The multifunctional histone-like protein Lsr2 protects mycobacteria against reactive oxygen intermediates

Abstract

Mycobacterium tuberculosis has evolved a number of strategies to survive within the hostile environment of host phagocytes. Reactive nitrogen and oxygen intermediates (RNI and ROI) are among the most effective antimycobacterial molecules generated by the host during infection. Lsr2 is a M. tuberculosis protein with histonelike features, including the ability to regulate a variety of transcriptional responses in mycobacteria. Here we demonstrate that Lsr2 protects mycobacteria against ROI in vitro and during macrophage infection. Furthermore, using macrophages derived from NOS ؊/؊ and Phox ؊/؊ mice, we demonstrate that Lsr2 is important in protecting against ROI but not RNI. The protection provided by Lsr2 protein is not the result of its ability to either bind iron or scavenge hydroxyl radicals. Instead, electron microscopy and DNAbinding studies suggest that Lsr2 shields DNA from reactive intermediates by binding bacterial DNA and physically protecting it. Thus, Lsr2 appears to be a unique protein with both histone-like properties and protective features that may be central to M. tuberculosis pathogenesis. In addition, evidence indicates that lsr2 is an essential gene in M. tuberculosis. Because of its essentiality, Lsr2 may represent an excellent candidate as a drug target.Mycobacterium tuberculosis ͉ ROI ͉ DPS ͉ DNA

Mycobacterial Biofilms Facilitate Horizontal DNA Transfer between Strains ofMycobacterium smegmatis

“…Thus, we anticipate finding other Lsr2-regulated genes that will be important for DNA transfer both on solid medium and in a biofilm. Indeed, transcriptional studies have shown that Lsr2 negatively regulates esx-1 genes (6,7,15), and we have demonstrated previously that Esx-1-mediated secretion negatively regulates transfer from the donor (12). However, the lsr2 mutants described in the present study were isolated in a ⌬esx-1 background, so we can rule out Lsr2 regulation of esx-1 as a factor in our experiments.…”

“…Lsr2 was first described as an immunodominant antigen of M. leprae (24); however, it has since been shown to modulate a diverse range of processes. The resultant phenotypes of lsr2 mutants can be attributed to the ability of Lsr2 to bind DNA nonspecifically (6,7,15). Lsr2 belongs to the family of histone-like DNA binding proteins, a fact that was demonstrated by showing that lsr2 can suppress hns mutant phenotypes in Escherichia coli and that hns can suppress lsr2 mutant phenotypes in M. smegmatis (14).…”

A Proteomic Signature of Dormancy in the Actinobacterium Micrococcus luteus

“…3) Using the NCBI Conserved Domain Search System (https://www.ncbi.nlm.nih.gov/ Structure/cdd/wrpsb.cgi) (86), we were able to identify a domain correlation between Mlut_10450 and an ancestral histone fold in a hyperthermophilic bacterium, Aquifex aeloicus (87). If the correlation is correct, Mlut_10450 could protect the bacterial genome against oxidative and stress damage, as described for another M. tuberculosis protein, Lsr2 (88). The association for Mlut_03760 is more tenuous and identifies a relationship with a predicted IG fold in a putative copper oxidoreductase, FixG.…”

Mycobacterium tuberculosisPPE68 and Rv2626c genes contribute to the host cell necrosis and bacterial escape from macrophages

“…4 Pathogen escapes killing mechanisms of toxic reactive oxygen or nitrogen intermediates by limiting phagocytic cells to generate these most effective anti-bacterial molecules. 5,6 Mtb contains molecular strategies to hijack trafficking pathways to prevent autophagy and the destruction of macrophages by apoptosis [7][8][9] that has been proposed to be the virulence characteristic of Mtb. Many manners, employed by Mtb, have been described to inhibit a macrophage self-death, [7][8][9][10][11] leading to the conclusion that this property must be an important one for the pathogen survival outcome.…”