Mycobacterium tuberculosis Acetyltransferase Suppresses Oxidative Stress by Inducing Peroxisome Formation in Macrophages.

Ananyaashree Behera,Mohd Saqib,Ulrich E Schaible,Bibhuti B Mishra,Kali Prasad Pattanaik,Süleyman Ergün,Mainak Biswas,Srikanth Karnati,Natalja Redinger,Kristine Hagens,Barsa Nayak,Avinash Padhi,Avinash Sonawane,Geetanjali Ganguli,Preeti Jain

doi:10.3390/ijms23052584

Abstract

Mycobacterium tuberculosis (Mtb) inhibits host oxidative stress responses facilitating its survival in macrophages; however, the underlying molecular mechanisms are poorly understood. Here, we identified a Mtb acetyltransferase (Rv3034c) as a novel counter actor of macrophage oxidative stress responses by inducing peroxisome formation. An inducible Rv3034c deletion mutant of Mtb failed to induce peroxisome biogenesis, expression of the peroxisomal β-oxidation pathway intermediates (ACOX1, ACAA1, MFP2) in macrophages, resulting in reduced intracellular survival compared to the parental strain. This reduced virulence phenotype was rescued by repletion of Rv3034c. Peroxisome induction depended on the interaction between Rv3034c and the macrophage mannose receptor (MR). Interaction between Rv3034c and MR induced expression of the peroxisomal biogenesis proteins PEX5p, PEX13p, PEX14p, PEX11β, PEX19p, the peroxisomal membrane lipid transporter ABCD3, and catalase. Expression of PEX14p and ABCD3 was also enhanced in lungs from Mtb aerosol-infected mice. This is the first report that peroxisome-mediated control of ROS balance is essential for innate immune responses to Mtb but can be counteracted by the mycobacterial acetyltransferase Rv3034c. Thus, peroxisomes represent interesting targets for host-directed therapeutics to tuberculosis.

Highlights

Mycobacterium tuberculosis (Mtb), the most infectious pathogen, is accountable for significant morbidity and mortality worldwide
Immunofluorescence imaging of lung tissue sections showed a significant increase in the expression of peroxisomal lipid transporter ABCD3 and marker protein for peroxisomes PEX14p, which are responsible for the transport of cargo proteins and enzymes in peroxisomes, as compared to uninfected lungs (p ≤ 0.01, p ≤ 0.05, Figure 1A)
In Msm-Rv3034c- and Msm-pSMT3-infected cells. These results demonstrate that the Mtb Rv3034c–mannose receptor (MR) interaction modulates the expression of peroxisomal proteins during Mtb infection

Summary

Introduction

Mycobacterium tuberculosis (Mtb), the most infectious pathogen, is accountable for significant morbidity and mortality worldwide. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains are posing a huge challenge on the control of TB [3]. Mtb is phagocytosed by alveolar macrophages, which are equipped with various antibacterial effector mechanisms to eliminate the intracellular pathogens, such as the production of reactive oxygen intermediates (ROI), reactive nitrogen intermediates (RNI), and proinflammatory cytokines, and the induction of autophagy. Mtb has evolved diverse evasion strategies to subvert the immune and metabolic responses, avoiding being killed by the hostile intracellular microenvironment of the host cells [4]. Studies have revealed distinct phenotypic heterogeneity of macrophages associated with functional plasticity, allowing differential responses and changes of their intracellular microenvironment depending on the Mtb strain encountered [5]

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