Cooption of Innate Immune Cells in Promoting and Combating Infections

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2018

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Abstract

The key components of innate immune defense to pathogens are various migratory as well as tissue resident innate immune cells, however, their interactions with pathogens as well as their immune-orchestrating roles are often poorly understood. While immune cells encounter pathogens at barrier sites and mount the first line of defense, pathogens are well adapted to bypass, inactivate and even exploit the functions of these cells. Better understanding of the interactions between pathogens and innate immune cells can teach us how pathogens avoid or exploit immune cells and how to overcome these mechanisms of pathogenesis by therapeutic interventions. In this work, we examined two scenarios of pathogen invasion and sought to understand the complex ways of external targeting of innate immunocytes that can either benefit the pathogen or the host.

First, we studied the migratory innate immunocytes in draining lymph nodes upon entry of Yersinia pestis via the skin and identified how this plague-causing bacterium coopted host cell death pathways of infiltrated mononuclear phagocytes. By employing time-lapse microscopy and flow cytometry, we demonstrated that within the confines of infected lymph nodes, bacteria-triggered necroptotic cell death resulted in the release of intracellular bacteria into the extracellular environment and attracted neighboring phagocytic cells, promoting their infection by these recently released bacteria. This expansion of bacteria-bearing immune cells which eventually migrate to secondary lymph nodes, enables large numbers of Y. pestis to disseminate from one node to the next via the lymphatic system. We show this mechanism of dissemination being essential for the transition of plague from a bubonic to septicemic stage and demonstrate immunotherapeutic potential of necroptosis inhibitors.

Next, we focused on mast cells, a resident innate immunocyte in the context of skin infection by Staphylococcus aureus. We showed that connective tissue mast cells promoted recruitment of neutrophils at the early stage and CD301b+ dendritic cells at the later stages of infection, which played critical roles in infection control and repair, respectively. We further demonstrated that exogenous activation of skin mast cells via a mast cell-specific G protein-coupled receptor controlled infection as well as enhanced mobilization of dendritic cells to draining lymph nodes in a mast-cell dependent manner and protected mice from re-infection. Therefore, selective activation of mast cells appears to orchestrate immunomodulation integrating both the innate and adaptive immune arms.

These studies reveal the yin and yang of innate immune cells in two very different infectious settings. They emphasize how different strategies to target these cells at the immune checkpoints can be beneficial for host-directed therapy against bacterial infections.

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Arifuzzaman, Mohammad (2018). Cooption of Innate Immune Cells in Promoting and Combating Infections. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/18241.

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