Our lab focuses on the molecular nature of innate immune interactions between microbial pathogens and the host. Pathogenic bacteria have evolved complex mechanisms to subvert host cell immune responses and host cell signaling pathways. Our work focuses on uncovering the molecular signaling events that occur during bacterial infection of host cells. Endotoxin - bacterial lipopolysaccharide (LPS) - is a driver of the lethal infection sepsis through activation of innate immune responses; we investigate innate immune responses to bacterial LPS that is presented in the cytosol of human cells during infection. We investigate the molecular mechanisms by which bacterial lipopolysaccharide and secreted bacterial proteins modulate host proteins to divert host signaling pathways involved in innate immune responses to LPS.
When delivered to the cytosol of macrophages, LPS (cLPS) induces the assembly of an inflammasome that contains caspases-4/5 in humans or caspase-11 in mice. Whereas activation of all other inflammasomes is triggered by sensing of pathogen products by a specific host cytosolic pattern recognition receptor protein, whether pattern recognition receptors for cLPS exist has been doubted by many investigators, as caspases-4, -5, and -11 bind and activate LPS directly in vitro. We discovered that NLRP11 is a pattern recognition receptor for bacterial lipopolysaccharide in the cytosol of human macrophages. NLRP11 is primate-specific and absent in mice, likely explaining why it has been missed in screens looking for innate immune signaling molecules, most of which have been carried out in mice. NLRP11 is a previously missing link and a component of the human caspase-4 inflammasome activation pathway.
In addition, we investigate the mechanisms of immune dysfunction during severe infection of humans. We focus on the mechanisms that lead to immune dysregulation in bacterial sepsis, a major contributor to the disease process and to adverse outcomes. I am PI of a multidisciplinary group that is identifying transcriptional signatures in humans presenting with sepsis. Using single cell RNA sequencing, we discovered a novel monocyte state (MS1) that is expanded in bacterial sepsis and severe COVID-19, suppresses T cell responses, and is marked by high transcription of several genes that encode proteins that we hypothesize contribute to immune dysregulation and vascular leak in these clinical syndromes. We are investigating whether MS1 cells contribute directly or via signaling pathways to the pathogenesis of bacterial sepsis.
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