Joseph A. Jackson

Review series on helminths, immune modulation and the hygiene hypothesis: Immunity against helminths and immunological phenomena in modern human populations: coevolutionary legacies?

Although the molecules and cells involved in triggering immune responses against parasitic worms (helminths) remain enigmatic, research has continued to implicate expansions of T‐helper type 2 (Th2) cells and regulatory T‐helper (Treg) cells as a characteristic response to these organisms. An intimate association has also emerged between Th2 responses and wound‐healing functions. As helminth infections in humans are associated with a strong Th2/Treg immunoregulatory footprint (often termed a ‘modified Th2’ response), plausible links have been made to increased susceptibility to microbial pathogens in helminth‐infected populations in the tropics and to the breakdowns in immunological control (allergy and autoimmunity) that are increasing in frequency in helminth‐free developed countries. Removal of helminths and their anti‐inflammatory influence may also have hazards for populations exposed to infectious agents, such as malaria and influenza, whose worst effects are mediated by excessive inflammatory reactions. The patterns seen in the control of helminth immunity are discussed from an evolutionary perspective. Whilst an inability to correctly regulate the immune system in the absence of helminth infection might seem highly counter‐adaptive, the very ancient and pervasive relationship between vertebrates and helminths supports a view that immunological control networks have been selected to function within the context of a modified Th2 environment. The absence of immunoregulatory stimuli from helminths may therefore uncover maladaptations that were not previously exposed to selection.

T Helper Cell Type 2 Responsiveness Predicts Future Susceptibility to Gastrointestinal Nematodes in Humans

Some humans are persistently more susceptible to gastrointestinal nematodes than others. Here, for the first time, susceptibility to reinfection has been linked to host cytokine responses. Ascaris lumbricoides and Trichuris trichiura abundance was assessed immediately before and 8-9 months after deworming in a Cameroonian population (starting n=191). Profiles of whole-blood cytokine responses to parasite antigens (for interleukin [IL]-5, IL-13, IL-10, IL-12p40, tumor necrosis factor- alpha , and interferon- gamma), assayed before treatment, were significantly related both to an overall measure of host susceptibility and to susceptibility to reinfection. Significant effects were primarily due to a negative association between IL-13 and IL-5 responses and infection. Persistently susceptible individuals were, therefore, characterized by a weak T helper cell type 2 response. The apparent plasticity of age-specific cytokine response-worm abundance relationships between different populations is also discussed.

Immunity, immunoregulation and the ecology of trichuriasis and ascariasis

Immune responses to human roundworm (Ascaris lumbricoides) and whipworm (Trichuris trichiura) and their role in controlling worm populations are reviewed. Recent immunoepidemiological data implicate Th2‐mediated responses in limiting A. lumbricoides and T. trichiura populations. Reinfection studies further suggest that IL‐5 cytokine responses are negatively associated with adult recruitment in T. trichiura but not A. lumbricoides and may therefore be involved in negative intraspecific and interspecific interactions mediated through the host immune system. The importance of inducible immunoregulatory networks in the ecology of the host–parasite relationship is considered, with particular regard to possible manipulative strategies by the parasites. This aspect of the worms’ interaction with the host immune system is both poorly known and potentially central to an understanding of parasite population dynamics and the evolutionary pressures that have shaped present‐day host–parasite associations. Some possible implications of worm‐mediated immunomodulation for the occurrence of bystander infectious diseases in human populations and the management of de‐worming programmes are also discussed.

Intensity of Intestinal Infection with Multiple Worm Species Is Related to Regulatory Cytokine Output and Immune Hyporesponsiveness

Increasing immunological dysfunction (atopy and autoimmunity) in western society may be linked to changes in undetermined environmental agents. We hypothesize that increased exposure to multiple gut worm species promotes stronger immunological regulation. We report here that African children constitutively secrete more immunoregulatory cytokines (interleukin [IL]-10 and transforming growth factor [TGF]- beta1) under conditions of hyperendemic exposure to the intestinal nematodes Ascaris lumbricoides and Trichuris trichiura, compared with conditions of mesoendemic exposure. Under conditions of hyperendemic exposure, estimators of combined intestinal nematode infection level relate positively to combined constitutive IL-10 and TGF-beta1 production and negatively to total immune reactivity (determined as IL-4, interferon-gamma, and cellular proliferative responses to Ascaris or Trichuris helminth antigens, Streptococcus pneumoniae bacterial antigen, or the mitogen phytohemaglutinin). Total immune reactivity and anti-inflammatory cytokine production relate inversely. Our data suggest that gut nematodes are important mediators of immunoregulation.

Genetic diversity in cytokines associated with immune variation and resistance to multiple pathogens in a natural rodent population

Pathogens are believed to drive genetic diversity at host loci involved in immunity to infectious disease. To date, studies exploring the genetic basis of pathogen resistance in the wild have focussed almost exclusively on genes of the Major Histocompatibility Complex (MHC); the role of genetic variation elsewhere in the genome as a basis for variation in pathogen resistance has rarely been explored in natural populations. Cytokines are signalling molecules with a role in many immunological and physiological processes. Here we use a natural population of field voles (Microtus agrestis) to examine how genetic diversity at a suite of cytokine and other immune loci impacts the immune response phenotype and resistance to several endemic pathogen species. By using linear models to first control for a range of non-genetic factors, we demonstrate strong effects of genetic variation at cytokine loci both on host immunological parameters and on resistance to multiple pathogens. These effects were primarily localized to three cytokine genes (Interleukin 1 beta (Il1b), Il2, and Il12b), rather than to other cytokines tested, or to membrane-bound, non-cytokine immune loci. The observed genetic effects were as great as for other intrinsic factors such as sex and body weight. Our results demonstrate that genetic diversity at cytokine loci is a novel and important source of individual variation in immune function and pathogen resistance in natural populations. The products of these loci are therefore likely to affect interactions between pathogens and help determine survival and reproductive success in natural populations. Our study also highlights the utility of wild rodents as a model of ecological immunology, to better understand the causes and consequences of variation in immune function in natural populations including humans.

Measuring immune system variation to help understand host-pathogen community dynamics

Carefully chosen immunological measurements, informed by recent advances in our understanding of the diversity and control of immune mechanisms, can add great interpretative value to ecological studies of infection. This is especially so for co-infection studies, where interactions between species are often mediated via the hosts immune response. Here we consider how immunological measurements can strengthen inference in different types of co-infection analysis. In particular, we identify how measuring immune response variables in field studies can help reveal inter-species interactions otherwise obscured by confounding processes operating on count or prevalence data. Furthermore, we suggest that, due to the difficulty of quantifying microbial pathogen communities in field studies, innate responses against broad pathogen types (mediated by pattern response receptors) may be useful quantitative markers of exposure to bacteria and viruses. An ultimate goal of ecological co-infection studies may also be to understand how dynamics within host-parasite assemblages emerge from trade-offs involving different arms of the immune system. We reflect on the phenotypic measures that might best represent levels of responsiveness and bias in immune function. These include mediators associated with different T-helper cell subsets and innate responses controlled by pattern response receptors, such as the Toll-like receptors (TLRs).

Parasite infectivity to hybridising host species: a link between hybrid resistance and allopolyploid speciation?

Variation in host-specific infectivity was studied in monogenean polystome parasites (Protopolystoma spp.) of the interfertile, parapatric anurans Xenopus laevis laevis and Xenopus muelleri. Laboratory-raised host F1 hybrids were resistant to parasites respectively specific to each parent taxon in nature. This resistance occurred against parasite isolates from both inside and outside a host hybrid/sympatric zone (and no isolate was compatible with the foreign host species under experimental conditions). Geographical Protopolystoma xenopodis isolates showed variable infectivity to a single full-sib group of their usual host, X. l. laevis, and strains with high or low infectivity to these sibs co-occurred in spatially distant local areas (separated by 1,700 km). The host compatibility of P. xenopodis was also subject to host genotypexparasite genotype interactions. Refractoriness to some parasites or pathogens, as a consequence of hybridisation, may have conferred a selective advantage on the allopolyploid pathway by which most Xenopus spp. are believed to have evolved.

The analysis of immunological profiles in wild animals: a case study on immunodynamics in the field vole, Microtus agrestis

A revolutionary advance in ecological immunology is that postgenomic technologies now allow molecular mediators defined in laboratory models to be measured at the mRNA level in field studies of many naturally occurring species. Here, we demonstrate the application of such an approach to generate meaningful immunological profiles for wild mammals. We sampled a natural field vole population across the year (n = 307) and developed a battery of cellular assays in which functionally different pro‐ and anti‐inflammatory signalling responses (transcription factors and cytokines) were activated and quantified by Q‐PCR. Temporal trends were the strongest feature in the expression data, although some life history stages (mating vs. nonmating males and pregnant females) were also associated with significant variation. There was a striking set of significant negative associations between inflammatory mediators and condition indices reflecting packed erythrocyte volume and relative liver size, spleen size and splenocyte count. Grouped (principal component) measures of inflammatory and anti‐inflammatory expression were high in winter, with minima in the breeding season that occurred earlier for grouped anti‐inflammatory responses than for grouped inflammatory responses. Some individual immunological mediators also showed patterns unrelated to the breeding season or annual periodic cues. For example, interferon regulatory factor 5 (IRF5) expression declined throughout the study period, indicating a systematic trend in antimicrobial defences. Pinpointing the causes and consequences of such variation may help identify underlying environmental drivers of individual fitness and demographic fluctuation.

An Immunological Marker of Tolerance to Infection in Wild Rodents

A large-scale field study in naturally occurring vole populations identified gene expression changes over time and demonstrates how wild mammals exhibit tolerance to chronic parasite infections.

Effects of environmental temperature on the susceptibility of Xenopus laevis and X. wittei (Anura) to Protopolystoma xenopodis (Monogenea)

Abstract. Immune responses in ectothermic vertebrates and the life-processes of their parasites are profoundly linked to ambient temperature, but the functional effect of thermal environment on infectivity and host-specificity in helminths from ectotherms is poorly known. Primary infection establishment of Protopolystomaxenopodis (Monogenea) in compatible hosts (Xenopuslaevis: Anura) is strongly modulated by ambient temperature. Significantly fewer worms survived to the urinary bladder stage at 25°C than at 15°C (relatively high and low temperatures for this system in nature). Pre-infection exposure of X. laevis to cold (10°C) did not significantly affect parasite establishment in the urinary bladder (at 15 or 25°C p.i.), nor shorter-term postlarval survival in the kidneys (at 20°C p.i.), suggesting that residual immunosuppressive effects on host susceptibility are not important. Low temperatures had no permissive effect on the establishment of P. xenopodis in incompatible hosts (Xenopuswittei). The link between thermal conditions and parasitic infection of ectotherms is discussed.