Download INDUCTION OF SEVERE DISEASE IN HAMSTERS BY TWO

Am. J. Trop. Med. Hyg., 69(3), 2003, pp. 269–276
Copyright © 2003 by The American Society of Tropical Medicine and Hygiene
INDUCTION OF SEVERE DISEASE IN HAMSTERS BY TWO SANDFLY FEVER
GROUP VIRUSES, PUNTA TORO AND GABEK FOREST (PHLEBOVIRUS,
BUNYAVIRIDAE), SIMILAR TO THAT CAUSED BY RIFT VALLEY FEVER VIRUS
ANN F. FISHER, ROBERT B. TESH, JESSICA TONRY, HILDA GUZMAN, DONGYING LIU, AND SHU-YUAN XIAO
Department of Pathology and Center for Biodefense and Emerging Infectious Diseases, and Department of Internal Medicine,
University of Texas Medical Branch, Galveston, Texas
Abstract. Adult golden hamsters inoculated subcutaneously with either of two sandfly fever group viruses, Punta
Toro and Gabek Forest (Phlebovirus, Bunyaviridae), developed a fulminating fatal illness characterized by hepatic and
splenic necrosis and interstitial pneumonitis. Most animals died within three days after infection; this was accompanied
by high levels of viremia. Necropsy and histopathologic examination of the infected animals revealed pathologic changes
involving multiple organs that resembled those described in Rift Valley fever. These two hamster-phlebovirus systems
may serve as alternative animal models for Rift Valley fever and should be useful in studying the pathogenesis of severe
phlebovirus infection and for testing potential therapeutic agents.
febrile field worker in eastern Panama in 197213 and had been
passaged four times in Vero cells; and 2) the prototype strain
(Sud An 754-61) of GFV, which was originally isolated from
a rodent (Acomys cahirinus) in Sudan in 1961.14 The latter
virus had been previously passaged once in newborn mice and
twice in Vero cell culture.
Animals. Adult female Syrian golden hamsters (Mesocricetus auratus), 10−12 weeks of age, were used in all experiments. These were obtained from Harlan Sprague Dowley
(Indianapolis, IN). The animals were cared for in accordance
with the guidelines of the Committee on Care and Use of
Laboratory Animals (Institute of Laboratory Animal Resources, National Research Council) under an approved University of Texas Medical Branch animal use protocol. All
work with the infected animals was carried out in BSL-3
facilities.
Infection of animals and sample collection. Twenty-four
hamsters were each inoculated with 104.6 plaque-forming
units (PFV) of PTV, and 22 animals were each inoculated
with 105.0 PFU of GFV. Both viruses were given by subcutaneous injection. Following inoculation of virus, four or more
animals in each virus group were killed and sampled daily to
follow the pathogenesis of the infections. Hamsters were
anesthetized with Halothane (Halocarbon Laboratories,
River Edge, NJ) and then exsanguinated by cardiac puncture.
A portion of the blood was frozen for virus titration; the
remainder was allowed to clot and the serum was used for
liver enzyme studies. Immediately after death, the animals
were dissected and their tissues were preserved in 10% buffered formalin for 24−48 hours, followed by 70% ethanol.
Liver, spleen, kidney, adrenal gland, heart, lung, and a portion of small intestine were collected from all animals. From
some of the hamsters, the entire gastrointestinal tract, brain,
ovaries, pancreas, and lymph nodes were also collected.
Histologic evaluation. After fixation, tissue samples were
processed for routine embedding in paraffin. Four to
5-␮m−thick sections were made and stained by the hematoxylin and eosin method.
Tissue sections were examined with an Olympus (Melville,
NY) BX51 microscope equipped with UPlan/Apo objectives.
For comparative purposes, a semi-quantitative analysis
scheme, described previously15 was used with modifications.
Liver sections were evaluated for inflammatory infiltration,
hepatic necrosis, and steatosis, using the following scores: For
INTRODUCTION
Rift Valley fever (RVF) is a mosquito-borne epidemic disease of sub-Saharan Africa that affects cattle, sheep, goats,
and humans.1–3 The disease is of considerable public health
and veterinary importance in that region. The causative
agent, RVF virus, is the type species of the genus Phlebovirus,
family Bunyaviridae.4 Recent outbreaks of this disease in
Egypt,3 Saudi Arabia, and Yemen5 indicate that RVF probably has the potential to invade other regions of the world
where cattle, sheep, goats, and mosquitoes are abundant. For
this reason, and because of the ease with which RVF virus can
be aerosolized, there is now concern that it could be used as
a bioterrorist agent.6,7 At present, there is no specific treatment or licensed human vaccine for RVF.
Despite the need for a better understanding of the pathogenesis of RVF and for effective therapies for the disease,
research with infectious RVF virus is inhibited by its current
assignment to biosafety level-4 (BSL-4) status.8 In the United
States, for example, work with RVF is restricted to a few
government-sanctioned maximum containment (BSL-4) facilities. A more accessible model of the disease is needed.
Rift Valley fever virus in lambs, calves, and kids produces
a fulminant disease characterized by hemorrhage, focal liver
necrosis, and death.1,2,9 In fact, the initial descriptions of RVF
referred to the disease as “enzootic hepatitis.”9–11 Findlay11
was the first to report that hamsters were highly susceptible to
RVF virus and that following infection these rodents developed a rapidly fatal disease similar to that seen in young
sheep and goats. More recently, two other phleboviruses,
Punta Toro virus (PTV) and Gabek Forest virus (GFV), have
also been reported to produce severe disease in hamsters.12,13
In contrast to RVF virus, PTV and GFV are classified as
BSL-2 and BSL-3 agents, respectively;8 consequently, PTV
and GFV are available to more investigators. The objective of
the present study was to characterize the pathology of PTV
and GFV infections in hamsters and to evaluate the feasibility
of using these two phleboviruses as models of the hemorrhagic fever form of RVF.
MATERIALS AND METHODS
Viruses. The two phleboviruses used were 1) the Adames
strain of PTV, which was originally isolated from blood of a
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inflammation, 0 ⳱ none; 1 ⳱ occasional inflammatory cells
(equivocal); 2 ⳱ mild but significant inflammatory infiltration; 3 ⳱ moderate inflammatory infiltration; 4 ⳱ marked
or diffuse inflammatory infiltration; for necrosis, 0 ⳱ none;
1 ⳱ occasional apoptotic cells; 2 ⳱ mild necrapoptosis; 3 ⳱
moderate necrapoptosis; and 4 ⳱ focal or diffuse confluent
necrosis. Steatosis was evaluated by a percentage portion of
the parenchyma involved. Splenic tissue was evaluated for
lymphoid reactive hyperplasia, lymphoid depletion/necrosis,
and splenic macrophage proliferation (hyperplasia). These
parameters were also scored from 0 to 4 (0 ⳱ normal; 1 ⳱
minimal; 2 ⳱ mild; 3 ⳱ moderate; and 4 ⳱ severe). In addition, lung tissue was evaluated for the degree of interstitial
pneumonitis, with a degree of severity based on a 1 to 4 scale.
Kidneys, ovaries, heart, adrenal glands, and pancreas were
evaluated and described histologically.
Immunohistochemical staining procedures were performed
to detect the presence of viral antigens in the hamster tissue
as previously described.15 After deparaffinization and dehydration, in xylene and decreasing concentrations of alcohol,
formalin-fixed, paraffin-embedded tissue sections (3-4−␮m
thick) were immersed in 3% hydrogen peroxide at room temperature for 30 minutes to block endogenous peroxidase activity. This was followed by an antigen retrieval step in a 10%
target retrieval solution (Dako, Carpinteria, CA) for 30 minutes at 90°C. For detecting GFV antigens, the primary antibody used was mouse hyperimmune ascitic fluid (MIAF),
prepared against the GFV prototype strain (Sudan 754-61);
it was used at a dilution of 1:100. For detecting PTV antigens,
a polyclonal MIAF prepared against the Adames strain of
PTV was used at a dilution of 1:100. The incubation of the
primary antibody was done overnight at 4°C. For subsequent
detection of bound antibody, a mouse-on-mouse ISO-IHC kit
(InnoGenex, San Ramon, CA) was used, following the manufacture’s instructions and as previously described.15
Virus assay. Blood from the hamsters infected with GFV
was titrated by plaque assay in monolayer cultures of Vero
cells. Serial 10-fold dilutions of each blood sample were prepared in phosphate-buffered saline (pH 7.4), containing 10%
fetal bovine serum. Duplicate wells of 24-well microplate
cultures of Vero cells were inoculated with each dilution. Cultures were inoculated at 37°C and plaques were counted
4−6 days later. Virus titers were defined as the number of
PFU/mL of blood.
The levels of viremia in hamsters infected with PTV were
not determined because this information is available in another publication.13
Liver enzymes. Levels of alanine aminotransferase (ALT)
were done on sera from the infected animals, using a commercial kit (Infinity ALT; Sigma Diagnostics, St. Louis, MO)
according to the manufacturer’s instructions.
TABLE 1
Serum levels of alanine amino transferase (ALT) in hamsters infected
by Punta Toro virus (PTV) and Gabek Forest virus (GFV)*
ALT levels (units/L)
PTV-infected
GFV-infected
Day of infection
n
Mean
SD
n
Mean
SD
1
2
3
Negative control
Positive control
4
5
5
42.1
70.7
427.9
26.5
353.6
8.6
25.0
189.4
4
5
7
40.3
293.4
328.3
12.8
115.3
46.1
142.6
121.5
* n ⳱ number of animals tested; Negative control ⳱ normal hamster serum; Positive
control ⳱ serum from yellow fever virus–infected hamster.
the mean ALT level was not significantly elevated; on day 2,
it was slightly elevated for PTV-infected; and by day 3, it was
markedly elevated, indicating hepatocellular damage and/or
dysfunction.
Pathologic findings in PTV-infected hamsters. In the first
two days following infection, the organs appeared grossly normal at necropsy. However, by day 3, the small intestines appeared hemorrhagic (dark red) (Figure 1A); the contents
were mahogany in color and liquid in consistency. Upon his-
RESULTS
Clinical and laboratory findings in PTV-infected hamsters. All of the animals appeared ill (extreme lethargy, anorexia, ruffled fur), and all but one were dead by the third day
of infection. One animal was still alive on day 4 when the
experiment was terminated.
The ALT levels in the sera of infected hamsters during the
first three days of infection are shown in Table 1. On day 1,
FIGURE 1. A, Gross view of gastrointestinal organs from a hamster two days after infection with Punta Toro virus. The dark red
discoloration of the small bowel corresponds to internal hemorrhages. B, Micrograph of the duodenum from the hamster showing hemorrhagic necrosis of the mucosal villi, with relative sparing of
the bottom of the crypts (hematoxylin and eosin stained, magnification × 20).
ANIMAL MODEL FOR PHLEBOVIRUS INFECTION
tologic examination, abnormalities were found to be limited
to the duodenum, which consisted of hemorrhage and necrosis of the mucosal villi (Figure 1B). The bottom of the mucosal crypts were spared. The pattern was similar to that seen
in an acute ischemic process (infarction) of the bowel; the
mechanism is unknown. The lower segments of the small
bowel, colon, esophagus, and stomach were histologically
normal.
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In the liver, cytoplasmic condensation, formation of acidophil bodies, and nuclear fragmentation were observed in scattered individual hepatocytes on day 2 of infection (Figure
2A). By day 3, this had progressed to multifocal hepatocytic
necrosis; however, the process was not as intense or severe as
the necrosis seen in other hepatotropic viral diseases, such as
yellow fever.15 There was no inflammatory cell infiltration,
and no fatty changes were observed in the liver. Confluent
FIGURE 2. Histologic changes in hamsters infected with Punta Toro virus. A, Liver, post-infection day (PID) 2. (magnification × 100).
B, Spleen, PID 2, showing marked necrosis involving both the lymphoid zone and the red pulp (magnification × 50). C, Lung, PID 2, showing
atelectasis (magnification × 50). D, Lung, PID 2, showing hemorrhagic necrosis (magnification × 100). E, Adrenal gland, PID 3, showing band-like
cortical necrapoptosis. The arrowhead shows changes in superficial layer of the cortex (sub-capsular) (magnification × 25). F, Adrenal gland,
PID 3, showing similar changes involving the corticomedullary junction (arrow) (magnification × 100). (Hematoxylin and eosin stained.)
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coagulation necrosis was not observed. The spleen exhibited
marked necrosis involving both the lymphoid zone and the
red pulp. The process was more focal in the lymphoid areas
(Figure 2B). The lungs showed focal interstitial inflammation,
and diffuse atelectasis was observed in a few hamsters (Figure
2C) on days 2 and 3. These changes were also seen in some
hamsters on day 1. In addition, hemorrhagic pulmonary necrosis was seen in some hamsters on day 2 (Figure 2D). The
adrenal glands had a peculiar pattern of necrosis, involving
the cortex. Bands of cells became apoptotic in the most superficial layer of the cortex (sub-capsular) (Figure 2E) and at
the corticomedullary junction (Figure 2F) corresponding to
the zona glomerulosa and zona reticularis, respectively. The
other regions and the medulla were normal. In addition, reactive hyperplasia accompanied by lymphoid necrosis was observed in the few lymph nodes examined, similar to changes in
the spleen. No histologic abnormalities were found in the
pancreas, kidneys, heart, or brain of the animals examined.
Clinical and laboratory findings in GFV-infected hamsters. Gabek Forest Virus also produced a fulminant infection
in the animals; all of the hamsters were either gravely ill or
dead by the third day. The mean levels of viremia in this
group of animals are shown in Figure 3. Within 24 hours, all
of the hamsters had detectable viremia (mean ⳱ 102.8 PFU/
mL). On the second and third days of infection, the viremia
with GFV was markedly elevated and sustained (means ⳱
107.4 and 107.8 PFU/mL, respectively).
The ALT levels in the GFV-infected hamsters paralleled
the viremia. The ALT levels were slightly elevated on day 1,
but were markedly elevated on days 2 and 3 (Table 1).
Histopathologic findings in GFV-infected hamsters. On
day 1 of infection, spleens from the four animals examined
exhibited mild reactive lymphoid hyperplasia. The lungs from
two of the four animals showed changes resembling severe
interstitial pneumonitis (IP). However, tissue from the gastrointestinal tract, pancreas, kidneys, liver, adrenal glands,
and heart were all normal histologically.
On day 2, marked histologic changes were observed in
many organs of five GFV-infected hamsters examined. Their
spleens showed necrosis of both white and red pulps. Necrosis
in the affected spleens was diffuse, with karyorrhexis noted in
the red pulp. The liver changes ranged from patchy inflammatory infiltration with increased sinusoidal lymphocytes,
Kupffer’s cells, and scattered necrapoptotic bodies, to severe
necrosis. However, there was no steatosis. The lungs contin-
FIGURE 3. Daily mean ± SD viremia in hamsters infected with
Gabek Forest virus. PFU ⳱ plaque-forming units.
ued to show interstitial pneumonitic changes (Figure 4A and
B) in all animals, with severity scores ranging from 2 to 4. In
addition, diffuse hemorrhages were seen in two of the hamsters. Two hamsters showed mild to moderate glomerular necrosis in the kidneys. No pathologic changes were seen in the
renal tubules. Pancreatic necrosis was seen in only one hamster; it was characterized by scattered small foci of karyorrhexis in the acini. No pathologic changes were observed in the
gastrointestinal tract or in the myocardium.
Eight surviving hamsters were examined on day 3 of infection. Their spleens showed severe necrosis (score ⳱ 4+), with
depletion of lymphoid tissue (Figure 4E and F). In some hamsters, reactive lymphoid hyperplasia co-existed with lymphoid
depletion (different areas), a phenomenon also observed in a
hamster model of severe yellow fever.15−17 In the liver,
necrapoptosis varied in severity, ranging in score from 2 to 4.
The hamsters with severe hepatic necrapoptosis (scores of 3
and 4) also showed mild steatosis (Figure 4D). The lungs
exhibited variable histologic abnormalities. The severity of IP
ranged from 1+ to 4+. The hamster with 4+ IP also had evidence of necrosis. Severe pulmonary edema was observed in
one of the hamsters (Figure 4C). Pancreatic necrosis was not
a consistent finding; it was present only in three hamsters and
ranged from multifocal individual cell necrosis to focal acinar
loss. Three hamsters had duodenal tissue available for assessment; two of the three animals demonstrated mild necrapoptosis of cells in the lamina propria. Other segments of the
gastrointestinal tracts were normal. The adrenal gland from
one animal examined showed mild scattered necrosis in the
cortex. In addition, ovaries from two hamsters were examined; both showed necrosis of the stroma and follicles (eggs)
(Figure 4G). Scattered cell necrosis was observed in glomeruli
of all hamsters examined, with histologic scores ranging from
2 to 3 (Figure 4H). As in the first two days of infection, no
abnormalities were observed in the myocardium on day 3.
Detection of viral antigen in tissues of infected hamsters. Tissue sections were subjected to immunohistochemical
staining to detect the presence of antigens of the infecting
viruses, as described in the Materials and Methods. Tissues
from uninfected hamsters or hamsters infected with yellow
fever virus15 were processed similarly and used as negative
controls. None of the control samples stained positively. In
hamsters infected with PTV, the liver showed positive staining, ranging from hepatocytes around the central veins and
the portal tracts (perivascular distribution of viral antigens),
to scattered individual hepatocytes in other regions (usually
with morphologic changes of cellular degeneration) (Figure
5A), to larger areas with overt necrosis (Figure 5B). Adrenal
glands showed antigen positivity in the superficial cortical
zone, and the cortical zone adjacent to the medulla, corresponding to zones with necrosis as seen in the hematoxylin
and eosin−stained sections as described earlier in this report.
Scattered macrophages in the interstitial areas of the parotid
glands and lungs were also positive. In addition, renal tubular
epithelia and myocardium of heart also showed weak focal
positivity. Interestingly, no positive staining was observed in
spleen or pancreas.
In tissues from hamsters inoculated with GFV, immunohistochemical staining of the spleen, myocardium, and pancreas
was negative for GFV antigen. In contrast, the tubular epithelia of kidneys were positive (in more than 60% of tubules)
(Figure 5C). Positive immunohistochemical straining was also
ANIMAL MODEL FOR PHLEBOVIRUS INFECTION
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FISHER AND OTHERS
←
FIGURE 4. Histopathology of hamsters infected with Gabek Forest virus. A, Lung, post-infection day (PID) 2, showing interstitial pneumonitis
and focal consolidation, and thickening of the septa containing mononuclear inflammatory cell infiltration (magnification × 50). B, Lung , PID
2, showing interstitial pneumonitis and thickened septa with mononuclear inflammatory cells and a few neutrophils (magnification × 100).
C, Lung, PID 3, showing diffuse edema and pink amorphous materials in the alveolar spaces (magnification × 50). D, Liver, PID 3, showing
multifocal necrapoptosis (arrowheads) and cytoplasmic vacuolization (magnification × 100). E, Spleen, PID 3, showing marked lymphoid
depletion due to necrosis. Only small residual foci of lymphoid areas are present (arrowheads) (magnification × 25). F, Spleen, PID 3, showing
necrosis of lymphoid area and the red pulp. Note the loss of small lymphocytes, marked karyorrhexis (“nuclear dust”) and residual large
immunoblasts (upper right corner) (magnification × 50). G, Necrosis of an ovary, PID 3. Note the cell damages in the stroma (arrowheads) and
center of a follicle (magnification × 50). H, Scattered apoptosis involving a glomerulus in the kidney, PID 3. The tubules were normal (magnification × 100). (Hematoxylin and eosin stained.)
seen in hepatocytes, especially in cells surrounding the central
veins and the portal tracts. Scattered individual hepatocytes
were also strongly positive. Only occasional macrophages in the
septa of lungs showed a positive staining reaction (Figure 5D).
DISCUSSION
The fulminant disease, intense viremia, and histopathologic
changes observed in hamsters with PTV and GFV infections
mimic those of severe RVF.1,9,11,18 Most investigators agree
that the primary lesion in RVF is in the liver, although other
organs are also affected. Hepatocyte necrosis, nuclear fragmentation, and eosinophilic inclusions are observed in the
liver of animals and humans dying of RVF.1,9,18,19 Liver function test results are also abnormal in the disease, indicating
hepatic dysfunction.1 Several investigators1,9,18,19 have noted
that the histopathology of the liver in RVF is very similar to
that seen in yellow fever, except that steatosis is minimal or
FIGURE 5. Immunohistochemical staining for Punta Toro virus (PTV) and Gable Forest virus (GFV) antigens. A, Liver from a hamster
infected with PTV showing a few perivascular hepatocytes with positive staining, and two hepatocytes with condensed dark nuclei with positive
staining (arrowheads). B, Liver from a hamster infected with PTV showing more advanced focal necrosis. Most of the hepatocytes surrounding
the focus of necrosis (arrow) are positive for viral antigens. C, Kidney from a hamster infected with GFV showing positivity in the epithelial cells
of the renal tubules. D, Lung from a hamster infected with GFV showing only focal mild positivity in the interstitial cells in the septa.
(Immunoperoxidase stained, magnification × 100.)
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ANIMAL MODEL FOR PHLEBOVIRUS INFECTION
absent. The results of our study, as well as those of previous
one by Anderson and others,13 demonstrate the similarity of
the pathology produced in hamsters by PTV, GFV, and RVF
viruses. In the case of PTV13 and GFV (Figure 3), there appeared to be a direct correlation between the intensity of
viremia and the degree of histopathology in the liver.
Splenic necrosis and karyorrhexis were observed in the
PTV-and GFV-infected hamsters. While most investigators
have focused on the liver pathology associated with RVF,
splenic hemorrhage, necrosis, and lymphoid depletion also
occur in the disease.1,9,11
Within 24 hours after infection with PTV or GFV, approximately half of our hamsters showed IP. At 48−72 hours, all of
the animals had IP, with histopathologic scores of 2−3. Pulmonary congestion and infiltration of the lungs with red blood
cells and polymorphonuclear leukocytes have also been reported in animals with RVF.9 Periarteritis and mild IP were
described previously by Anderson and others13 in their Punta
Toro animal model. In human cases of RVF, clinical and
pathologic evidence of IP had been occasionally reported
from Rhodesia20 and Egypt,21 respectively.
Histopathologic changes were observed in the adrenal
glands of the PTV-infected hamsters. These were similar to
those previously described,13 although this earlier report only
noted involvement of the zona reticularis. The marked involvement of the adrenal cortex may have caused adrenal
cortical insufficiency in the infected hamsters, since the zona
glomerulosa is the main source of mineralocorticoids (aldosterone) and the zone reticularis is responsible for some of the
glucocorticoids (cortisol). The resulting acute adrenal insufficiency probably contributes to death in the infected animals.
Segmental mucosal necrosis involving the duodenum was
observed in the PTV-infected hamsters. This type of “ischemic” necrosis was also described in PTV-infected hamsters by
Anderson and others,13 who attributed the mechanisms to
diffuse intravascular coagulation (DIC). In our opinion, this is
not a credible explanation for the observed pathology, since
DIC is a diffuse process and therefore should involve other
segments of the gastrointestinal tract. In the case of the PTVinfected hamsters, the pathology was localized to the duodenum. This finding suggests that other viral effects may be
involved in the observed small bowel necrosis. Nevertheless,
these changes may serve as the pathologic basis for the gastrointestinal hemorrhages. It is well known that gastrointestinal bleeding occurs in laboratory and domestic animals infected with RVF virus.1,9,11 Profuse gastrointestinal hemorrhage occasionally occurs in human cases of RVF as well.1
Despite obvious histologic changes in the spleen, viral antigens could not be detected in this tissue immunohistochemically. In contrast, viral antigens were consistently identified
in the liver, first in the perivascular zones, and later spread to
discrete hepatocytes in other areas (mostly cells showing degenerative changes or apoptosis), and to more evident necrotic foci (Figure 5). Staining for viral antigens in the kidney
was variable, showing positivity in epithelial cells in some of
the tubules. Interestingly, although no positive staining was
found in the adrenal glands in GFV-infected hamsters, zonal
distribution of viral antigens was demonstrated in the adrenal
glands in PTV-infected hamsters, corresponding to necrosis
in these areas. Thus, the infection patterns of GFV and PTV
in hamsters have similarities and differences in terms of organ
involvement and antigen distribution. The results from the
immunohistochemical analysis confirmed the establishment
of viral infection in these models, and correlated the viral
replication in the tissues to pathologic injuries. These results
are encouraging because they demonstrate the feasibility of
using this technique for tissue-based diagnosis of viral disease
in archival tissue samples.
In summary, the similarities of the clinical disease and pathology produced by these phleboviruses in hamsters suggest
that PTV and GFV would be good alternative models for
studying the pathogenesis of RVF and for testing potential
therapeutic agents for the prevention and treatment of severe
phlebovirus infection.
Received February 27, 2003. Accepted for publication May 27, 2003.
Financial support: This study was supported by the National Institutes of Health (grants AI-10984 and AI-50175 and contract NO1AI-25489). Ann F. Fisher was supported by a National Institutes of
Health T32 training grant in Emerging and Re-emerging Infectious
Disease (AI-07536).
Authors’ addresses: Ann F. Fisher, Department of Internal Medicine,
University of Texas Medical Branch, Galveston, TX 77555-0588.
Robert B. Tesh, Jessica Tonry, Hilda Guzman, and Dongying Liu,
Department of Pathology and Center for Biodefense and Emerging
Infectious Diseases, University of Texas Medical Branch, Galveston,
TX 77555-0588. Shu-Yuan Xiao, Department of Pathology and Center for Biodefense and Emerging Infectious Diseases, and Department of Internal Medicine, University of Texas Medical Branch, 301
University Boulevard, Galveston, TX 77555-0588, Telephone: 409772-8447, Fax: 409-772-4676, E-mail: [email protected].
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