Occurrence and repair of alkylating stress in the intracellular pathogen Brucella abortus

Poncin, Katy; Roba, Agnès; Jimmidi, Ravikumar; Potemberg, Georges; Fioravanti, Antonella; Francis, Nayla; Willemart, Kévin; Zeippen, Nicolas; Machelart, Arnaud; Biondi, Emanuele E.G.; Muraille, Eric; Vincent, Stéphane S.P.; Bolle, Xavier De

doi:10.1038/s41467-019-12516-8

Cited by 19 publications

(12 citation statements)

References 81 publications

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“…Mtb is exposed to nitrosative stress during macrophage infection (Ehrt and Schnappinger, 2009; Stallings and Glickman, 2010). A recent study reported that the pathogenic bacterium Brucella abortus encounters alkylating stress during macrophage infection and that the alkylation-specific repair systems are required for long-term mouse infection (Poncin et al, 2019). In Mtb, the deletion of similar alkylation-specific repair systems causes sensitivity to alkylating agents but does not impact virulence (Durbach et al, 2003; Yang et al, 2011), suggesting a possible functional redundancy between alkylation-specific repair systems and the TLS polymerases.…”

Section: Discussionmentioning

confidence: 99%

Distinctive roles of translesion polymerases DinB1 and DnaE2 in diversification of the mycobacterial genome through substitution and frameshift mutagenesis

Dupuy

Ghosh

Adefisayo

et al. 2022

Preprint

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Antibiotic resistance of Mycobacterium tuberculosis is exclusively a consequence of chromosomal mutations. Translesion synthesis (TLS) is a widely conserved mechanism of DNA damage tolerance and mutagenesis, executed by translesion polymerases such as DinBs. In mycobacteria, DnaE2 is the only known agent of TLS and the role of DinB polymerases is unknown. Here we demonstrate that mycobacterial DinB1 abets insertion and deletion frameshift mutagenesis in homo-oligonucleotide runs. DinB1 is the primary mediator of spontaneous -1 frameshift mutations in homo-oligonucleotide runs whereas DnaE2 and DinBs are redundant in DNA damage-induced -1 frameshift mutagenesis. DinB1 also promotes missense mutations conferring resistance to rifampicin, with a mutational signature distinct from that of DnaE2. These results highlight DinB1 and DnaE2 as drivers of mycobacterial genome diversification with relevance to antimicrobial resistance and host adaptation.

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Section: Discussionmentioning

confidence: 99%

Distinctive roles of translesion polymerases DinB1 and DnaE2 in diversification of the mycobacterial genome through substitution and frameshift mutagenesis

Dupuy

Ghosh

Adefisayo

et al. 2022

Preprint

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“…One attractive characteristic not directly linked to the structure of the cell envelope is the resistance of Brucella organisms to DNA alkylating stress mediated by phagocytic cells. Genes involved in repair and base excision repair pathways are required by the bacterium to confront alkylation stress within phagosomes (155). This event is commensurate with the absence of bacterial replication within PMNs, a characteristic that favors resistance to the killing action.…”

Section: Brucella Organisms Are Resistant To Bactericidal Substancesmentioning

confidence: 99%

The Role of Neutrophils in Brucellosis

Moreno

Barquero-Calvo

2020

Microbiol Mol Biol Rev

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SUMMARY Brucellosis is a bacterial disease of domestic animals and humans. The pathogenic ability of Brucella organisms relies on their stealthy strategy and their capacity to replicate within host cells and to induce long-lasting infections. Brucella organisms barely induce neutrophil activation and survive within these leukocytes by resisting microbicidal mechanisms. Very few Brucella-infected neutrophils are found in the target organs, except for the bone marrow, early in infection. Still, Brucella induces a mild reactive oxygen species formation and, through its lipopolysaccharide, promotes the premature death of neutrophils, which release chemokines and express “eat me” signals. This effect drives the phagocytosis of infected neutrophils by mononuclear cells that become thoroughly susceptible to Brucella replication and vehicles for bacterial dispersion. The premature death of the infected neutrophils proceeds without NETosis, necrosis/oncosis, or classical apoptosis morphology. In the absence of neutrophils, the Th1 response exacerbates and promotes bacterial removal, indicating that Brucella-infected neutrophils dampen adaptive immunity. This modulatory effect opens a window for bacterial dispersion in host tissues before adaptive immunity becomes fully activated. However, the hyperactivation of immunity is not without a price, since neutropenic Brucella-infected animals develop cachexia in the early phases of the disease. The delay in the immunological response seems a sine qua non requirement for the development of long-lasting brucellosis. This property may be shared with other pathogenic alphaproteobacteria closely related to Brucella. We propose a model in which Brucella-infected polymorphonuclear neutrophils (PMNs) function as “Trojan horse” vehicles for bacterial dispersal and as modulators of the Th1 adaptive immunity in infection.

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“…The pulse predominantly affects a subpopulation of cells that experience delayed adaptation to the stress ( Figure 2B). Considering that infection of macrophages is associated with DNA alkylation stress [99], such an effect may also contribute to the dynamics of mutagenesis inside a host.…”

Section: Variation In Mutagenesismentioning

confidence: 99%

Bacterial phenotypic heterogeneity in DNA repair and mutagenesis

Vincent

Uphoff

2020

Biochemical Society Transactions

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Genetically identical cells frequently exhibit striking heterogeneity in various phenotypic traits such as their morphology, growth rate, or gene expression. Such non-genetic diversity can help clonal bacterial populations overcome transient environmental challenges without compromising genome stability, while genetic change is required for long-term heritable adaptation. At the heart of the balance between genome stability and plasticity are the DNA repair pathways that shield DNA from lesions and reverse errors arising from the imperfect DNA replication machinery. In principle, phenotypic heterogeneity in the expression and activity of DNA repair pathways can modulate mutation rates in single cells and thus be a source of heritable genetic diversity, effectively reversing the genotype-to-phenotype dogma. Long-standing evidence for mutation rate heterogeneity comes from genetics experiments on cell populations, which are now complemented by direct measurements on individual living cells. These measurements are increasingly performed using fluorescence microscopy with a temporal and spatial resolution that enables localising, tracking, and counting proteins with single-molecule sensitivity. In this review, we discuss which molecular processes lead to phenotypic heterogeneity in DNA repair and consider the potential consequences on genome stability and dynamics in bacteria. We further inspect these concepts in the context of DNA damage and mutation induced by antibiotics.

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Occurrence and repair of alkylating stress in the intracellular pathogen Brucella abortus

Cited by 19 publications

References 81 publications

Distinctive roles of translesion polymerases DinB1 and DnaE2 in diversification of the mycobacterial genome through substitution and frameshift mutagenesis

Distinctive roles of translesion polymerases DinB1 and DnaE2 in diversification of the mycobacterial genome through substitution and frameshift mutagenesis

The Role of Neutrophils in Brucellosis

Bacterial phenotypic heterogeneity in DNA repair and mutagenesis

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