View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central Opinion Nutritional Immunology: A Multi-Dimensional Approach Fleur Ponton1*, Kenneth Wilson2, Sheena C. Cotter3, David Raubenheimer4, Stephen J. Simpson1 1 School of Biological Sciences, The University of Sydney, Sydney, New South Wales, Australia, 2 Lancaster Environment Centre, Lancaster University, Lancaster, United Kingdom, 3 School of Biological Sciences, Queen’s University, Belfast, United Kingdom, 4 Institute of Natural Sciences, Massey University, Auckland, New Zealand Nutrition is critical to immune defence understanding of the nutritional con- [18–20]. The complexity of the nutritional and resistance to pathogens, with conse- straints on pathogen defence (see also interactions between hosts and pathogens quences that affect the health, welfare, [2]). The Geometric Framework (GF) is made substantially greater by the fact and reproductive success of individual [12–14] was specifically developed to that animals play host not only to invading organisms [1,2], and also has profound capture these multi-dimensional aspects pathogens, but also to entire communities ecological and evolutionary implications of nutrition and offers promise for the of commensal and symbiotic microorgan- [3–5]. In humans, under-nutrition, nota- study of nutritional immunology, allowing isms that receive their nutrition from the bly of protein, is a major contributor to quantitative predictions that can be statis- host and in turn contribute essential morbidity and mortality due to infectious tically tested. The GF identifies nutritional nutrients and play a role in immune diseases, particularly in the developing optima (intake and growth targets) in defence [21–24]. Gut microbiota have world [1]. Likewise, over-nutrition and its multi-dimensional nutritional space and been shown to have profound and unan- associated metabolic disorders may im- thus provides a rigorous definition and ticipated effects on immune defence and pair immune function, disrupt the rela- quantification of ‘‘under’’- and ‘‘over’’- inflammatory responses [23,25–27], and tionship with symbiotic and commensal nutrition, as well as a mean of associating in mammals, disturbances of the gut microbiota, and increase susceptibility to immune responses, host performance, microbiota have been implicated in dis- infectious disease [6]. Despite the un- responses of host microbial communities, eases such as obesity, type 1 diabetes, and doubted importance of nutrition to im- and pathogen growth rates with particular various cancers [21,23,28]. Furthermore, mune defence, the challenge remains to nutritional states. diet has a strong effect on the gut capture the complexity of this relation- The importance of considering the microbiota [29–32], both by serving as a ship. There are three main aspects to this simultaneous and interactive effects of vector for microorganisms and by affecting complexity: (i) nutrition is a complex multiple nutrients when studying immune the physical, chemical, and structural multi-dimensional problem for hosts, function has been illustrated by a number properties of the gut [33–37]. pathogens, and commensals; (ii) host of studies on insects and rodents [15–18]. immunity is a complex, multi-dimensional For example, Peck et al. [18] found that The Immune System Has trait; and (iii) nutrition and immunity mice survived better on diets containing a interact via multiple direct and indirect Multiple Components That higher ratio of protein (P) to carbohydrate React Differently to Nutrients pathways, including involvement of the (C) following inoculation with Salmonella host’s microbiota. typhimurium. Similarly, the ability of cater- Immune loci are the most gene-dense pillars to resist viral and bacterial infection regions of the genome in vertebrates (e.g., Nutrition Is a Multi-Dimensional increased as dietary P:C rose, and infected [38]), and even in insects, which lack an Problem for Hosts, Pathogens, insects selected a higher protein diet, adaptive immune response and rely solely and Commensal Organisms indicating a form of nutritional self- on the innate immune system, there are medication [15–17]. abundant components to the immune Although widely used, the terms ‘‘over- Hosts are not the only organisms facing response, each designed to meet particular nutrition’’ and ‘‘under-nutrition’’ are rare- the complexity of nutrition. Parasites and types of immune challenge [39]. It has ly defined in studies, and often the key pathogens rely on the host for provision of recently been discovered using GF designs nutritional variables have not been iden- resources and may not share the same that immune components respond differ- tified. Many studies consider foods as nutritional requirements, setting up the ently to host nutritional state. Cotter et al. uniform commodities and manipulate the potential for resource competition and [40] restricted control and immune-chal- amount available without considering the manipulation between the different parties lenged caterpillars to one of 20 diets food’s nutritional composition or having a quantitative understanding of the animal’s nutrient requirements (see for instance Citation: Ponton F, Wilson K, Cotter SC, Raubenheimer D, Simpson SJ (2011) Nutritional Immunology: A Multi- [7,8]). Other studies focus on a single Dimensional Approach. PLoS Pathog 7(12): e1002223. doi:10.1371/journal.ppat.1002223 dietary attribute (typically its calorie con- Editor: Glenn F. Rall, The Fox Chase Cancer Center, United States of America tent) or nutritional component (e.g., the Published December 1, 2011 amount of protein or nitrogen in the diet), Copyright: ß 2011 Ponton et al. This is an open-access article distributed under the terms of the Creative and experimentally manipulate this whilst Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, maintaining other dietary components at a provided the original author and source are credited. constant level, thus confounding changes Funding: FP was supported by a postdoctoral grant from The University of Sydney. SJS was supported by ARC in the focal nutrient/attribute with chang- federation and Laureate Fellowships, Australia. SCC was an NERC fellow. KW was funded by a Royal Society es in the ratio of nutrients in the diet [9– Travel For Collaboration grant and a University of Sydney Visiting Research Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 11]. Although these studies have had their successes, we believe that this single Competing Interests: The authors have declared that no competing interests exist. currency approach provides only a limited * E-mail: [email protected] PLoS Pathogens | www.plospathogens.org 1 December 2011 | Volume 7 | Issue 12 | e1002223 Figure1. Response landscapes for three immune traits in caterpillars fed one of 20 diets differing in the ratios and amounts of protein and carbohydrate. Adapted after Cotter et al. [40]. doi:10.1371/journal.ppat.1002223.g001 varying in both the quantity and ratio of P shown to be repeatable and heritable A Framework to Address the and C. Statistical analysis of response [41,42] and linked to functional immune Complexity of Nutritional surfaces (Figure 1) showed that immune outcomes [43,44]. This raises the intrigu- Immunology traits are differentially affected by macro- ing prospect that an animal might adjust nutrient intake and that no diet can its food selection to support immune When the above mentioned complexi- simultaneously optimize all components components that best resist a given ties are considered, it becomes clear that of the immune system (see below). Varia- infection and perhaps also support a an understanding of nutritional immunol- tion in these different traits has been healthy microbial community. ogy must take account of a web of Figure 2. The network of interactions between nutrition and immunity. Diet affects host nutritional state and immune status, both of which interact with microbial symbionts, commensals, and pathogens to affect the fitness of all partners. Because nutrient feedbacks modulate host feeding behaviour, the potential exists for the host to adjust its diet to optimise its microbial interactions and increase resistance to infection. Alternatively, parasites and pathogens might subvert host feeding behaviour to their nutritional advantage. doi:10.1371/journal.ppat.1002223.g002 PLoS Pathogens | www.plospathogens.org 2 December 2011 | Volume 7 | Issue 12 | e1002223 interactions between components. These above) mapped several immune traits onto immune response; using RNAi to knock- include the nutritional quality of the diet, P-C intake arrays (Figure 1), providing down particular immune genes; or by host feeding behaviour, host nutritional evidence that immune components re- manipulating the commensal microbiota state, the growth of pathogen populations, sponded in a nutrient-specific manner. through antibiotic treatment. Finally, hosts the host-associated microbial community, Whether these different responses were could be offered the opportunity to express multiple measures of host immune func- driven by differing nutritional demands of nutritional self-medication in experimental tion and, ultimately, evolutionary consid- the various immune traits, direct effects of designs in which they are offered a choice erations such as host and microbial