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Since its introduction to control overabundant invasive European rabbits (Oryctolagus cuniculus), the highly virulent rabbit haemorrhagic disease virus (RHDV) has caused regular annual disease outbreaks in Australian rabbit populations. Although initially reducing rabbit abundance by 60%, continent���wide, experimental evidence has since indicated increased genetic resistance in wild rabbits that have experienced RHDV���driven selection. To identify genetic adaptations, which explain the increased resistance to this biocontrol virus, we investigated genome���wide SNP (single nucleotide polymorphism) allele frequency changes in a South Australian rabbit population that was sampled in 1996 (pre���RHD genomes) and after 16 years of RHDV outbreaks. We identified several SNPs with changed allele frequencies within or close to genes potentially important for increased RHD resistance. The identified genes are known to be involved in virus infections and immune reactions or had previously been identified as being differentially expressed in healthy versus acutely RHDV���infected rabbits. Furthermore, we show in a simulation study that the allele/genotype frequency changes cannot be explained by drift alone and that several candidate genes had also been identified as being associated with surviving RHD in a different Australian rabbit population. Our unique data set allowed us to identify candidate genes for RHDV resistance that have evolved under natural conditions, and over a time span that would not have been feasible in an experimental setting. Moreover, it provides a rare example of host genetic adaptations to virus���driven selection in response to a suddenly emerging infectious disease., publishedVersion

Microbial infections are most often countered by inflammatory responses that are initiated through the recognition of conserved microbial products by innate immune receptors and result in pathogen expulsion1-6. However, inflammation can also lead to pathology. Tissues such as the intestinal epithelium, which are exposed to microbial products, are therefore subject to stringent negative regulatory mechanisms to prevent signalling through innate immune receptors6-11. This presents a challenge to the enteric pathogen Salmonella Typhimurium, which requires intestinal inflammation to compete against the resident microbiota and to acquire the nutrients and electron acceptors that sustain its replication12,13. We show here that S. Typhimurium stimulates pro-inflammatory signalling by a unique mechanism initiated by effector proteins that are delivered by its type III protein secretion system. These effectors activate Cdc42 and the p21-activated kinase 1 (PAK1) leading to the recruitment of TNF receptor-associated factor 6 (TRAF6) and mitogen-activated protein kinase kinase kinase 7 (TAK1), and the stimulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inflammatory signalling. The removal of Cdc42, PAK1, TRAF6 or TAK1 prevented S. Typhimurium from stimulating NF-κB signalling in cultured cells. In addition, oral administration of a highly specific PAK inhibitor blocked Salmonella-induced intestinal inflammation and bacterial replication in the mouse intestine, although it resulted in a significant increase in the bacterial loads in systemic tissues. Thus, S. Typhimurium stimulates inflammatory signalling in the intestinal tract by engaging critical downstream signalling components of innate immune receptors. These findings illustrate the unique balance that emerges from host-pathogen co-evolution, in that pathogen-initiated responses that help pathogen replication are also important to prevent pathogen spread to deeper tissues.

Consistent patterns of positive selection in functionally similar genes can suggest a common selective pressure across a group of species. We use alignments of orthologous protein-coding genes from 39 species of birds to estimate parameters related to positive selection for 11,000 genes conserved across birds. We show that functional pathways related to the immune system, recombination, lipid metabolism, and phototransduction are enriched for positively selected genes. By comparing our results with mammalian data, we find a significant enrichment for positively selected genes shared between taxa, and that these shared selected genes are enriched for viral immune pathways. Using pathogen-challenge transcriptome data, we show that genes up-regulated in response to pathogens are also enriched for positively selected genes. Together, our results suggest that pathogens, particularly viruses, consistently target the same genes across divergent clades, and that these genes are hotspots of host-pathogen conflict over deep evolutionary time.

Natural killer (NK) cells innate immune cells that play a crucial role against viral infections and tumors. To be tolerant against healthy tissue and simultaneously attack infected cells, the activity of NK cells must be tightly regulated. Unlike B and T cells, NK cell do not undergo DNA rearrangements to generate a diverse repertoire of cell surface receptors. Instead, NK cells use a sophisticated array of germline-encoded activating and inhibiting receptors. The best characterized mechanism of NK cell activation is “missing self” detection, i.e. the recognition of virally infected or transformed cells that reduce their MHC expression to evade cytotoxic T cells. To monitor the expression of MHC-I on target cells, NK cells have monomorphic inhibitory receptors which interact with conserved MHC molecules. However, there are other NK cell receptors (NKRs) encoded by gene families showing a remarkable genetic diversity. Thus, NKR haplotypes contain several genes encoding for receptors with activating and inhibiting signaling, and that vary in gene content and allelic polymorphism. But if missing-self detection can be achieved by a monomorphic NKR system why have these polygenic and polymorphic receptors evolved? In this thesis, we use computational evolutionary modelling, data analysis, and mathematical modelling to answer the question of why NK cell receptors have evolved to become specific, polygenic, and polymorphic. We propose that NKRs might have possibly diversified due to the selection pressure imposed by the successful immunoevasive mechanisms evolved by several pathogens. We focus on different hypotheses related to viral evasion mechanisms, i.e. we study the effects of viral evolution of MHC-decoys, and selective MHC down-regulation on the evolution of NK cell receptors. Additionally, we study whether NKRs should diversify to be able to detect peptides of viral origin presented on MHC molecules. We find that NK cell receptors evolve to become specific to distinguish self from non-self and that the required specificity selects for the evolution of polygenicity and polymorphism. The degree of the evolved genetic diversity varies depending on the viral strategy used to escape the NK cell response. While our studies suggest that selective MHC downregulation and peptide sensitivity can drive the evolution of polygenic haplotypes encoding NK cell receptors, the highest genetic diversity evolves in host populations infected with viruses that readily evolve MHC-like decoys. The results in this thesis shed light on the evolutionary processes of NK cell receptors, providing plausible explanations for this fascinating complex system.

Natural killer (NK) cells innate immune cells that play a crucial role against viral infections and tumors. To be tolerant against healthy tissue and simultaneously attack infected cells, the activity of NK cells must be tightly regulated. Unlike B and T cells, NK cell do not undergo DNA rearrangements to generate a diverse repertoire of cell surface receptors. Instead, NK cells use a sophisticated array of germline-encoded activating and inhibiting receptors. The best characterized mechanism of NK cell activation is “missing self” detection, i.e. the recognition of virally infected or transformed cells that reduce their MHC expression to evade cytotoxic T cells. To monitor the expression of MHC-I on target cells, NK cells have monomorphic inhibitory receptors which interact with conserved MHC molecules. However, there are other NK cell receptors (NKRs) encoded by gene families showing a remarkable genetic diversity. Thus, NKR haplotypes contain several genes encoding for receptors with activating and inhibiting signaling, and that vary in gene content and allelic polymorphism. But if missing-self detection can be achieved by a monomorphic NKR system why have these polygenic and polymorphic receptors evolved? In this thesis, we use computational evolutionary modelling, data analysis, and mathematical modelling to answer the question of why NK cell receptors have evolved to become specific, polygenic, and polymorphic. We propose that NKRs might have possibly diversified due to the selection pressure imposed by the successful immunoevasive mechanisms evolved by several pathogens. We focus on different hypotheses related to viral evasion mechanisms, i.e. we study the effects of viral evolution of MHC-decoys, and selective MHC down-regulation on the evolution of NK cell receptors. Additionally, we study whether NKRs should diversify to be able to detect peptides of viral origin presented on MHC molecules. We find that NK cell receptors evolve to become specific to distinguish self from non-self and that the required specificity selects for the evolution of polygenicity and polymorphism. The degree of the evolved genetic diversity varies depending on the viral strategy used to escape the NK cell response. While our studies suggest that selective MHC downregulation and peptide sensitivity can drive the evolution of polygenic haplotypes encoding NK cell receptors, the highest genetic diversity evolves in host populations infected with viruses that readily evolve MHC-like decoys. The results in this thesis shed light on the evolutionary processes of NK cell receptors, providing plausible explanations for this fascinating complex system.

A major goal in infectious disease research is to identify the genetic variants—both human and pathogenic—that explain the observed differences in human response to microbial pathogenesis. Neither pathogenic strain nor human genetic variation in isolation has proven adequate to explain the heterogeneity of disease pathology. We suggest that disrupted coevolution between a pathogen and its human hosts can explain variation in disease outcomes, and that genome-by-genome interactions should therefore be incorporated into genetic models of disease caused by infectious agents. Genetic epidemiological studies that fail to take both the pathogen and host into account can lead to false and misleading conclusions about disease etiology. We discuss our model in the context of three pathogens, Helicobacter pylori, Mycobacterium tuberculosis and Human papillomavirus, and generalize the conditions under which it may be applicable.

International audience; Fungal species belonging to the genus Melampsora (Basidiomycota, Pucciniales) comprise rust pathogens that alternate between Salicaceae and other plant hosts. Species delineation and identification are difficult within this group due to the paucity of observable morphological features. Several Melampsora rusts are highly host-specific and this feature has been used for identification at the species level. However, this criterion is not always reliable since different Melampsora rust species can overlap on one host but specialize on a different one. To date, two different species recognition methods are used to recognize and define species within the Melampsora genus: (i) morphological species recognition, which is based solely on morphological criteria; and (ii) ecological species recognition, which combines morphological criteria with host range to recognize and define species. In order to clarify species recognition within the Melampsora genus, we applied phylogenetic species recognition to Melampsora poplar rusts by conducting molecular phylogenetic analyses on 15 Melampsora taxa using six nuclear and mitochondrial loci. By assessing the genealogical concordance between phylogenies, we identified 12 lineages that evolved independently, corresponding to distinct phylogenetic species. All 12 lineages were concordant with host specialization, but only three belonged to strictly defined morphological species. The estimation of the species tree obtained with Bayesian concordance analysis highlighted a potential co-evolutionary history between Melampsora species and their reciprocal aecial host plants. Within the Melampsora speciation process, aecial host may have had a strong effect on ancestral evolution, whereas telial host specificity seems to have evolved more recently. The morphological characters initially used to define species boundaries in the Melampsora genus are not reflective of the evolutionary and genetic relationships among poplar rusts. In order to construct a more meaningful taxonomy, host specificity must be considered an important criterion for delineating and describing species within the genus Melampsora as previously suggested by ecological species recognition.