Chlamydia abortus is the most common known infectious cause of ovine abortion worldwide but is rarely linked with bovine abortion. The reasons for this differential pathogenesis are unknown but may involve differences in innate immune recognition and immune responsiveness. This is supported by the observation that chlamydial abortion in sheep is associated with an inflammatory cytokine/chemokine cascade that is not commonly observed in cattle. Studies with other Chlamydia species have demonstrated that innate inflammatory pathways including inflammasome activation contribute to both pathogen clearance and pathology. Pattern recognition receptors (PRRs) activate these innate immune signalling pathways but are relatively poorly characterized in ruminants. We hypothesize that the ruminant hosts differ in their ability to innately sense C. abortus infection and activate the inflammasome. The main aims of this project were to: analyse PRR expression in innate immune cells; assess cytokine production from innate immune cells in response to C. abortus; investigate the role of PRRs in the induction of innate immune responses to C. abortus; and, conduct RNA-seq analysis on macrophages following infection with C. abortus to identify important immune signalling pathways. Ruminant oro-nasal turbinate cells, monocyte derived dendritic cells (MDDCs) and monocyte derived macrophages (MDMs) express the cell-surface PRRs TLR2 and TLR4 and also the intracellular PRRs NOD 1 and NLRP3. Oro-nasal turbinate cells produce CXCL8 late into the chlamydial developmental cycle independent of IL-1β. In contrast, ruminant MDMs and MDDCs secrete early IL-1β in response to C. abortus infection. In MDMs and MDDCs, live and UV-inactivated C. abortus induced TNF-α and CXCL8 but live infection was required for IL-1β secretion. Therefore, intracellular C. abortus multiplication is necessary to stimulate the IL-1β processing pathway within these cells. In order to determine PRR function, NOD1 and NLRP3 were knocked down in ruminant MDMs using siRNA. In both ovine and bovine MDMs, NOD1 was identified as a factor in C. abortus mediated IL-1β production. NLRP3 knockdown in bovine but not ovine MDMs also reduced IL-1β production, indicating species-specific differences in C. abortus recognition. The RNA-seq analysis of ruminant MDMs identified novel pathways of immune activation by C. abortus and potentially important species-specific differences. An improved understanding of the innate immune pathways activated in susceptible and resistant hosts following C. abortus infection will inform on disease pathogenesis and could contribute to novel chlamydial vaccine design.

Cette thèse étudie les relations entre comportement spatial et parasitisme dans un contexte croissant d'interactions entre faune domestique et sauvage. Nous émettons l'hypothèse que la cohabitation du Chevreuil avec la faune domestique augmente son exposition et son infestation en parasites, ce qui modifie en retour le comportement du Chevreuil. Nos résultats montrent que (i) la cohabitation du Chevreuil avec les activités humaines augmente son exposition à Toxoplasma gondii et son infestation par des nématodes gastro-intestinaux (NGI), mais pas son exposition à Chlamydia abortus, suggérant pour ce parasite un cycle de transmission restreint aux espèces sauvages ; et (ii) que les chevreuils infestés par des NGI se dispersent moins et plus tardivement. Ce travail contribue à une meilleure compréhension de la circulation de parasites entre la faune domestique et sauvage, et souligne l'importance de considérer le comportement spatial des hôtes sauvages dans l'épidémiologie de maladies dont les effets sur la faune sauvage sont encore mal connus. / This thesis investigates the relationships between spatial behaviour and parasitism in the context of increasing interactions between wildlife and domestic animals. We hypothesise that the cohabitation of roe deer with domestic fauna increases its exposure and infestation to parasites, which modify in return the behaviour of roe deer. Our results show that (i) the cohabitation of roe deer with human activities increases its exposure to Toxoplasma gondii and its infestation by gastro-intestinal nematodes (GIN), but not its exposures to Chlamydia abortus, which suggest a possible wild cycle of transmission for this last parasite ; and (ii) roe deer infested by GIN disperse less and later. This work contributes to a better understanding of the circulation of parasites between domestic and the wild animals, and highlights the importance of considering the spatial behaviour of wild hosts in the epidemiology of diseases whose effects on wildlife are still poorly understood.