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Abstract Positive and balancing selection on pattern recognition receptors (PRRs) is widely thought to target ligand-binding domains and affect the specificity of recognition of different pathogens. Alternatively, positive/balancing selection on PRRs could affect general responsiveness by targeting for example signaling domains or cis-regulatory variation. Studies of a wild rodent (the bank vole, Clethrionomys glareolus) have shown that Tlr2—a lipoprotein-binding PRR—is highly polymorphic with divergent haplotypes and signatures of balancing selection and that Tlr2 genotype is associated with susceptibility to Borrelia afzelii infection in the wild. To investigate what aspect of TLR2 function has been under selection, we here perform integrated population genetic and functional analyses. Ex vivo infection experiments show that the protective Tlr2 haplotype produces a stronger proinflammatory response to B. afzelii compared to the haplotype associated with susceptibility. Tlr2 genotype has a similar, albeit not statistically significant, effect on responsiveness to the phylogenetically distant pathogen Streptococcus pyogenes. We find that the strongest signature of balancing selection is 4.6 kb upstream of the Tlr2 CDS, near a putative enhancer, and that Tlr2 exhibits allele-specific expression such that the protective haplotype is more expressed. Collectively, these results indicate that balancing selection has primarily acted on cis-regulatory variation affecting the general responsiveness via TLR2 signaling rather than on polymorphisms affecting TLR2 ligand-binding specificity.

Bank voles (Myodes glareolus syn. Clethrionomys glareolus) are frequently used as an animal model in ecological and biomedical studies and are an important reservoir of viral and bacterial zoonotic pathogens, e.g., Puumala hantavirus (PUUV). Here we describe an accidental PUUV outbreak in a large bank vole laboratory colony caused by an accidental introduction of infected wild-trapped bank voles, and the successful eradication of the virus. The eradication plan was based on results of previous studies showing that maternal antibodies (MatAb) protect the young from infection for up to 40 days after weaning, four weeks longer than the estimated duration of PUUV infectivity in the environment. After ensuring that most animals were infected, 620 pairs were mated on the same day. Only females that showed PUUV-specific antibodies and produced offspring within 26 days after mating were retained. All individuals of the parental generation were euthanized before the last weaning. The weaned offspring were moved to individually ventilated cages (IVC) and repeatedly tested for the presence of PUUV-specific antibodies and RNA. A few infected or suspect animals were euthanized. The animals were then mated (in IVC) and, after producing grand-offspring generation, euthanized and tested for PUUV RNA in the lungs. No PUUV RNA was detected, and no animals showed PUUV-specific antibodies in subsequent generations. The successful clearance confirmed the protective efficiency of PUUV-specific MatAb. The procedure for PUUV clearance in the bank vole colony may represent a blueprint for similar approaches in valuable colonies of other rodents infected by similar pathogens.

Major histocompatibility complex (MHC) genes encode proteins that initiate adaptive immune responses through the presentation of foreign antigens to T cells. The high polymorphism found at these genes, thought to be promoted and maintained by pathogen-mediated selection, contrasts with the limited number of MHC loci found in most vertebrates. Although expressing many diverse MHC genes should broaden the range of detectable pathogens, it has been hypothesized to also cause deletion of larger fractions of self-reactive T cells, leading to a detrimental reduction of the T cell receptor (TCR) repertoire. However, a key prediction of this TCR depletion hypothesis, that the TCR repertoire should be inversely related to the individual MHC diversity, has never been tested. Here, using high-throughput sequencing and advanced sequencing error correction, we provide evidence of such an association in a rodent species with high interindividual variation in the number of expressed MHC molecules, the bank vole (Myodes glareolus). Higher individual diversity of MHC class I, but not class II, was associated with smaller TCR repertoires. Our results thus provide partial support for the TCR depletion model, while also highlighting the complex, potentially MHC class-specific mechanisms by which autoreactivity may trade off against evolutionary expansion of the MHC gene family.

Microtus fortis ( M. fortis ) is the only mammal known in China that is intrinsically resistant to Schistosoma japonicum ( S. japonicum ) infection. Nevertheless, the underlying resistance mechanism of M. fortis against schistosomes are still unclear. In this study, we detected and compared colon aqueous extracts and serum metabolic profiles between M. fortis and ICR mice before and after S. japonicum infection using liquid chromatography–mass spectrometry (LC–MS). We identified 232 specific colon aqueous extract metabolites and 79 specific serum metabolites of M. fortis infected with or without S. japonicum at two weeks compared with those of ICR mice, which might be closely correlated with the time-course of schistosomiasis progression and could also be used as indicators for the M. fortis against S. japonicum , for example, nonadecanoic acid, hesperetin, glycocholic acid, 2-Aminobenzoic acid, 6-hydroxydaidzein and spermidine. And the enriched pathways were further identified, our findings revealed that S. japonicum infection induced the metabolic changes involved in a variety of metabolic pathways including amino acid metabolism, lipid metabolism, ABC transporters, central carbon metabolism in cancer and bile secretion. These results indicated that the colon aqueous extracts and serum metabolic profiles were significantly different between M. fortis and ICR mice before and after S. japonicum infection and will provide new insights into the underlying resistance mechanism of M. fortis against S. japonicum infection and identify promising candidates for the use of drugs against schistosomes.

The reed vole ( Microtus fortis ) serves as a significant rodent model, particularly distinguished by its robust natural resistance to Schistosoma japonicum infection. To unravel the genetic basis of this remarkable immunity, we present the first chromosome-level genome assembly for M. fortis . Employing PacBio HiFi long-read sequencing combined with Hi-C scaffolding, we constructed a high-quality 2.29 Gb genome. This assembly is anchored into 26 pseudomolecules, achieving a contig N50 of 68.89 Mb and incorporating 97.73% of the sequence into scaffolds. The genome demonstrates high completeness (BUSCO score 96.3%, glires_odb10) and a repeat content of 42.93%. Comparative genomic analysis revealed a high degree of synteny (95%) and a well-conserved chromosomal structure between M. fortis and Mus musculus .Phylogenetic analysis positions M. fortis diverging approximately 4.9 million years ago from other examined Microtus species and supports its classification within the Alexandromys subgenus. Notably, gene family evolution analysis identified significant expansions in immunity-related pathways. These expansions prominently involve T-cell receptor (TRAV, TRBV) and Major Histocompatibility Complex (MHC) class I and II genes. Further analysis highlighted an extensive lineage-specific expansion and diversification of the MHC class I gene family, predominantly clustered on chromosome 22. These genomic attributes, particularly the amplified T-cell receptor and MHC gene repertoires, are likely key contributors to the potent immune response and natural parasite resistance of M. fortis . This high-quality genome assembly provides an invaluable resource for advancing research into the adaptive evolution and unique biological traits of M. fortis , especially its parasite resistance mechanisms.

The reed vole, , is the only known natural non-permissive mammalian host of . However, the molecular mechanisms underlying this resistance have not been fully understood. We performed single-cell RNA-seq to investigate the peripheral blood mononuclear cells (PBMCs) responses to in and the susceptible host, Kunming mice. The samples were collected from uninfected animals (control group) and infected animals at 10 dpi. The major cell types identified in the PBMCs of the two species were monocytes, dendritic cells (DCs), T cells, NK cells, B cells, and erythrocytes. We observed that the population of monocytes decreased considerably in the bloodstream after infection in both and Kunming mice. However, differential gene expression analysis revealed that Cxcl9 was upregulated in monocytes after infection, while it was not detected as a DEG in Kunming mice. In addition, we observed that infection induced the upregulation of IL2 and IL4 in CD4+ T cells, and the expansion of the Th2 cell population. Regarding B cells, we did not observe any significant alteration among B cell subpopulations after infection compared to the control. However, DEG analysis revealed that Igha, Ighg1, and Ighg3 were upregulated in antibody secreting cells (ASCs) but not in Kunming mice. Together, our results suggest that both the innate and adaptive immune responses were activated in the peripheral blood of at 10 dpi, while their activation was not obvious in Kunming mice at the same moment.

Knowledge on the possible sources of human leptospirosis, other than rats, is currently lacking. To assess the distribution pattern of exposure and infection by Leptospira serogroups in the two main semi-aquatic rodents of Western France, coypus (Myocastor coypus) and muskrats (Ondatra zibethicus), results of micro-agglutination testing and renal tissue PCR were used. In coypus, the apparent prevalence was 11% (n = 524, CI95% = [9% - 14%]), seroprevalence was 42% (n = 590, CI95% = [38% - 46%]), and the predominant serogroup was Australis (84%). In muskrats, the apparent prevalence was 33% (n = 274, CI95% = [27% - 39%]), seroprevalence was 57% (n = 305, CI95% = [52% - 63%]), and the predominant serogroup was Grippotyphosa (47%). Muskrats should therefore be considered an important source of Grippotyphosa infection in humans and domestic animals exposed in this part of France.

Life history theory assumes there are trade-offs between competing functions such as reproduction and immunity. Although well studied in birds, studies of the trade-offs between reproduction and immunity in small mammals are scarce. Here we examined whether reduced immunity is a consequence of reproductive effort in lactating Brandt's voles (Lasiopodomys brandtii). Specifically, we tested the effects of lactation on immune function (Experiment I). The results showed that food intake and resting metabolic rate (RMR) were higher in lactating voles (6≤ litter size ≤8) than that in non-reproductive voles. Contrary to our expectation, lactating voles also had higher levels of serum total Immunoglobulin G (IgG) and anti-keyhole limpet hemocyanin (KLH) IgG and no change in phytohemagglutinin (PHA) response and anti-KLH Immunoglobulin M (IgM) compared with non-reproductive voles, suggesting improved rather than reduced immune function. To further test the effect of differences in reproductive investment on immunity, we compared the responses between natural large (n≥8) and small litter size (n≤6) (Experiment II) and manipulated large (11-13) and small litter size (2-3) (Experiment III). During peak lactation, acquired immunity (PHA response, anti-KLH IgG and anti-KLH IgM) was not significantly different between voles raising large or small litters in both experiments, despite the measured difference in reproductive investment (greater litter size, litter mass, RMR and food intake in the voles raising larger litters). Total IgG was higher in voles with natural large litter size than those with natural small litter size, but decreased in the enlarged litter size group compared with control and reduced group. Our results showed that immune function is not suppressed to compensate the high energy demands during lactation in Brandt's voles and contrasting the situation in birds, is unlikely to be an important aspect mediating the trade-off between reproduction and survival.

The discovery of the key role of Toll-like receptors (TLRs) in initiating innate immune responses and modulating adaptive immunity has revolutionized our understanding of vertebrate defence against pathogens. Yet, despite their central role in pathogen recognition and defence initiation, there is little information on how variation in TLRs influences disease susceptibility in natural populations. Here, we assessed the extent of naturally occurring polymorphisms at TLR2 in wild bank voles (Myodes glareolus) and tested for associations between TLR2 variants and infection with Borrelia afzelii, a common tick-transmitted pathogen in rodents and one of the causative agents of human Lyme disease. Bank voles in our population had 15 different TLR2 haplotypes (10 different haplotypes at the amino acid level), which grouped in three well-separated clusters. In a large-scale capture–mark–recapture study, we show that voles carrying TLR2 haplotypes of one particular cluster (TLR2c2) were almost three times less likely to be Borrelia infected than animals carrying other haplotypes. Moreover, neutrality tests suggested that TLR2 has been under positive selection. This is, to our knowledge, the first demonstration of an association between TLR polymorphism and parasitism in wildlife, and a striking example that genetic variation at innate immune receptors can have a large impact on host resistance.

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.