Mycobacterium tuberculosis PE_PGRS38 Enhances Intracellular Survival of Mycobacteria by Inhibiting TLR4/NF-κB-Dependent Inflammation and Apoptosis of the Host.

Simple Summary: PE_PGRS38 is a member of the PE/PPE protein family of M. tuberculosis. PE_PGRS members are unique, restricted to virulent mycobacteria, and their role in host–pathogen interactions is not yet fully elucidated. In this study, we constructed recombinant strains of M. smegmatis expressing the PE_PGRS38 protein of M. tuberculosis. Using in vitro and in vivo infection models, we investigated the role of PE_PGRS38 in host–pathogen interactions and the pathogenicity of tuberculosis. PE_PGRS38 enhanced the intracellular survival of recombinant M. smegmatis by downregulating proinflammatory responses. PE_PGRS38 also inhibited inflammation, the inflammasome, and apoptosis in RAW264.7 cells during infection. Similarly, PE_PGRS38 inhibited the expression level of TLR4 and NF-ĸB in the lungs of infected mice. These findings indicate that PE_PGRS38 is a potential virulence factor that contributes to pathogenicity by evading the host's immune responses and could aid in the development of antimycobacterial drugs and vaccines. Mycobacterium tuberculosis (Mtb) ranks as the most lethal human pathogen, able to fend off repeated attacks by the immune system or medications. PE_PGRS proteins are hallmarks of the pathogenicity of Mtb and contribute to its antigenic diversity, virulence, and persistence during infection. M. smegmatis is a nonpathogenic mycobacterium that naturally lacks PE_PGRS and is used as a model to express Mtb proteins. PE_PGRS has the capability to evade host immune responses and enhance the intracellular survival of M. smegmatis. Despite the intense investigations into PE_PGRS proteins, their role in tuberculosis remains elusive. We engineered the recombinant M. smegmatis strain Ms-PE_PGRS38. The result shows that PE_PGRS38 is expressed in the cell wall of M. smegmatis. PE_PGRS38 contributes to biofilm formation, confers permeability to the cell wall, and shows variable responses to exogenous stresses. PE_PGRS38 downregulated TLR4/NF-κB signaling in RAW264.7 macrophages and lung tissues of infected mice. In addition, PE_PGRS38 decreased NLRP3-dependent IL-1β release and limited pathogen-mediated inflammasome activity during infection. Moreover, PE_PGRS38 inhibited the apoptosis of RAW264.7 cells by downregulating the expression of apoptotic markers including Bax, cytochrome c, caspase-3, and caspase-9. In a nutshell, our findings demonstrate that PE_PGRS38 is a virulence factor for Mtb that enables recombinant M. smegmatis to survive by resisting and evading the host's immune responses during infection. [ABSTRACT FROM AUTHOR]