The bacterial DNA repair protein Mfd confers resistance to the host nitrogen immune response

Abstract

Production of reactive nitrogen species (NO) is a key step in the immune response following infections. NO induces lesions to bacterial DNA, thus limiting bacterial growth within hosts. Using two pathogenic bacteria, Bacillus cereus and Shigella flexneri, we show that the DNA-repair protein Mfd (Mutation-Frequency-Decline) is required for bacterial resistance to the host-NO-response. In both species, a mutant deficient for mfd does not survive to NO, produced in vitro or by phagocytic cells. In vivo, the ∆mfd mutant is avirulent and unable to survive the NO-stress. Moreover, NO induces DNA-double-strand-breaks and point mutations in the Δmfd mutant. In overall, these observations demonstrate that NO damages bacterial DNA and that Mfd is required to maintain bacterial genomic integrity. This unexpected discovery reveals that Mfd, a typical housekeeping gene, turns out to be a true virulence factor allowing survival and growth of the pathogen in its host, due to its capacity to protect the bacterium against NO, a key molecule of the innate immune defense. As Mfd is widely conserved in the bacterial kingdom, these data highlight a mechanism that may be used by a large spectrum of bacteria to overcome the host immune response and especially the mutagenic properties of NO.

The Bacterial Mfd Protein Prevents DNA Damage Induced by the Host Nitrogen Immune Response in a NER-Independent but RecBC-Dependent Pathway

“…coli [ 39 ]. To gain further insights into the role of Mfd during the host nitrogen response [ 40 ], bone marrow (peritoneal) macrophages were isolated from wild type and iNOS-KO mice deficient in NO production (C57/Bl6 nos2-/-). The macrophages were infected with wild type and Δmfd mutant strains and bacterial survival was recorded over time.…”

InhA1-Mediated Cleavage of the Metalloprotease NprA Allows Bacillus cereus to Escape From Macrophages

“…This implies that the bacteria have developed means to resist to the inflammatory cells and thus to the host immune system. We have consistently shown that B. cereus is able to circumvent the host immune response ( Tran and Ramarao, 2013 ; Darrigo et al, 2016 ; Guillemet et al, 2016 ). B. cereus spores survive, germinate, and multiply in contact with macrophages ( Ramarao and Lereclus, 2005 ), eventually leading to the production of toxins responsible for macrophage death ( Tran et al, 2011a , b ; Ramarao and Sanchis, 2013 ).…”

Identification of genomic islands in Chilean Piscirickettsia salmonis strains and analysis of gene expression involved in virulence

“…It is considered a virulence factor for the bacterium, allowing survival and growth in the host (Guillemet et al . ).…”

“…These species damage bacterium DNA, and this protein is responsible for counteracting the damage, maintaining bacterial genomic integrity. It is considered a virulence factor for the bacterium, allowing survival and growth in the host (Guillemet et al 2016).…”