The Mycobacterium tuberculosis PE proteins Rv0285 and Rv1386 modulate innate immunity and mediate bacillary survival in macrophages

• Published in: PloS one 2012-12, Vol.7 (12), p.e51686-e51686
• Main Authors: Tiwari, Bhavana Mishra, Kannan, Nisha, Vemu, Lakshmi, Raghunand, Tirumalai R
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Apoptosis; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biology; Blotting, Western; Cell Proliferation; Cell Survival; Cytokines; Cytokines - metabolism; Deoxyribonucleic acid; DNA; E coli; Extracellular signal-regulated kinase; Flow Cytometry; Gene expression; Genes; Genomes; Genomics; Health aspects; Host-Pathogen Interactions; Humans; Immune response; Immune system; Immunity; Immunity, Innate; Infections; Inflammation; Innate immunity; Interleukin 10; Kinases; Lymphocytes T; Macrophages; Macrophages - cytology; Macrophages - immunology; Macrophages - microbiology; MAP Kinase Signaling System; Medicine; Molecular biology; Molecular Sequence Data; Mycobacterium smegmatis; Mycobacterium tuberculosis; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - immunology; Nitric oxide; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; p38 Mitogen-Activated Protein Kinases; Pathogenesis; Pharmacology; Phosphorylation; Phylogeny; Proteins; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Sequence Homology, Amino Acid; Survival; Transcription; Tuberculosis; Tuberculosis - immunology; Tuberculosis - microbiology; Virulence - immunology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0051686

The unique PE/PPE multigene family of proteins occupies almost 10% of the coding sequence of Mycobacterium tuberculosis (M.tb), the causative agent of human tuberculosis. Although some members of this family have been shown to be involved in pathways essential to M.tb pathogenesis, their precise physiological functions remain largely undefined. Here, we investigate the roles of the conserved members of the 'PE only' subfamily Rv0285 (PE5) and Rv1386 (PE15) in mediating host-pathogen interactions. Recombinant Mycobacterium smegmatis strains expressing PE5 and PE15 showed enhanced survival vs controls in J774.1 and THP-1 macrophages - this increase in viable counts was correlated with a reduction in transcript levels of inducible nitric oxide synthase. An up-regulation of anti- and down-regulation of pro-inflammatory cytokine levels was also observed in infected macrophages implying an immuno-modulatory function for these proteins. Induction of IL-10 production upon infection of THP-1 macrophages was associated with increased phosphorylation of the MAP Kinases p38 and ERK1/2, which was abolished in the presence of the pharmacological inhibitors SB203580 and PD98059. The PE5-PPE4 and PE15-PPE20 gene pairs were observed to be co-operonic in M.tb, hinting at an additional level of complexity in the functioning of these proteins. We conclude that M.tb exploits the PE proteins to evade the host immune response by altering the Th1 and Th2 type balance thereby favouring in vivo bacillary survival.