Anti-Bacterial Immune Regulation – Abir

Infections by intracellular bacterial pathogens of the genus Salmonella spp. and Listeria spp. remain leading causes of foodborne illnesses. For instance, typhoid fever, a disease caused by Salmonella typhi affects about 16 million people and causes 500,000 to 600,000 deaths each year. Listeria infection is of great concern for pregnant women, the elderly, and immunocompromised patients. In such individuals it can cause listeriosis, a disease with fatal outcome in 20-30% of cases. Listeria infection is also amongst the leading causes of stillbirth. These infections can usually be treated by chemotherapy, but the accelerating emergence of multidrug-resistant strains constitutes a recurrent threat. This raises the need for the development of novel preventive and therapeutic tools, including vaccines, as well as for the identification of biomarkers permitting the stratification of patients according to their susceptibility to the most severe forms of these diseases. A better understanding of the interactions between the host immune system and these pathogens will help to meet these needs. It is accepted that mononuclear phagocytes, as well as T and B cells play critical roles in host defense during these infections, yet
outstanding gaps remain in our knowledge of how this cellular network contributes to control of these pathogens. In particular, the molecular mechanisms used by monocytes/macrophages to restrict bacterial growth in vivo remain incompletely understood, due to the lack of a technology enabling a global view of the transcriptome expressed by these phagocytes in their physiological context upon infection. Although the development of effective vaccines requires targeting of antigen(s) to the relevant antigen-presenting cell sub-populations in vivo, the roles of individual dendritic cell (DC) subsets for the
induction of protective effector and memory T cell responses to Salmonella and Listeria has received little attention. Finally, the impact of the inhibitory activities of B cells, which have recently emerged as powerful negative regulators of anti-microbial immunity, via cytokine-mediated suppression of mononuclear phagocytes, is still poorly understood. To approach these issues, and obtain a better view of host-pathogen interactions we have assembled a consortium that integrates unique expertise in biology of monocyte/macrophages, DC, B cells, and intracellular bacterial pathogens. State-of-the-art approaches will be developed to provide - at an unprecedented level of resolution - a global picture of the molecular and cellular pathways involved in anti-microbial immunity against intracellular bacterial pathogens, and to derive therapeutic tools.