PROJECT SUMMARY Tuberculosis (TB) remains a leading global health problem with about 9 million new tuberculosis cases and nearly 1.3 million TB-related deaths worldwide each year. Drug-resistant Mycobacterium tuberculosis (Mtb) makes TB an even more difficult challenge for current anti-Mtb therapy. Persistence of Mtb infection in macrophages is mediated by suppression of host immune responses. The mechanisms of immune suppression by Mtb, however, are still poorly understood. Our preliminary data indicate a new RNA-binding protein, monocyte chemotactic protein-induce protein 1 (MCPIP1) is such a protein for immune evasion of Mtb. MCPIP1 is rapidly induced in macrophages in response to inflammatory stimuli such as TNF, IL-1β and LPS. MCPIP1-deficient mice develop complex phenotypes, including autoimmune disorders and severe inflammatory responses. MCPIP1 inhibits several proinflammatory cytokines (including IL-1, IL-6 and IL-12), and also acts like a brake for T cell activation. So far, MCPIP1 has been shown by us and others to be a negative regulator in controlling inflammation and maintaining homeostasis. However, it remains largely unknown whether MCPIP1 affects Mtb replication or involves in control of TB activation. We have recently found that MCPIP1 knockout mice infected with Mtb via the aerosol route have a significant reduction of bacterial burden compared with wild type mice, along with an increase in MCPIP1 expression in lungs of the WT mice. Interestingly, MCPIP1 mRNA levels are significantly higher in caseous granulomas of active TB patients than normal lung parenchyma. Moreover, MCPIP1 mRNA levels are also significantly increased in lungs of rhesus macaques with active and reactive TB as well as those with latent TB. Based on our discovery, we propose that virulent Mycobacterium tuberculosis evades host immune attack by inducing MCPIP1 which suppresses anti-TB immune responses. In this application, we propose to (1) understand the mechanisms of MCPIP1 induction by Mtb and subsequent effects on Mtb infection; (2) define in vivo role of macrophage- derived MCPIP1 in preventing optimal control of mycobacterial growth and the translational potential for host- directed therapy. Results of this study will provide us a better understanding of TB immune evasion and therapeutic potential of MCPIP1-targeted therapy in treatment of Mtb infection, especially those patients infected with MDR stains of mycobacteria.

PROJECT NARRATIVE This proposal will elucidate the mechanisms by which Mtb induces MCPIP1 and MCPIP1-mediated immune suppression, and ultimately to develop therapeutic approaches that could be used to target MCPIP1 in macrophages to enhance effective TB immunotherapies.