Control of Macrophage Responses to Borrelia Burgdorferi by IFNg

University Of Massachusetts Amherst, Amherst MA

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Abstract

The response of macrophages to infectious microorganisms is enhanced by interferon (IFN) g through gene expression modulation, which results in an increased ability to respond to infection, phagocytose and present antigen. We have shown that the local production of IFNg in the heart, mediated by iNKT cells, protects mice during infection with Borrelia burgdorferi (Bb), the causative agent of Lyme disease. Our preliminary data also show that a mechanism that mediates the action of IFNg in macrophages is through the repression of expression of methylation-controlled J protein (MCJ), a member of the DnaJ protein family of cochaperones. MCJ loss of expression has been implicated in the resistance of cancer cells to chemotherapeutic drugs. However, its physiological function, especially in innate immune cells is unknown. Our preliminary data show for the first time, that MCJ is a negative regulator of macrophage responses to Bb. MCJ modulates TLR-mediated responses, and regulates the surface expression of the antigen-presenting molecule CD1d. Our central hypothesis is that the cochaperone MCJ negatively regulates the expression of CD1d by macrophages and the production of IFNg by iNKT cells that infiltrate the infected heart, affecting the regulatory loop of macrophage activation. As a corollary, we propose that IFNg protects against Lyme carditis by repressing the expression of MCJ in macrophages. To test this hypothesis we intend to (aim 1) assess the modulation of Lyme carditis and the local immune response, including iNKT cell activation, in mice that lack MCJ;as well as the specific contribution of macrophage MCJ;and (aim 2) address the regulation of macrophage responses by MCJ, including their capacity to present antigens to iNKT cells, through the control of the level of proteins that mediate these responses. These studies will provide evidence of the contribution of the IFNg target, MCJ to the response of macrophages to infectious agents and the identification of potential targets of therapeutic intervention.