Secreted mammalian DNases protect against systemic bacterial infection by digesting biofilms.

Extracellular DNase DNASE1L3 maintains tolerance to self-DNA in humans and mice, whereas the role of its homolog DNASE1 remains controversial, and the overall function of secreted DNases in immunity is unclear. We report that deletion of murine DNASE1 neither caused autoreactivity in isolation nor exacerbated lupus-like disease in DNASE1L3-deficient mice. However, combined deficiency of DNASE1 and DNASE1L3 rendered mice susceptible to bloodstream infection with Staphylococcus aureus. DNASE1/DNASE1L3 double-deficient mice mounted a normal innate response to S. aureus and did not accumulate neutrophil extracellular traps (NETs). However, their kidneys manifested severe pathology, increased bacterial burden, and biofilm-like bacterial lesions that contained bacterial DNA and excluded neutrophils. Furthermore, systemic administration of recombinant DNASE1 protein during S. aureus infection rescued the mortality of DNase-deficient mice and ameliorated the disease in wild-type mice. Thus, DNASE1 and DNASE1L3 jointly facilitate the control of bacterial infection by digesting extracellular microbial DNA in biofilms, suggesting the original evolutionary function of secreted DNases as antimicrobial agents. © 2023 Lacey et al.

Citation

Keenan A Lacey, Lee Serpas, Sohei Makita, Yueyang Wang, Ali Rashidfarrokhi, Chetna Soni, Sandra Gonzalez, Andre Moreira, Victor J Torres, Boris Reizis. Secreted mammalian DNases protect against systemic bacterial infection by digesting biofilms. The Journal of experimental medicine. 2023 Jun 05;220(6)

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PMID: 36928522

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