preventing a normal immune response (Orosz et al., 1985). Whether the
virus (components) also interferes with the non-specific defence mechanisms, such as neutrophil
and M~b functions or induction/production of interferon-alpha and -beta which are of
importance early in an infection, remains to be investigated.
Much less is known about the effect of bovine leukaemia virus (BoLV) on the immunological
responsiveness and antimicrobial defence mechanisms of cattle. However, BoLV is known to
suppress the humoral response to administered antigens, especially the IgM response (Trainin et
al., 1973, 1976). The blastogenic response to phytohaemagglutinin and concanavalin A is also
decreased in cattle with persistent lymphocytosis (the preneoplastic stage) whereas the
pokeweed mitogen response is increased (Muscoplat et al., 1974a). This may be due, at least in
part, to the greatly increased proportion of B lymphocytes in the peripheral blood of cattle with
persistent lymphocytosis and lymphosarcoma (Muscoplat et al., 1974b; Kenyon & Piper,
1977a), especially BoLV-specific B cells (Kenyon & Piper, 1977b; Thorn et al., 1981). This
subpopulation is separable from the BoLV-containing B cells (Kenyon & Piper, 1977 b) and may
be BoLV-specific memory cells (Thorn et al., 1981). Interestingly, the actual and relative size of
this latter subpopulation decreases drastically at the time of development of clinical lymphosarcoma (Kenyon & Piper, 1977b), thus indicating that a memory lymphocyte population may
have a role in the control of virus infection (Thorn et al., 1981). BoLV appears to be an
exogenous type C retrovirus which in most infected cattle persists without inducing persistent
lymphocytosis or lymphosarcoma (Ferrer et al., 1974, 1980). Thus, in view of recent
developments within the area of human viral carcinogenesis, bovine leukaemia could certainly
be explored as a model for studying the mechanisms controlling cell transformation, and benign
and malignant proliferation (Ferrer et al., 1980), as well as the direct and indirect effects of the
virus infection on the susceptibility of the host to pathogenic and opportunistic microbial
infections. In these contexts it is also interesting to note that susceptibility to BoLV infection
shows a strong familial association which is perhaps best explained in terms of inherited
variations in immune responsiveness (Blood et al., 1979; Ferrer, 1980). Finally, BoLV appears to
be antigenically related to the AIDS-associated retroviruses (Thiry et al., 1985).
Rinderpest is an acute, highly contagious disease of ruminants and swine caused by a virus of
the genus Morbillivirus within the family Paramyxoviridae (Kingsbury et al., 1978). The disease
is characterized by high fever and focal, erosive lesions confined largely to the mucosa of the
alimentary tract (Blood et al., 1979). Rinderpest virus (RPV) has, like two other morbilliviruses
CDV and measles virus, a marked affinity for lymphoid cells, which are lytically infected
(Yamanouchi, 1980). A marked leukopenia subsequently develops, even in an otherwise
clinically mild infection, and also following vaccination (Blood et al., 1979). Immunosuppression is therefore to be expected, but most probably only of a transient nature, as a strong
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15
immunity develops conferring resistance to subsequent infections (Kahrs, 1981). RPV is not
known to cause persistent infection (ter Meulen & Carter, 1982; Kahrs, 1981), but this aspect
has perhaps not been sufficiently studied (Kahrs, 1981). Susceptibility to RPV is strongly
dependent on the genetic make-up of the host (Blood et al., 1979; Scott, 1985). For this reason as
well as for the apparent lack of ability or tendency of RPV to establish persistent infections, in
contrast to measles virus and CDV, it might be rewarding to study the immunology of RPV
infection in more detail. It may thus be asked whether the mechanism(s) behind the
immunosuppression caused by CDV and RPV, respectively, differ and whether this explains
why CDV-associated immune dysfunction persists (Krakowka et al., 1980) whereas apparently
RPV-associated suppression is overcome (Yamanouchi, 1980). Much could be learned about
virus-host interactions from this comparative model.
The classical picture of canine parvovirus (CPV)-induced disease is that of an acute, severe
gastroenteritis. However, as with many other viral diseases, the clinical picture is changing,
either due to increased population immunity or to changes in virus virulence or both. Thus,
subacute disease and subclinical infections are now becoming prevalent. Perhaps somewhat out
of context, but not to be forgotten, is also the myocarditis caused by CPV and which in itself
presents a model system for viral pathology. However, despite the lack of clinical CPV disease,
the dog may become immunosuppressed, as revealed by decreased responsiveness of peripheral
blood lymphocytes and Peyer's patch lymphocytes to mitogens, and an increased susceptibility
to other canine pathogens (Olsen & Krakowka, 1984; Olsen et al., 1984). The mechanism
whereby CPV suppresses lymphocyte reactivity remains to be elucidated. Nevertheless, one can
anticipate the serious consequences a suppression of the common mucosal immune system
(McDermott & Bienenstock, 1979; Silverman et al., 1983) may have on resistance to infections
in general. In this context it might also be rewarding to look at the effect of other enteric viruses
(Babiuk, 1984; Tyrrell & Kapikian, 1982) on the general immunological responsiveness of the
host, in order to understand better the mechanisms of pathogenesis of dual infections, so as to be
able to control them.
Another parvovirus, feline panleukopenia virus (FPLV), also causes enteritis. However, the
most remarkable lesions are found in the lymphoid tissues (Gillespie & Scott, 1973), which
become severely depleted of lymphocytes and even atrophic. It is therefore not surprising that
mortality in the naturally occurring disease has been attributed primarily to secondary bacterial
and viral infections (Rohovsky & Griesemer, 1967; Rohovsky & Fowler, 1971), as severe
immunological dysfunction would be expected to follow the formation of such lesions.
Nevertheless, using various in vivo and in vitro tests to evaluate immune functions in FPLVinfected cats, Schultz et al. (1976) found only minimal effects of FPLV on the cell-mediated
immune response (T cell functions) and no effect on the humoral immune response. Increased
susceptibility to secondary infections could, however, also be due to inhibition of non-specific
defence mechanisms. This has so far not been studied in detail. Depite the lack of detailed
knowledge about the mechanisms involved in virus-related immunosuppression it may not be
too far-fetched to conclude that even within a particular virus group (e.g. parvovirus,
morbillivirus) different viruses may influence the immune system of their respective natural
hosts by different mechanisms but with a similar outcome: immunological dysfunction and
increased susceptibility to other pathogenic micro-organisms, thus demonstrating the need to
choose the appropriate model system for the virus-induced immunosuppression that one is
interested in deciphering.
The complexity of virus-induced immunosuppression is well illustrated in bovine herpesvirus
type 1 (BHV-1 ; synonym infectious bovine rhinotracheitis virus) infections of cattle. Again the
consequence is increased susceptibility to secondary bacterial infections resulting in severe
pneumonia (Yates, 1982). Careful monitoring of various functions has shown that some are
increased, others are decreased, whereas others are not affected at all. Thus, migration of PMN,
natural cell-mediated cytotoxicity and mitogen responses of peripheral blood lymphocytes are
suppressed (Bielefeldt Ohmann & Babiuk, 1985) as are some, but not all functional activities of
alveolar macrophages (McGuire & Babiuk, 1984; H. Bielefeldt Ohmann, unpublished data). In
contrast, superoxide anion production by PMN is transiently increased and T helper cell
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H. B I E L E F E L D T O H M A N N A N D L. A. B A B i U K
function (interleukin-2 production) only marginally affected. Interferon-induced suppression
and suppressor cells can be ruled out as decisive factors in the decreased cell functions. Thus, so
far no single factor has been found which can cause the diverse effects on immune
responsiveness (Bielefeldt Ohmann & Babiuk, 1985). However, because of the experimental
reproducibility of the disease and the many parallels with pneumonia in humans, induced by
influenza virus and bacteria (Couch, 1981 ; Bielefeldt Ohmann & Babiuk, 1985), this naturally
occurring disease complex may offer tremendous advantages for both human and veterinary
medicine as a model system to study mechanisms of virus-induced dysfunction of host
immunological defence mechanisms in respiratory infections.
Despite the early description of severe pneumonia that follows a dual infection by influenza
virus and Haemophilus influenzae subspecies suis in swine (Shope & Francis, 1936), no attempts
seem to have been made using this natural model system to elucidate the effects of influenza on
host defences. Thus, most studies on the complications similar to those in human influenza have
been conducted in mice, ferrets and guinea-pigs to which human (and swine) influenza virus can
be adapted, or in natural human cases (for review, see Couch, 1981). Knowledge about the
porcine immune system is steadily increasing (Binns, 1982; Pescovitz et al., 1985); miniature
pigs are increasingly being used as experimental animals in immunology, transplantation
research, etc. Thus, the means are available to study immune functions before, during and after
naturally occurring influenza in a homologous virus-host system, and will hopefully facilitate
the understanding of the disease in humans (Couch, 1981). Likewise, the swine influenza model
could be used for studies of vaccination regimes (Renshaw, 1975), which may be of special value
at this time when new approaches in vaccine production via biotechnology are feasible
(Chanock & Lerner, 1984).
CONCLUDING
REMARKS
In this review a number of natural infections in domestic animals have been considered as
models for studies of virus-host interactions in acute, chronic and persistent infections. With the
growing knowledge of disease mechanisms obtained from small laboratory animals, it has
become evident that to understand fully the interplay between virus and host, further studies
must integrate immunological, pathological and virological factors. However, such complex
systems can, if conducted in a heterologous virus-host system, be difficult to control with respect
to experimental artefacts. The obvious alternative is to study natural diseases in easily accessible
animal species, with domestic animals lending themselves as obvious tools. Moreover, the new
technical tools now available, including monoclonal antibodies, genetic engineering, embryo
splitting and embryo transfer are already available within the veterinary field (Davis et al.,
1985; Cha~nock & Lerner, 1984). Thus, it should now be possible to exploit this field to determine
the cellular interactions involved in viral persistence, tolerance, immunosuppression and
pathology and eventually to be able to manipulate such interactions for circumvention or
alleviation of the disease in the patient, whether human or animal.
We express our appreciation to Irene Kosokowsky for her skilful typing of this manuscript. Our work at the
Department of Veterinary Microbiology, University of Saskatchewan is supported by the Medical Research
Council of Canada and Genentech Inc., South San Francisco, Ca., U.S.A.
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