Michal Olszewski, D.V.M., Ph.D.
Cryptococcus neoformans is an opportunistic pathogen that is capable of establishing a chronic pulmonary infection in immunocompromised hosts, including AIDS patients, transplant recipients, and recently, patients being treated with TNFα antagonist therapies. An early TNFα response is critical to the establishment of a protective cell mediated immune response. Previous work with C. neoformans infection during anti-TNFα treatment has shown that a single dose of anti-TNFα antibody at the time of infection is sufficient to skew the immune response from a protective Th1 response, which results in fungal clearance, to a non-protective Th2 response, which results in a chronic infection. The mechanism by which this occurs is unknown. My thesis project will examine the effects of TNFα antagonists on dendritic cells in the context of C. neoformans infection, including early changes in maturation and activation, epigenetic regulation and immune training, changes in DC trafficking to lymph nodes, and DC-T cell interactions in the lung and lymph node. I hypothesize that anti-TNFα antibodies exert their effects both through blocking TNFα signaling to receptors and through “reverse signaling” through transmembrane TNFα resulting in epigenetic changes. To accomplish this, I plan to utilize both in vivo, and in vitro techniques including infection of WT and modified mice, protein and mRNA analysis, live animal imaging studies, mathematical modeling of cytokine network during infection, and possibly, analysis of epigenetic changes through ChIP assays and ChIPseq. I plan to analyze the effects of a-TNF on DC in vitro and use adoptive transfer experiments to link the effects of a-TNF with the specific cell susbest(s).
Rackham Conference Travel Grant, University of Michigan, 2012