Dysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory manifestations. By analyzing AT patient samples and Atm(-/-) mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm(-/-) mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and amplified response to microbial and environmental threats.

No abstract

These authors share the last authorship *Correspondence to: tomas.edgren@umu.se; hans.wolf-watz@umu.se. Abstract:Pathogenic bacteria have evolved numerous virulence mechanisms that are essential for establishing infections. The enterobacteria, Yersinia, uses a Type III Secretion System (T3SS), encoded by a 70-kb, low-copy, IncFII-class virulence plasmid. Here, we report a novel virulence strategy in Y. pseudotuberculosis in which this pathogen up-regulates the plasmid copynumber during infection. We show that increased dose of plasmid-encoded genes is indispensable for virulence and substantially elevates the expression and function of the T3SS.Remarkably, we found direct, tight coupling between plasmid replication and T3SS function.This regulatory pathway provides a framework for further exploration of the environmental sensing mechanisms of pathogenic bacteria.

Hydrogen peroxide (H 2 O 2 ) has a major function in host-microbial interactions. Although most studies have focused on the endogenous H 2 O 2 produced by immune cells to kill microbes, bacteria can also produce H 2 O 2 . How microbial H 2 O 2 influences the dynamics of host-microbial interactions is unclear. Here we show that H 2 O 2 released by Streptococcus pneumoniae inhibits inflammasomes, key components of the innate immune system, contributing to the pathogen colonization of the host. We also show that the oral commensal H 2 O 2 -producing bacteria Streptococcus oralis can block inflammasome activation. This study uncovers an unexpected role of H 2 O 2 in immune suppression and demonstrates how, through this mechanism, bacteria might restrain the immune system to co-exist with the host.

The ATM kinase is a central component of the DNA damage repair machinery and redox balance. ATM dysfunction results in the multisystem disease ataxia-telangiectasia (AT). A major cause of mortality in AT is respiratory bacterial infections. Whether ATM deficiency causes innate immune defects that might contribute to bacterial infections is not known. Here we have shown that loss of ATM impairs inflammasome-dependent anti-bacterial innate immunity. Cells from AT patients or Atm(-/-) mice exhibited diminished interleukin-1β (IL-1β) production in response to bacteria. In vivo, Atm(-/-) mice were more susceptible to pulmonary S. pneumoniae infection in a manner consistent with inflammasome defects. Our data indicate that such defects were due to oxidative inhibition of inflammasome complex assembly. This study reveals an unanticipated function of reactive oxygen species (ROS) in negative regulation of inflammasomes and proposes a theory for the notable susceptibility of AT patients to pulmonary bacterial infection.