Inflammation is a physiological process whereby immune cell populations are recruited from the blood into body tissues. In the context of an acute infection or injury, these recruited immune cells seek out and destroy invading pathogens, remove dead cells and debris, and promote repair to the damaged tissue. However, when inflammatory cells are present in excessive numbers or are activated inappropriately, they themselves cause damage to host tissue. Such excessive or prolonged inflammation contributes to considerable illness and death. This is true not just in individuals with chronic infections but also in the context of diverse chronic diseases not necessarily caused by infections - such as cancers, cardiovascular, and neurodegenerative diseases.
Given the clinical relevance of excessive inflammation, a key underlying goal of the research in our laboratory is to discover and better understand molecular mechanisms that shape the activity of inflammatory immune cells. This information is vital for devising new therapeutic approaches that can be used to prevent or treat excessive inflammation.
Research in the lab uses a variety of infection models and focuses on specific inflammatory/immune cell types. These include myeloid cells (monocytes, neutrophils, dendritic cells and macrophages) and innate lymphocytes (natural killer, or “NK” cells). We study how these cells decide to secrete molecules such as cytokines that can promote or dampen inflammation. We also study at the molecular level how the response of inflammatory cells to these activating or inhibitory molecules is regulated. Several of our published studies have revealed interplay of type I and II interferons, mechanisms for and the impact of regulating interferon receptor expression in myeloid and other cells, and the importance and regulation of interleukin-10 (IL-10) production by NK cells.
A more unique aspect of the work that we do and a major current focus in the lab involves our efforts to define how proteins secreted by pathogenic or commensal microbes target immune cells to “steer” their activity to dampen host inflammatory responses.
One aspect of this work involves efforts to understand how the bacterial pathogen Listeria monocytogenes targets specific myeloid cell types to steer immune cell activity and dampen inflammation. L. monocytogenes is a common food contaminant that causes severe infections in a subset of vulnerable individuals. It is also amongst the most widely used model pathogens due to its ability to elicit robust and reproducible immune responses in mice and other animal hosts. Using wildtype and mutant L. monocytogenes we have identified a protein that the bacterium uses to target dendritic cells (DC), a myeloid cell population that plays a central role in the regulation of inflammatory and immune responses. Streptococcus pneumoniae and other commensal or probiotic bacteria produce somewhat homologous proteins, some of which we and others have found can also dampen inflammatory responses. Ongoing efforts in the lab seek to discern how these proteins bind and trigger anti-inflammatory responses in DCs or other myeloid cell types.
A second area of ongoing research in the lab builds on our expertise in animal models and cytokine biology and several unique reagents to study how an initial exposure to infection or non-infectious immune stimuli exerts prolonged antigen-independent effects to influence the outcome of subsequent mucosal infections by L. monocytogenes, S. pneumoniae, or influenza A virus.
