Polymorphic Major Histocompatibility Complex Research Articles

Host factors influencing variable symptoms of COVID-19.

Similar to many other viruses, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) causes various symptoms in individuals who have been exposed to the virus. Individuals exposed to the virus can be asymptomatic, mild, severe, and critical for mortality. Most hypotheses explaining the uncertainty of symptoms are based on innate immunity, which is unclear in explaining some issues. For example, 1. uncertain symptoms of SARS-CoV-2 infection, 2. failure to induce immunity for prevention by vaccines in some individuals, and 3. repeated infections in some individuals. With the ambition of explaining this clearly, this article proposed another perspective to explain the cause of uncertain symptoms in SARS-CoV-2-positive individuals. This could be influenced by host factors with a variety of cellular molecules (viral receptors/co-receptors) and major histocompatibility complex (MHC) polymorphisms, which are crucial factors in explaining this question. Hopefully, this perspective could encourage further research and pave the way for developing new public health policies to deal with COVID-19 and emergent viral epidemics in the future.

Functional and biological implications of clonotypic diversity among human donor-unrestricted T cells.

Tcells express a T-cell receptor (TCR) heterodimer that is the product of germline rearrangement and junctional editing resulting in immense clonotypic diversity. The generation of diverse TCR repertoires enables the recognition of pathogen-derived peptide antigens presented by polymorphic major histocompatibility complex (MHC) molecules. However, Tcells also recognize nonpeptide antigens through nearly monomorphic antigen-presenting systems, such as cluster of differentiation 1 (CD1), MHC-related protein 1 (MR1) and butyrophilins (BTNs). This potential for shared immune responses across genetically diverse populations led to their designation as donor-unrestricted Tcells (DURTs). As might be expected, some CD1-, MR1- and BTN-restricted Tcells express a TCR that is conserved across unrelated individuals. However, several recent studies have reported unexpected diversity among DURT TCRs, and increasing evidence suggests that this diversity has functional consequences. Recent reports also challenge the dogma that immune cells are either innate or adaptive and suggest that DURT TCRs may act in both capacities. Here, we review this evidence and propose an expanded view of the role for clonotypic diversity among DURTs in humans, including new perspectives on how DURT TCRs may integrate their adaptive and innate immune functions.

The electrostatic landscape of MHC-peptide binding revealed using inception networks

Predictive modeling of macromolecular recognition and protein-protein complementarity represents one of the cornerstones of biophysical sciences. However, such models are often hindered by the combinatorial complexity of interactions at the molecular interfaces. Exemplary of this problem is peptide presentation by the highly polymorphic major histocompatibility complex class I (MHC-I) molecule, a principal component of immune recognition. We developed human leukocyte antigen (HLA)-Inception, a deep biophysical convolutional neural network, which integrates molecular electrostatics to capture non-bonded interactions for predicting peptide binding motifs across 5,821 MHC-I alleles. These predictions of generated motifs correlate strongly with experimental peptide binding and presentation data. Beyond molecular interactions, the study demonstrates the application of predicted motifs in analyzing MHC-I allele associations with HIV disease progression and patient response to immune checkpoint inhibitors. A record of this paper's transparent peer review process is included in the supplemental information.

Only rare classical MHC-I alleles are highly expressed in the European house sparrow.

The exceptional polymorphism observed within genes of the major histocompatibility complex (MHC), a core component of the vertebrate immune system, has long fascinated biologists. The highly polymorphic classical MHC class-I (MHC-I) genes are maintained by pathogen-mediated balancing selection (PMBS), as shown by many sites subject to positive selection, while the more monomorphic non-classical MHC-I genes show signatures of purifying selection. In line with PMBS, at any point in time, rare classical MHC alleles are more likely than common classical MHC alleles to confer a selective advantage in host-pathogen interactions. Combining genomic and expression data from the blood of wild house sparrows Passer domesticus, we found that only rare classical MHC-I alleles were highly expressed, while common classical MHC-I alleles were lowly expressed or not expressed. Moreover, highly expressed rare classical MHC-I alleles had more positively selected sites, indicating exposure to stronger PMBS, compared with lowly expressed classical alleles. As predicted, the level of expression was unrelated to allele frequency in the monomorphic non-classical MHC-I alleles. Going beyond previous studies, we offer a fine-scale view of selection on classical MHC-I genes in a wild population by revealing differences in the strength of PMBS according to allele frequency and expression level.

MHC-DRB alleles with amino acids Val11, Phe13, and the shared epitopes promote collagen-induced arthritis and a rapid IgG1 response in Filipino cynomolgus macaques.

Macaques are useful animal models for studying the pathogenesis of rheumatoid arthritis (RA) and the development of anti-rheumatic drugs. The purpose of this study was to identify the major histocompatibility complex (MHC) polymorphisms associated with the pathology of collagen-induced arthritis (CIA) and anti-collagen IgG induction in a cynomolgus macaque model, as MHC polymorphisms affect the onset of CIA in other animal models. Nine female Filipino cynomolgus macaques were immunized with bovine type II collagen (b-CII) to induce CIA, which was diagnosed clinically by scoring the symptoms of joint swelling over 9 weeks. MHC polymorphisms and anti-b-CII antibody titers were compared between symptomatic and asymptomatic macaques. Four of 9 (44%) macaques were defined as the CIA-affected group. Anti-b-CII IgG in the affected group increased in titer approximately 3 weeks earlier compared with the asymptomatic group. The mean plasma IgG1 titer in the CIA-affected group was significantly higher (p < 0.05) than that of the asymptomatic group. Furthermore, the cynomolgus macaque MHC (Mafa)-DRB1*10:05 or Mafa-DRB1*10:07 alleles, which contain the well-documented RA-susceptibility five amino acid sequence known as the shared epitope (SE) in positions 70 to 74, with valine at position 11 (Val11, V11) and phenylalanine at position 13 (Phe13, F13), were detected in the affected group. In contrast, no MHC polymorphisms specific to the asymptomatic group were identified. In conclusion, the presence of V11 and F13 along with SE in the MHC-DRB1 alleles seems essential for the production of IgG1 and the rapid induction of severe CIA in female Filipino cynomolgus macaques.

Climate heterogeneity, season variation, and sexual dimorphism modulate the association between MHC II diversity and parasite variation in striped hamster

AbstractParasite‐mediated selection is widely believed to play a crucial role in maintaining the diversity of the major histocompatibility complex (MHC) genes, which is thought to be maintained through heterozygote advantage, rare‐allele advantage, and fluctuating selection. However, the relationship between parasite pressure and MHC diversity has yielded inconsistent findings. These inconsistencies may arise from the influence of environmental factors and individual variations in traits on host–parasite interactions. To address these issues, our study extensively investigated populations of striped hamsters inhabiting regions characterized by environmental heterogeneity. The primary objective was to examine the universality of parasite‐mediated selection mechanisms. Our observations revealed the presence of multiple parasite infections, accompanied by spatial and temporal variations in parasite communities and infection patterns among individual hamsters. Specifically, the temperature was found to influence all four parasite indices, while the presence of gamasid mites and parasite richness decreased with increasing precipitation. We also noted significant seasonal variation in parasite dynamics. Moreover, a significant sexual dimorphism was observed with males exhibiting a considerably higher parasite burden compared to their female counterparts. Lastly, we identified the maintenance of MHC polymorphism in striped hamsters as being driven by the heterozygote advantage and fluctuating selection mechanisms. This study underscores the significance of ecological processes in comprehending host–parasite systems and highlights the necessity of considering environmental factors and individual traits when elucidating the mechanisms underlying MHC diversity mediated by parasites.

Adaptation of HLA testing to characterize the cynomolgus macaque MHC polymorphisms and alloantibody signatures.

Nonhuman primates are the closest animal models to humans with respect to genetics and physiology. Consequently, a critical component of immunogenetics research relies on drawing inferences from the cynomolgus macaque to inform human trials. Despite the conserved organization of the Major Histocompatibility Complex (MHC) between cynomolgus macaques and humans, MHC genotyping of cynomolgus macaques is challenging due to high rates of copy number variants, duplications, and rearrangements, particularly at the MHC class I loci. Furthermore, the limited availability of commercial reagents specific to cynomolgus macaques that can be used to characterize anti-MHC class I and class II antibody (Ab) specificities in cynomolgus macaques presents a major bottleneck in translational research. Here we successfully characterized cynomolgus macaque Mafa class I and class II serologic specificities in 86 animals originating from various geographical regions using the complement dependent cytotoxicity (CDC) assay with human HLA class I and class II monoclonal antibody (mAb) typing trays. Further, we successfully induced and characterized anti-Mafa class I and class II alloantibody specificity using HLA single antigen bead assays. We also subsequently tracked the alloAb burden in the animals during treatment with anti-B lymphocyte stimulator (BLyS) treatment. Altogether, these methods can be easily used in translational research to serotype MHC class I and class II specificity in macaques, characterize their alloAb specificity, and evaluate the efficacy of novel therapeutic modalities in depleting circulating alloAbs in these animals.

Integration of the immune memory into the pathogen-driven MHC polymorphism hypothesis.

Major histocompatibility complex (MHC) genes (referred to as human leukocyte antigen or HLA in humans) are a key component of vertebrate immune systems, coding for proteins which present antigens to T-cells. These genes are outstanding in their degree of polymorphism, with important consequences for human and animal health. The polymorphism is thought to arise from selection pressures imposed by pathogens on MHC allomorphs, which differ in their antigen-binding capacity. However, the existing theory has not considered MHC selection in relation to the formation of immune memory. In this paper, we argue that this omission limits our understanding of the evolution of MHC polymorphism and its role in disease. We review recent evidence that has emerged from the massive research effort related to the SARS-CoV-2 pandemics, and which provides new evidence for the role of MHC in shaping immune memory. We then discuss why the inclusion of immune memory within the existing theory may have non-trivial consequence for our understanding of the evolution of MHC polymorphism. Finally, we will argue that neglecting immune memory hinders our interpretation of empirical findings, and postulate that future studies focusing on pathogen-driven MHC selection would benefit from stratifying the available data according to the history of infection (and vaccination, if relevant).

Adaptive immune response selects for postponed maturation and increased body size

Abstract The Major Histocompatibility Complex (MHC) genes encode proteins that initiate the adaptive immune response by presenting pathogen‐derived antigenic peptides to T lymphocytes. Host–pathogen coevolution drives MHC polymorphism, introducing intraspecific variation in host life expectancy. This variation interacts with optimal growth strategy, as growth increases reproductive potential. While mortality rate and body size‐dependent fecundity are major factors shaping life histories, the effect of intraspecific variation in MHC‐based immunity on the evolution of growth strategies and host body size remains unknown. Here, we model how host MHC–pathogen coevolution—and its concomitant impact on host mortality—can affect the evolution of host life histories, as represented by age at maturation and body size. Life histories were compared in scenarios with and without adaptive immune response under equal population‐level mortality rates. We show that host–pathogen coevolutionary dynamics selects for postponed maturation and increased body size. Although MHC genes and genes that determine body size were physically unlinked, selection imposed by the Red Queen process generated linkage disequilibrium between immunocompetent MHC alleles and the maturation‐postponing alleles that prolong growth phase and increase body size. Particularly large body size was attained when pathogens mutated slowly, thus allowing the advantage of resistant MHC alleles to persist over multiple generations. The emergence of adaptive immunity, which is pathogen‐specific and enables immunological memory, is considered a major evolutionary innovation of vertebrates. Our work suggests that the adaptive immune response, mediated by polymorphic MHC genes, may drive the evolution of host body size. This form of adaptive immunity may have thus predisposed vertebrates to evolve large body size and exhibit the macroevolutionary patterns of increasing body size over time that have been detected in comparative studies. Read the free Plain Language Summary for this article on the Journal blog.

Widespread introgression of MHC genes in Iberian Podarcis lizards.

Major histocompatibility complex (MHC) genes are crucial for the adaptive immune response of jawed vertebrates. Their variation, reaching extreme levels, is driven mainly by an arms race between hosts and pathogens. One hypothesised mechanism contributing to MHC polymorphism is adaptive introgression, the exchange of genetic variants between hybridising species favoured by selection, yet its effect on MHC variation is poorly understood. Detection of adaptive MHC introgression, though challenging, may be facilitated by the analysis of species complexes forming multiple hybrid zones. Here, we investigated MHC introgression in six hybrid zones formed by seven species of Podarcis lizards inhabiting the Iberian Peninsula. To differentiate adaptive introgression from neutral introgression, we compared the patterns of gene exchange in MHC and genome-wide markers. We found elevated sharing of MHC alleles in the proximity of contact beyond the areas of detectable genome-wide admixture in most hybrid zones and, in half of them, asymmetric MHC exchange. In general, the elevated MHC allele sharing between species pairs with abutting ranges compared to geographically isolated species pairs also supports the prevalence of introgression. Collectively, our results demonstrate widespread MHC introgression in the Iberian Podarcis complex and suggest its adaptiveness. Contrary to previous results from Triturus newts, we did not observe differences in the rate of introgression between MHC classes. Our work adds support to the emerging view of adaptive introgression as a key mechanism shaping MHC diversity. It also raises questions about the effect of elevated MHC variation and factors leading to the asymmetry of adaptive introgression.

Does MHC Heterozygosity Promote IgA Plasmablast Diversity in the Gut?

Abstract The diversity of protein antigens the adaptive immune system can respond to is governed by polymorphic major histocompatibility complex (MHC) molecules. Because MHC alleles are co-dominantly expressed, MHC heterozygosity should allow for a wider diversity of antigens to activate T cells. B cells present antigen via MHC molecules to T cells, and through the ensuing T cell interaction, differentiate into plasma cells. Because of this, MHC heterozygosity should result in the generation of a plasma cell pool able to generate antibodies that target a wider array of antigens. To investigate this claim, we compared B cell selection dynamics between homozygote and heterozygote MHC congenic mice within the germinal centers (GCs) of Peyer’s patches; the major secondary lymphoid tissues of the gut where plasma cells develop in response to the microbiota. I have observed differences in the distribution of GC B cells between the dark zone (DZ) and light zone (LZ) of GCs. Specifically, GC B cells in MHC heterozygotes are found in greater abundance in the LZ and lower abundance in the DZ compared the GC B cells from MHC homozygote mice, which suggests that B cells are more capable of interacting with T cells in MHC heterozygotes. MHC heterozygotes also have significantly higher abundance of GC-T FHcells in their Peyer’s patches. I have observed that MHC heterozygote mice show enhanced binding of IgA to SI-resident bacteria. Future experiments seek to sort-purify IgA-bound SI-resident bacteria from MHC heterozygotes and homozygotes for 16S analysis to determine if MHC heterozygotes bind a more diverse array of bacterial species. We will also perform IgH-sequencing to define the effect of MHC heterozygosity on repertoire diversity of plasma cell populations. Supported by grants from the NIH (R21AI142409, R01AII55887)

Pretoria: An effective computational approach for accurate and high-throughput identification of CD8+ t-cell epitopes of eukaryotic pathogens

T-cells recognize antigenic epitopes present on major histocompatibility complex (MHC) molecules, triggering an adaptive immune response in the host. T-cell epitope (TCE) identification is challenging because of the extensive number of undetermined proteins found in eukaryotic pathogens, as well as MHC polymorphisms. In addition, conventional experimental approaches for TCE identification are time-consuming and expensive. Thus, computational approaches that can accurately and rapidly identify CD8+ T-cell epitopes (TCEs) of eukaryotic pathogens based solely on sequence information may facilitate the discovery of novel CD8+ TCEs in a cost-effective manner. Here, Pretoria (Predictor of CD8+ TCEs of eukaryotic pathogens) is proposed as the first stack-based approach for accurate and large-scale identification of CD8+ TCEs of eukaryotic pathogens. In particular, Pretoria enabled the extraction and exploration of crucial information embedded in CD8+ TCEs by employing a comprehensive set of 12 well-known feature descriptors extracted from multiple groups, including physicochemical properties, composition-transition-distribution, pseudo-amino acid composition, and amino acid composition. These feature descriptors were then utilized to construct a pool of 144 different machine learning (ML)-based classifiers based on 12 popular ML algorithms. Finally, the feature selection method was used to effectively determine the important ML classifiers for the construction of our stacked model. The experimental results indicated that Pretoria is an accurate and effective computational approach for CD8+ TCE prediction; it was superior to several conventional ML classifiers and the existing method in terms of the independent test, with an accuracy of 0.866, MCC of 0.732, and AUC of 0.921. Additionally, to maximize user convenience for high-throughput identification of CD8+ TCEs of eukaryotic pathogens, a user-friendly web server of Pretoria (http://pmlabstack.pythonanywhere.com/Pretoria) was developed and made freely available.

MHC polymorphism in the immune system

An antigen will be able to stimulate an immune response if the antigen has been presented and recognized by T-cells. Major Histocompatibility Complex (MHC) molecules are molecules that will recognize and present the peptides of the antigen. In humans, two classes of MHC are known to carry out this role, namely Class-I MHC and Class-II MHC, while Class-III MHC has a function that is not directly related to peptide binding. The genes that code for MHC molecules are so polymorphic that each individual is certain to have a different allele (heterozygous). In Class-I MHC, only the α-chain is polymorphic while in Class-II MHC both α and β-chains are polymorphic. MHC polymorphism will affect (1) the ability to create immune responses including antibody production, (2) resistance or susceptibility to infectious diseases, and (3) resistance or susceptibility to autoimmune and allergic diseases. That is why MHC is so polymorphic. The immune system has to fight many different pathogens. By having many different MHC molecules, one can present widely different antigens and can spur an effective immune response.

Interspecific introgression of MHC genes in Triturus newts: Evidence from multiple contact zones.

The major histocompatibility complex (MHC) genes are central to the adaptive immune response in vertebrates. Selection generally maintains high MHC variation because the spectrum of recognized pathogens depends on MHC polymorphism. Novel alleles favoured by selection originate by interallelic recombination or de novo mutations but may also be acquired by introgression from related species. However, the extent and prevalence of MHC introgression remain an open question. In this study, we tested for MHC introgression in six hybrid zones formed by six Triturus newt species. We sequenced and genotyped the polymorphic second exons of the MHC class I and II genes and compared their interspecific similarity at various distances from the centre of the hybrid zone. We found evidence for introgression of both MHC classes in the majority of examined hybrid zones, with support for a more substantial class I introgression. Furthermore, the overall MHC allele sharing outside of hybrid zones was elevated between pairs of Triturus species with abutting ranges, regardless of the phylogenetic distance between them. No effect of past hybrid zone movement on MHC allele sharing was found. Finally, using previously published genome-wide data, we demonstrated that MHC introgression was more extensive than genome-wide introgression, supporting its adaptive potential. Our study thus provides evidence for the prevalence of MHC introgression across multiple Triturus hybrid zones, indicating that MHC introgression between divergent hybridizing species may be widespread and adaptive.

The MHC Motif Atlas: a database of MHC binding specificities and ligands.

The highly polymorphic Major Histocompatibility Complex (MHC) genes are responsible for the binding and cell surface presentation of pathogen or cancer specific T-cell epitopes. This process is fundamental for eliciting T-cell recognition of infected or malignant cells. Epitopes displayed on MHC molecules further provide therapeutic targets for personalized cancer vaccines or adoptive T-cell therapy. To help visualizing, analyzing and comparing the different binding specificities of MHC molecules, we developed the MHC Motif Atlas (http://mhcmotifatlas.org/). This database contains information about thousands of class I and class II MHC molecules, including binding motifs, peptide length distributions, motifs of phosphorylated ligands, multiple specificities or links to X-ray crystallography structures. The database further enables users to download curated datasets of MHC ligands. By combining intuitive visualization of the main binding properties of MHC molecules together with access to more than a million ligands, the MHC Motif Atlas provides a central resource to analyze and interpret the binding specificities of MHC molecules.

The Gallus gallus RJF reference genome reveals an MHCY haplotype organized in gene blocks that contain 107 loci including 45 specialized, polymorphic MHC class I loci, 41 C-type lectin-like loci, and other loci amid hundreds of transposable elements.

MHCY is a second major histocompatibility complex-like gene region in chickens originally identified by the presence of major histocompatibility complex class I-like and class II-like gene sequences. Up to now, the MHCY gene region has been poorly represented in genomic sequence data. A high density of repetitive sequence and multiple members of several gene families prevented the accurate assembly of short-read sequence data for MHCY. Identified here by single-molecule real-time sequencing sequencing of BAC clones for the Gallus gallus Red Jungle Fowl reference genome are 107 MHCY region genes (45 major histocompatibility complex class I-like, 41 c-type-lectin-like, 8 major histocompatibility complex class IIβ, 8 LENG9-like, 4 zinc finger protein loci, and a single only zinc finger-like locus) located amid hundreds of retroelements within 4 contigs representing the region. Sequences obtained for nearby ribosomal RNA genes have allowed MHCY to be precisely mapped with respect to the nucleolar organizer region. Gene sequences provide insights into the unusual structure of the MHCY class I molecules. The MHCY class I loci are polymorphic and group into 22 types based on predicted amino acid sequences. Some MHCY class I loci are full-length major histocompatibility complex class I genes. Others with altered gene structure are considered gene candidates. The amino acid side chains at many of the polymorphic positions in MHCY class I are directed away rather than into the antigen-binding groove as is typical of peptide-binding major histocompatibility complex class I molecules. Identical and nearly identical blocks of genomic sequence contribute to the observed multiplicity of identical MHCY genes and the large size (&gt;639 kb) of the Red Jungle Fowl MHCY haplotype. Multiple points of hybridization observed in fluorescence in situ hybridization suggest that the Red Jungle Fowl MHCY haplotype is made up of linked, but physically separated genomic segments. The unusual gene content, the evidence of highly similar duplicated segments, and additional evidence of variation in haplotype size distinguish polymorphic MHCY from classical polymorphic major histocompatibility complex regions.

Genotyping of canine MHC gene DLA-88 by next-generation sequencing reveals high frequencies of new allele discovery and gene duplication.

Dogs have served as one of the most reliable preclinical models for a variety of diseases and treatments, including stem/progenitor cell transplantation. At the genetic epicenter of dog transplantation models, polymorphic major histocompatibility complex (MHC) genes are most impactful on transplantation success. Among the canine class I and class II genes, DLA-88 has been best studied in transplantation matching and outcomes, with 129 DLA-88 alleles identified. In this study we developed and tested a next generation (NGS) sequencing protocol for rapid identification of DLA-88 genotypes in dogs and compared the workflow and data generated with an established DLA-88 Sanger sequencing protocol that has been in common prior use for clinical studies. By testing the NGS protocol on a random population of 382 dogs, it was possible to demonstrate superior efficacy based on laboratory execution and overall cost. In addition, NGS proved far more effective at discovering new alleles and detecting multiple alleles associated with gene duplication. A total of 51 new DLA-88 alleles are reported here. This rate of new allele discovery indicates that a large pool of yet un-discovered DLA-88 alleles exists in the domestic dog population. In addition, more than 46% of dogs carried three or more copies of DLA-88, further emphasizing the need for more sensitive and cost-effective DLA typing methodology for the dog clinical model.

Invasive Bullfrogs Maintain MHC Polymorphism Including Alleles Associated with Chytrid Fungal Infection.

Maintenance of genetic diversity at adaptive loci may facilitate invasions by non-native species by allowing populations to adapt to novel environments, despite the loss of diversity at neutral loci that typically occurs during founder events. To evaluate this prediction, we compared genetic diversity at major histocompatibility complex (MHC) and cytochrome b (cytb) loci from 20 populations of the American bullfrog (Rana catesbeiana) across theinvasive and native ranges in North America and quantified the presence of the pathogen Batrachochytrium dendrobatidis (Bd). Compared to native populations, invasive populations had significantly higher Bd prevalence and intensity, significantly higher pairwise MHC and cytb FST, and significantly lower cytb diversity, but maintained similar levels of MHC diversity. The two most common MHC alleles (LiCA_B and Rapi_33) were associated with a significant decreased risk of Bd infection, and we detected positive selection acting on four peptide binding residues. Phylogenetic analysis suggested invasive populations likely arose from a single founding population in the American Midwest with a possible subsequent invasion in the northwest. Overall, our study suggests that the maintenance of diversity at adaptive loci may contribute to invasion success and highlights the importance of quantifying diversity at functional loci to assess the evolutionary potential of invasive populations.

Long term patterns of association between MHC and helminth burdens in the bank vole support Red Queen dynamics.

Major histocompatibility complex (MHC) genes encode proteins crucial for adaptive immunity of vertebrates. Negative frequency‐dependent selection (NFDS), resulting from adaptation of parasites to common MHC types, has been hypothesized to maintain high, functionally relevant polymorphism of MHC, but demonstration of this relationship has remained elusive. In particular, differentiation of NFDS from fluctuating selection, resulting from changes in parasite communities in time and space (FS), has proved difficult in short‐term studies. Here, we used temporal data, accumulated through long‐term monitoring of helminths infecting bank voles (Myodes glareolus), to test specific predictions of NFDS on MHC class II. Data were collected in three, moderately genetically differentiated subpopulations in Poland, which were characterized by some stable spatiotemporal helminth communities but also events indicating introduction of new species and loss of others. We found a complex association between individual MHC diversity and species richness, where intermediate numbers of DRB supertypes correlated with lowest species richness, but the opposite was true for DQB supertypes—arguing against universal selection for immunogenetic optimality. We also showed that particular MHC supertypes explain a portion of the variance in prevalence and abundance of helminths, but this effect was subpopulation‐specific, which is consistent with both NFDS and FS. Finally, in line with NFDS, we found that certain helminths that have recently colonized or spread in a given subpopulation, more frequently or intensely infected voles with MHC supertypes that have been common in the recent past. Overall, our results highlight complex spatial and temporal patterns of MHC‐parasite associations, the latter being consistent with Red Queen coevolutionary dynamics.

Interaction between MHC diversity and constitution, gut microbiota and Astrovirus infections in a neotropical bat.

Astroviruses (AstVs) infect numerous mammalian species including reservoirs such as bats. Peptides encoded by the genes of the highly polymorphic Major Histocompatibility Complex (MHC) form the first line of host defence against pathogens. Aside from direct involvement in mounting adaptive immune responses, MHC class II genes are hypothesized to regulate gut commensal diversity and shape the production of immune-modulatory substances by microbes, indirectly affecting host susceptibility. Despite initial empirical evidence for the link between host MHC and the microbiota, associations among these factors remain largely unknown. To fill this gap, we examined MHC allelic diversity and constitution, the gut bacterial community and abundance pattern of a wild population of a neotropical bat (Artibeus jamaicensis) challenged by AstV infections. First, we show an age-dependent relationship between the host MHC class II diversity and constitution and the gut microbiota in AstV-uninfected bats. Crucially, these associations changed in AstV-infected bats. Additionally, we identify changes in the abundance of specific bacterial taxa linked to the presence of certain MHC supertypes and AstV infection. We suggest changes in the microbiota to be either a result of AstV infection or the MHC-mediated modulation of microbial communities. The latter could subsequently affect microbe-mediated immunity and resistance against AstV infection. Our results emphasize that the reciprocal nature of host immune genetics, gut microbial diversity and pathogen infection require attention, which are particularly important given their repercussions for disease susceptibility and severity in wild animal populations with a history of zoonotic spillover and frequent human contact.