Bacteria have evolved a multitude of strategies for manipulating and exploiting the host to establish an infection and replicate, while keeping the host cells, and thus their replicative niche, alive.
Bacterial infections can cause DNA damage in host cells, either directly by secreting genotoxic proteins or through mechanisms involving host response to the infection.
Some bacterial species simultaneously disrupt the host's DNA damage response through multiple pathways. This can lead to genomic instability and, in consequence, tumorigenic transformation.
The environment established upon infection may promote the escape of such transformed cells from tumour surveillance mechanisms.
Chronic infections that evade the immune system seem to be particularly dangerous in this context, and several of them, such as chronic infections by Helicobacter pylori, Chlamydia trachomatis and Salmonella enterica subsp. enterica serovar Typhi, have been associated with the development of human cancers.
Mammalian cells possess sophisticated genome surveillance and repair mechanisms, executed by the so-called DNA damage response (DDR), failure of which leads to accumulation of DNA damage and genomic instability. Mounting evidence suggests that bacterial infections can elicit DNA damage in host cells, and certain pathogens induce such damage as part of their multi-faceted infection programme. Bacteria-mediated DNA damage can occur either directly through the formation of toxins with genotoxic activities or indirectly as a result of the activation of cell-autonomous or immune defence mechanisms against the pathogen. Moreover, host-cell signalling routes involved in the DDR can be altered in response to an infection, and this, in the context of DNA damage elicited by the pathogen, has the potential to trigger mutations and cancer.
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The authors thank D. Schad for help with the figures to this manuscript.
The authors declare no competing financial interests.
- Bacterial secretion systems
Molecular machineries used to transport bacterial effector molecules to their environment or simultaneously across the host cell membrane.
(Nucleotide-binding oligomerization domain, leucine-rich repeat containing X1 protein). A member of the NOD-like receptor family that translocates to the mitochondria and has been shown to augment reactive oxygen species production from the mitochondria in response to infections.
Membrane-bound organelle that degrades proteins from internalized particles into peptides.
- Nosocomial diseases
Diseases caused by hospital-acquired infections, frequently caused by antibiotic-resistant bacteria, posing a high risk to susceptible patients.
Bacterial secreted toxins that can bind to a cell surface receptor and stimulate intracellular signalling pathways (type I), damage the cell membrane (type II) or exert effects intracellularly (type III), causing damage to the host by destroying cells or disrupting their normal metabolism.
- Bacterial virulence factor
Chromosome- or plasmid-encoded molecules, including bacterial toxins that contribute to colonization or pathogenicity.
(Cytotoxin-associated gene A). A 120–145 kDa protein expressed by Cag pathogenicity island-positive Helicobacter pylori strains. CagA is translocated into host cells and is associated with increased inflammation and risk of gastric cancer.
- Cag pathogenicity island
(CagPAI). A 40 kb DNA segment of Helicobacter pylori, encoding 20 genes, including CagA and proteins involved in its translocation to the host cell.
- Somatic hypermutation
Mutation of variable immunoglobulin gene regions in immune cells induced by activation-induced cytidine deaminase (AID), which drives B cell diversification and immune adaptation.
- Class switch recombination
Programmed removal of sections of the antibody heavy chain locus from B cell chromosomes through generation of double-strand breaks, followed by rejoining of the segments by non-homologous end-joining, leading to generation of a different antibody class.
- Replication fork stalling
Pausing (sometimes indefinite) of the progress of the replication fork complex (where DNA unwinding and DNA synthesis take place), owing to the presence of impediments, such as DNA lesions.
- pks genomic island
A 54-kb genomic island of Escherichia coli, which encodes several genes that are responsible for the synthesis of the genotoxin colibactin.
- Gram-negative bacteria
Bacterial species that do not have a thick cell wall, as detected by the Gram stain for peptidoglycan.
- p38 MAPK
A class of MAPKs that respond to stress stimuli and have a major role in apoptosis, differentiation, survival, proliferation, development and inflammation.
Ser139 phosphorylated histone H2AX, which serves as an early cellular response and a sensitive marker for DNA double-strand breaks.
- Anaphase bridges
Chromatin bridges formed during anaphase, caused by fusion of telomeres of sister chromatids, leading to failure to completely segregate them into their respective daughter cells.
- Spindle assembly checkpoint
A process ensuring accurate chromosome segregation into daughter cells, which acts by delaying cell division during mitosis and meiosis until proper attachment of chromosomes to the microtubule spindle apparatus is achieved.
Small, extranuclear bodies, resulting from chromosome fragments or whole chromosomes being separated from daughter nuclei during mitosis, either by breaking of an anaphase bridge or by a double-strand break in the DNA.
- Microsatellite instability
Hypermutability of short tandem repeat DNA sequences, which results from defects in mismatch repair.
- Senescence-associated secretory phenotype
(SASP). Expression of a set of secreted growth factors, inflammatory cytokines, proteases and matrix components by senescent cells, which is associated with pro-malignant changes in surrounding cells.
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Chumduri, C., Gurumurthy, R., Zietlow, R. et al. Subversion of host genome integrity by bacterial pathogens. Nat Rev Mol Cell Biol 17, 659–673 (2016). https://doi.org/10.1038/nrm.2016.100
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