Integrative and Comparative Biology Advance Access originally published online on June 1, 2007
Integrative and Comparative Biology 2007 47(2):310-316; doi:10.1093/icb/icm006
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Host resource supplies influence the dynamics and outcome of infectious disease
Department of Ecology and Evolutionary Biology, University of Kansas, Lawrence, KS 66045
Correspondence: 1E-mail: vsmith{at}ku.edu
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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.
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Introduction |
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SynopsisIntroductionEffects of resource availability...Effects of resource availability...Implications and conclusionsAcknowledgmentsReferences |
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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.
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Effects of resource availability on plant diseases |
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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) 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.
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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 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.
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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 light-driven variations in the host cells’ intrinsic rate of population growth. In addition, both P-limitation and light-limitation modify production and infectivity of 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).
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Effects of resource availability on animal diseases |
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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 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).
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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.
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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 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.
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Implications and conclusions |
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SynopsisIntroductionEffects of resource availability...Effects of resource availability...Implications and conclusionsAcknowledgmentsReferences |
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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.
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 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.
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Acknowledgments |
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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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Footnotes |
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From the symposium "Ecological Dimorphisms in Vertebrates: Proximate and Ultimate Causes" presented at the annual meeting of the Society for Integrative and Comparative Biology, January 3–7, 2007, at Phoenix, Arizona.
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