Secreted mammalian DNases protect against systemic bacterial infection by digesting biofilms

Abstract

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.

Unanticipated interacting features of human gut-associated lymphoid tissues link microbiota, intestinal immunity and autoimmunity

“…Because of their enrichment in the SED in a region between sampled microbiota and the host we propose that DNASE1L3 and C1q are involved in management of bacteria sampled from the gut lumen. In particular, potential for high concentration of secreted DNASE1L3 in the SED is consistent with it having a role in digestion of bacterial DNA as observed previously in other contexts 50 . Bacterial DNA could be potentially pathogenic and could drive aberrant activity of DN2 B cells that are situated together with the DNASE1L3- expressing DC 20 .…”

“…However, here we show that DNASE1L3 is not expressed in the GC in human GALT, tonsil or lymph node but is located in the SED. DNASE1L3 is found both intra- and extracellularly, can digest bacterial DNA and even contribute to the disruption of biofilm 50 . Mouse models have contributed in many ways to the current view of the relationship between apoptosis and lupus pathogenesis, yet much data may not be translationally relevant because of the marked species difference in the distribution of DNASE1L3 that we identify here 56 .…”

“…We also observe by spatial transcriptomics resolved to single cells that the most enriched transcript in FAE and SED encodes the lupus associated autoantigen DNASE1L3, which is expressed together with C1q. DNASE1L3 has a known role in degrading pathogen derived DNA 50 . In line with the uptake of bacterial antigens into the SED, we propose that DNASE1L3 and C1q have key functions managing bacterial antigens on the epithelial boundary.…”

Prophage-encoded methyltransferase drives adaptation of community-acquired methicillin-resistantStaphylococcus aureus

“…Although deletion of an upstream fragment (∆32-43) had no impact on abscess size, deletion of the center gene block (∆44-57) eliminated the skin abscess phenotype (Figures 1C-D). These data localized skin abscess candidates to 14 genes (44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57) in mΦ11 for further analysis. Of the 14 genes, eight gene sequences were unrelated to prototypical Φ11 or other known prophages and therefore were considered promising candidates for further analysis (Table S1).…”

Ternary low-temperature phototherapy nano-systems for the treatment of diabetic wounds

“…Related studies have reported that DNase I can kill bacteria and inhibit bacterial biofilm formation by cleavage of DNA. 31 Based on the photothermal bactericidal effect of MPDA and the antibacterial effect of Zn 2+ and DNase I, the nanosystem prepared in this study is expected to achieve efficient bacterial killing and effective biofilm removal under mild NIR irradiation. In addition, based on the unique paraben structure of MPDA, the system has excellent ROS scavenging ability, which can effectively reduce/mitigate oxidative stress damage at the trauma site and accelerate the damage repair process.…”