Download Host resource supplies influence the dynamics

310
Host resource supplies influence the dynamics and outcome
of infectious disease
Val Smith1
Department of Ecology and Evolutionary Biology, University of Kansas, Lawrence, KS 66045
Synopsis Pathogens and their host organisms share a wide range of resource needs that are required to support normal
metabolism and growth. Because the development of infectious disease on or within the host involves the processes of
invasion and resource consumption, competition for growth-limiting resources potentially may occur between pathogens
and cellular or sub-cellular components of the host ecosystem. Examples from the plant, animal, and microbiological
literature provide unambiguous evidence that external resource supplies to the host organism can have profound effects
on the outcome of infection by a broad diversity of bacterial, fungal, metazoan, protozoan, and viral pathogens.
Introduction
Animals, plants, and their associated pathogens share
a wide range of resources that are required to
support their metabolism, growth, and reproduction.
In fact, the infected host can be viewed as a growth
medium (Garber 1960): the ability of the host to
respond to invasion by a pathogen, and the
microbial invader’s ability to replicate and proliferate, both require constant provision of the essential
inorganic and organic molecules required for their
metabolism and growth. The internal pools of many
of these essential resources are strongly dependent
upon their external availability for host consumption, and the strong possibility thus exists that the
supply rates of resources to the host organism can
potentially influence the population growth of a
diverse array of viral, bacterial, fungal, protozoan,
and metazoan pathogens (Smith 1993a, 1993b;
Smith et al. 2005).
In this article, infection is viewed as a pathogenic
invasion of the host ecosystem and the subsequent
development of disease is considered to be an
ecological phenomenon that involves the ecological
processes of invasion, competition, and consumption
of resources (Bohannan 2000). Pathogenesis is thus
considered here to be an ecological process in which a
pathogen first colonizes and then persists on, or within,
the host, producing a population sufficiently large,
active, and well located to exert a pathological effect
(Costerton et al. 1987).
Because requirements for many key resources may
be identical for many host organisms and pathogens,
I focus on the effects of resource availability on growth
of the pathogen. Examples suggesting strong control by
nutrients of the outcome of infection are provided for
a diverse set of plant and animal hosts, and I also
speculate briefly on the implications of host nutrition
for the management and treatment of disease.
Effects of resource availability on plant
diseases
Terrestrial plants
Disease can play an important role in determining
the structure and function of terrestrial plant
communities (Alexander 1990; Burdon et al. 2006),
and emerging new plant pathogens pose threats to
conservation and public health (Anderson et al.
2004). Walters (1985) suggested that consideration of
the physiological and biochemical aspects of the
host/pathogen interaction is crucial not only for
understanding the nature of plant disease, but also
for the development of effective control measures.
I suggest that an understanding of ecological relationships between the host plant and its pathogens may
be equally important.
Resource competition is frequently cited as a
common
interaction
among
plant-associated
microbes (Bell et al. 1990), and Newman (1978)
has suggested that competition for nutrients and
light can influence the interrelationships between
the plant and its associated microflora. For example,
strong correlations between shoot weight, shoot
nitrogen concentration, and rhizosphere bacterial
abundance observed by Turkington et al. (1988)
From the symposium ‘‘Ecology and Evolution of Disease Dynamics’’ presented at the annual meeting of the Society for Integrative and
Comparative Biology, January 3–7, 2007, at Phoenix, Arizona.
1
E-mail: [email protected]
Integrative and Comparative Biology, volume 47, number 2, pp. 310–316
doi:10.1093/icb/icm006
Advanced Access publication June 1, 2007
ß The Author 2007. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved.
For permissions please email: [email protected].
311
Host resource supplies and infectious disease
Fig. 1 Relationship between the severity of leaf blight and
experimental nitrogen supplies (kg N/ha) to onion plants. Data
from Gent and Schwartz (2005).
suggest that plant-associated microbial activity is
strongly influenced by the supply of resources to the
host plant. Effects of availability of nutrients and
light on susceptibility of vascular plants to pathogens
have indeed been widely reported (Snoeijers et al.
2000; Solomon et al. 2003; Roberts and Paul 2006).
The well documented sensivity of plant diseases to
availability of resources can sometimes present a
major dilemma in food production. Fertilizers are
applied worldwide to enhance growth of agricultural
crops and to maximize harvested yields. However,
if fertilization with nutrients also increases the
likelihood and the severity of key plant diseases,
then determining the optimal level for applying
fertilizers can become complex. For example,
Xanthomonas axonopodis pv. Allii (leaf blight)
infections of onion plants have been found to be
strongly dependent upon availability of nitrogen
(Fig. 1). Severity of leaf blight (as indexed by the
relative area under the disease-progress curve,
RAUDPC) increased sharply with increasing rate of
N-fertilization (Gent and Schwartz 2005). Similarly,
the severity of yellow-rust disease of winter wheat is
linearly dependent upon nitrogen content of the
leaves (Neumann et al. 2004). Mukherjee et al.
(2005) observed similar effects of increasing nitrogen
availability on the severity of rice blast, a leaf disease
caused by the pathogenic fungus Pyricularia grisea.
However, evidence for contrasting effects of plant
mineral nutrition can be found in studies of take-all,
a root disease of cereals and grasses caused by
infection with the fungus Gaeumannomyces graminis
var. tritici. Deficiencies of nitrogen and phosphorus
have been implicated for more than 60 years as
factors in the susceptibility of wheat to this very
Fig. 2 Relationship between severity of take-all disease and
different levels of supply of urea and superphosphate (kg/ha)
to winter wheat. Data from Brennan (1992).
costly pathogen, which can, in extreme cases, result
in complete losses of a planted crop (leading to its
common name, take-all). Unlike the three leaf
diseases discussed earlier, experimental research by
Brennan (1992) suggested that increasing availability
of soil resources decreases the severity of take-all root
disease (Fig. 2): fungal infection was consistently
reduced by P-fertilization in all but the zero
N-controls, and N-fertilization led to reductions in
severity of disease in all treatments.
Freshwater and marine phytoplankton
Recent evidence suggests a role of resource availability
in the dynamics of pathogens in aquatic ecosystems as
well. For example, Bruning (1991a, 1991b, 1991c,
1991d) and Bruning et al. (1992) found pronounced
effects of light and of availability of phosphorus on
the epidemiology of infections of the freshwater
diatom Asterionella formosa by the chytrid fungus
Rhizophydium planktonicum Canter emend. In an
experimental test of the effects of chytrid fungi on
natural populations of Asterionella, Kudoh and
Takahishi (1992) found that it was possible to alter
the outcome of initial infection by altering light
availability to the algal cells. Although these results in
part may be explained by mass-action effects associated
with changes in the probability of encounter between
the host and pathogen (Kudoh and Takahashi 1992),
direct effects of resource supply are unquestionably
involved as drivers of the dynamics of this host–
pathogen system. The growth rate of the chytrid
population is, for example, strongly coupled to lightdriven variations in the host cells’ intrinsic rate of
population growth. In addition, both P-limitation and
light-limitation modify production and infectivity of
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chytrid zoospores, and alter the developmental time
of sporangia; conditions of moderate limitation of
phosphorus or light favor the development of a chytrid
epidemic (Bruning 1991a, 1991c; Ibelings et al. 2004).
Viral infections of both eukaryotic and prokaryotic
phytoplankton are sensitive to resource availability
as well. For example, ecological stoichiometry
theory (Sterner and Elser 2002) predicts that success
of infection and postinfection viral production
should be depressed under conditions of high
carbon : phosphorus (C : P) supply conditions, due
to insufficient intracellular phosphorus for the
production of P-rich viral particles. Clasen and
Elser (2007) tested this hypothesis using laboratory
cultures of the green alga Chlorella NC64A, and
confirmed that postinfection production of PBCV-1
virus was strongly affected by the host cells’ C : P
ratio. Overall, infected Chlorella in the high C : P
treatment produced 91% fewer viruses than did the
low C : P treatment. Similarly, Wilson et al. (1996)
found that strong limitation by P greatly restricted
replication of cyanophages infecting the marine
cyanobacterium Synechococcus sp. WH7803. In a
study to determine whether local nutrient availability
affects the switch from lysogeny to lytic viral
production, McDaniel and Paul (2005) reported
inverse relationships between local primary productivity levels and cyanophage induction in natural
populations of Synechococcus sp. Future research on
aquatic viruses thus should consider nutrient availability and the physiological condition of the host, in
order to better understand both the distribution and
ecological significance of viruses in freshwater and
marine ecosystems (Clasen and Elser 2007).
Effects of resource availability on animal
diseases
The structure and function of animal populations,
including human populations, can be strongly influenced by infectious disease (Real 1996; Hudson et al.
2002). Many wildlife species serve as major reservoirs
for pathogens that potentially threaten both domestic
animal and human health; in addition, emerging
wildlife infectious diseases pose a substantial threat to
the conservation of global biodiversity (Daszak et al.
2000). Moreover, the activities and dynamics of
pathogenic organisms can have ecosystem-level implications (Thomas et al. 2005).
Strong nutritional interactions can occur between
pathogens and their metazoan hosts (Crompton and
Nesheim 1982; Crompton 1991). Bush et al. (2001)
offer an outstanding overview of this literature and
conclude that frequently parasites can be enormously
V. Smith
successful in this interaction. In this section, I provide
examples that demonstrate very strong nutritional
modulation of the outcome of viral, bacterial, protozoan, and metazoan infections of vertebrate animals.
Viral infection
Nutrients have long been known to influence animal
host resistance of animal hosts to infection (Field
et al. 2002), but recent work suggests that not only
can the host’s nutritional status affect the immune
response to viral infection, but it can also affect
the viral pathogen itself (Beck and Levander 2000).
In their mouse model of coxsackievirus B3 infection,
a benign viral strain was found to become virulent
and caused myocarditis in both selenium-deficient
and vitamin E-deficient mice. This change in
pathogenicity was attributed to nutritionally-induced
mutations in the viral genome, which converted an
avirulent virus into a virulent one. Once these
genomic changes occur, even mice with normal
nutritional status are at risk of developing myocarditis after infection.
Bacterial infection
Because both host and parasite share a common and
finite pool of nutrients, an invading parasite must
compete for these nutrients in order to obtain the
structural resources and energy resources needed to
complete its life cycle (Bush et al. 2001) in the face
of the host’s immune response. One key shared
resource is the supply of carbohydrates, which
provide both carbon skeletons and energy for the
host’s anabolic and catabolic pathways. Using a
mouse model of disease, Peck et al. (1992) examined
the role of host nutrition in the outcome of
infections
with
the
intracellular
pathogen
Salmonella typhimurium. Female A/J mice were fed
diets of four different contents of carbohydrate,
lipid, and protein, and two daily feeding rates
(100% and 50%); after 3 weeks the mice were
injected intraperitoneally with Salmonella, and mortality was followed for 2 weeks. When all data were
considered (Fig. 3), mouse mortality increased
linearly with increases in carbohydrate supply
rate beyond an apparent threshold of 456 g/kg.
Conversely, mortality tended to decrease consistently
with increases in percent protein in the host’s diet.
However, mortality response to dietary percent
protein varied with the host’s total caloric intake
(data not shown), suggesting possible effects of the
protein:energy supply ratio on the outcome of
disease (Smith and Holt 1996).
Host resource supplies and infectious disease
Fig. 3 Relationship between percent mortality and dietary
carbohydrate supply (g/kg) in a rodent model of Salmonella
typhimurium infection. Data from Peck et al. (1992).
313
Fig. 4 Relationship between maximum percent parasitemia and
protein content of the diet in a rodent model of malaria.
Data from Eridisinghe et al. (1981).
Protozoan infection
Rodent malaria, which often proves to be fatal,
usually develops in rats following infection by the
virulent blood pathogen Plasmodium berghei
(Crompton and Nesheim 1982). However, unlike
the bacterial example discussed above, protein
restriction can protect rats against mortality from
the effects of this protozoan pathogen. For example,
Eridisinghe et al. (1981) provided infected animals
with isocaloric diets containing four different protein
levels (0, 4.2, 8.5 and 17%), provided as casein
fortified with L-methionine. As can be seen in Fig. 4,
the degree of parasitemia increased strongly and
nonlinearly with increasing dietary protein; furthermore, 80% mortality was observed at 17% protein,
but no mortality occurred at lower levels of protein
supply. The cause of this pronounced sensitivity of
P. berghei to the host’s protein supply is not yet
completely understood, but Keshavarz-Valian et al.
(1985) concluded that both the quantity of dietary
protein and the quality of its amino-acid composition can have profound effects on the susceptibility
of mice to malaria. However, strong effects of
the protein:energy supply ratio were observed in
a second set of experiments: mortality at the
17% protein level could be sharply reduced
from 93% to 33% by cutting the host’s total caloric
intake by half.
Parasitic worm infection
Keymer et al. (1983) used a CFHB rat model of
disease to examine the effects of carbohydrate
nutrition on the body burden and fecundity of the
acanthocephalan parasite Moniliformis dubius.
Each rat was infected orally with one of five dose
Fig. 5 Relationship between total worm burden and dietary
fructose levels in a rodent model of infection by the parasitic
worm, Moniliformis dubius. Data from Keymer et al. (1983).
levels of cystacanths, and was allowed to feed ad
libitum on one of four isocaloric diets containing
different carbohydrate contents (1, 2, 3, and 12%
fructose). After 5 weeks these animals were sacrificed,
and their worm burdens were evaluated.
Like Salmonella, this metazoan parasite responded
positively to increases in the host’s carbohydrate
supply rate. The total worm biomass per rat was
hyperbolically related to dietary fructose level
(Fig. 5). Moreover, total egg production by all
female worms resident in the host’s gut responded
even more sensitively, increasing almost 25-fold over
the range of dietary fructose (Fig. 6). Increasing
dietary carbohydrate supplies thus increased the
host’s parasite burden and disproportionately
increased the number of propagules that could
potentially be transmitted into the local
environment.
314
Fig. 6 Relationship between total egg production and dietary
fructose levels in a rodent model of infection by the parasitic
worm, Moniliformis dubius. Data from Keymer et al. (1983).
Implications and conclusions
The evidence presented in this brief overview
suggests that supplies of resources to the host can
play a key role in determining the outcome of
infectious diseases in plants as well as in animals
(Smith 1993a, 1993b). Such a conclusion is perhaps
not surprising in view of evidence that the regulation
of gene expression in response to changes in
nutrients is common and well-documented in both
prokaryotes and eukaryotes (De Caterina and
Madonna 2004) and that there is remarkable
universality in gene expression across the tree of
life (Ueda et al. 2004). Given the demonstrated
sensitivity of diverse infectious agents to nutrient
availability, it should logically follow that the
regulation of critically important nutrients in the
host’s external supply, or controlling the size of
the host’s internal nutrient pools, could be used to
limit growth of pathogens and thus to alter the
outcome of disease.
In the case of plants, Roberts et al. (2004) have
developed models to account for the interactions
between rate of addition of nitrogen, nitrogen source,
and disease in determining optimal levels of spring
N-fertilization for the cultivation of winter wheat.
In addition, it has been found that the severity of rice
blast can be controlled by manipulations of availability of soil silicon: experimental studies by
Hayasaka et al. (2005) suggested that maintaining a
SiO2 content of at least 5% in the rice plant can
control this disease at the nursery stage under any
conditions. Carefully crafted manipulations of
resource availability thus could potentially become
an increasingly important tool in the future management of economically important plant diseases.
V. Smith
It is certain that knowledge of nutritional interactions between mammalian hosts and their associated pathogens can help inform the practice of
human and veterinary medicine. Since the 1940s,
we have relied heavily upon the use of antibiotics
and antivirals in order to control many of these
diseases. However, the incidence of drug-resistance
by pathogens is increasing worldwide; our arsenal of
effective antibiotics is dwindling rapidly and many
diseases remain for which drug treatments are
expensive, limited in availability, or even nonexistent.
New approaches to the management and control of
infectious disease thus are badly needed.
It is also important that we begin to identify and
to clarify the mechanisms through which variations
in nutrition modify the severity and outcome of
disease in both plant and animal hosts. The exact
nature of these resource-mediated mechanisms may
prove to differ greatly between plants and animals.
Among animals, these mechanisms may also differ
with the presence and the degree of sophistication of
any innate and adaptive immune responses. In the
special case of vertebrate animals, Smith et al. (2005)
have suggested that the external nutrient supply
to the host can alter the postinfection outcome by
(1) interacting with pharmaceutical agents being
taken by the host; (2) causing stimulatory or
inhibitory effects on host physiology and homeostasis; (3) causing stimulatory or inhibitory effects
on components of the host’s immune system
(indirect ecological effects through predator–prey
interactions); and (4) causing stimulatory or inhibitory effects on the growth and proliferation of the
pathogen itself (direct ecological effects on limiting
resources and host–pathogen resource competition).
As the essential resource requirements of mammalian hosts and their pathogens become better
quantified, it should become possible to make
predictions concerning the nutrient supply ratios
and the nutrient supply rates to the host that will
result in the most favorable disease outcome
(Smith et al. 2005). For example, the presence of
iron-binding proteins in both vertebrates and
invertebrates is testament that a strategy of withholding iron is a crucial component of innate
immunity in animals (Ong et al. 2006). Weinberg
(1998, 1999) has for more than two decades
demonstrated the critically important role of the
management of iron in treatment of disease, and I
believe that his ecological viewpoint can be expanded
to other key nutrients as well. I strongly agree with
Costerton (2004), who suggested that good things
happen when medical scientists can apply time-tested
Host resource supplies and infectious disease
concepts from ecology to help better understand the
severe challenges experienced by their patients.
It is thus heartening that significant changes may be
underway in the area of clinical nutrition. In a recent
invited review, Jeejeebhoy (2004) noted that it has been
common practice since the 1970s to apply the concept
of hyperalimentation, in which hospitalized patients
are fed 40–100% above their basal metabolic rate, in
order to avoid the weight loss associated with critical
illness. In contrast, however, he emphasized that there
are observed benefits to the permissive underfeeding of
critically ill patients. There is evidence that hyperglycemia increases the risk of infective complications and
controlled trials of preoperative nutrition suggests that
patients receiving 1000 kcal above the basal metabolic
rate tend to exhibit increased postoperative infectious
complications. Both of these observations are broadly
consistent with the data shown in Fig. 3–6, which
suggest the ecological outcome of many bacterial,
metazoan, and protozoan diseases can potentially be
shaped using careful modifications of the mammalian
host’s dietary supplies of carbohydrates and protein.
Acknowledgments
This work was supported by NSF grant
DMS–0342239 to VHS. I thank Yang Kuang for
the invitation to participate in this SICB symposium
and for helping develop and promote this collaborative disease research program. Conflict of interest:
None declared.
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