After pathogen recognition, macrophages initiate an inflammatory response, a critical event that orchestrates both the innate and adaptive immune responses to pathogens. Whereas inflammation is required for a productive immune response, inflammation in excess can cause pathological consequences, including tissue damage, inflammatory and autoimmune disease, or, in its most severe form, systemic shock. Therefore, appropriate control of the inflammatory response is essential for pathogen clearance and protection from excessive inflammation. B cell adapter for PI3-kinase (BCAP) is a novel negative regulator of macrophage inflammatory responses induced by Toll-like receptors through its ability to activate PI3K. BCAP also inhibits innate immune responses to Listeria monocytogenes (Lm) infection, highlighting the detrimental aspects of inhibitors of inflammation to bacterial clearance. In comparison with wild-type mice, mice lacking BCAP had increased clearance of systemic Lm infection, and a dramatic increase in inflammatory monocyte accumulation in the spleen, which we hypothesize results in the increased clearance of bacteria. BCAP also regulates splenic monocyte accumulation during infection with Salmonella enterica serovar Typhimurium. Therefore, BCAP is a key modulator of innate responses to bacterial infection.
The aims of this proposal seek to better understand the mechanisms by which BCAP regulates the innate immune response to infection with Lm.
In Aim 1, we will define the specific mechanisms by which BCAP inhibits TLR signaling, testing whether BCAP uses Flii and/or Lrrfip2, p110beta and Foxo1 to inhibit TLR responses. We will also test whether BCAP similarly inhibits TLR responses in human monocytes through activation of PI3K.
In Aim 2, we will determine how BCAP regulates inflammatory monocyte accumulation during and Lm clearance in vivo. We will examine 1) whether BCAP-deficiency in inflammatory monocytes is required for increased clearance of Lm and increased accumulation of splenic monocytes, 2) whether BCAP regulates monocyte accumulation by affecting cell proliferation and/or survival, and 3) if increasing PI3K activity in monocytes can reverse the phenotype of BCAP-/- mice during Lm infection. We will also extend these studies to infection with Salmonella Typhimurium. Together, these experiments will give a comprehensive view of how BCAP controls monocyte responses to bacterial infections of clinical importance. Understanding the mechanisms by which BCAP regulates inflammation will define how to therapeutically target the BCAP signaling axis for the control of infection and inflammatory diseases.
Macrophages and monocytes are critical components of the early immune response to bacterial infection through the initiation of inflammation. This proposal investigates one mechanism that controls the inflammatory response and how it affects the immune response to the foodborne bacterial pathogens, Listeria monocytogenes and Salmonella enterica serovar Typhimurium.
