Modulation of macrophage defense responses by Mycobacterial persistence protein MprA (Rv0981) in human THP-1 cells: effect of single amino acid variation on host-pathogen interactions

Abstract

M. tuberculosis is one of the most successful human pathogens causing tuberculosis that leads to highest daily morbidity worldwide. The evasion of the host immune responses is an important strategy that M. tuberculosis adopts. MprA (Rv0981), the response regulator of two component system is known for DNA binding activity in the pathogen and its role in persistent infection in the host. MprA is recognized as a late stage antigen during infection. A variant form of the protein MprA with G70S polymorphism (MprA*) is observed in one of our local and in several global clinical isolates of M. tuberculosis. Here we report the nuclear localization of MprA and MprA* in differentiated macrophages. MprA and MprA* increase the expression of TGF-β and IL-10, the immune suppressive cytokines in THP-1 derived macrophage cells. Concurrently the phago-lysosome fusion is significantly reduced as shown by infection with M.bovis BCG. We show that single nucleotide variation in clinical isolates lead to quantitative variations resulting in host immune suppression and support the survival and persistence of the pathogen.