Anti-inflammatory effects of reverse transcriptase inhibitors during bacterial infection

About This Grant

PROJECT SUMMARY Inflammatory responses are critical for host control of bacterial infection. However, excessive inflammation can have deleterious consequences by causing collateral damage to the host. One of the most lethal consequences of bacterial infections is sepsis, which is characterized by systemic hyperactivation of the innate immune response. Sepsis kills millions of people annually and the development of new therapeutics has stagnated in recent decades. Therefore, it is essential to understand how the host senses infection and amplifies inflammatory responses to bacteria and develop new treatment strategies for sepsis. We recently discovered a novel facet of the inflammatory response in mice, where bacterial infection triggers massive induction of endogenous retroviruses (ERVs), which are chromosomally integrated retroviruses. ERVs encode reverse transcriptases, which have previously been demonstrated to heighten inflammatory responses in non- infectious contexts. Indeed, treatment of mice with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) diminishes systemic inflammatory responses in a model of E. coli bloodstream infection, prevents inflammation-induced tissue necrosis, and protects mice from lipopolysaccharide-induce hypothermia and death. Despite the strong anti-inflammatory effects of NRTIs during E. coli infection, it is unclear whether NRTIs would have similar therapeutic benefits in other infection contexts. In addition, the mechanisms underlying the anti-inflammatory effects of NRTIs, and the corresponding pro-inflammatory effects of ERVs, are unknown. Filling this gap in knowledge is important as it would provide critical insight into whether NRTIs hold practical utility in combating infection in humans and define a new axis of host defense. Therefore, in this study, we will define the anti-inflammatory scope of NRTIs across diverse infection contexts and define the underlying mechanisms. We hypothesize that canonical TLR signaling drives expression of ERVs. The activities of ERV-encoded reverse transcriptases lead to production of DNA or RNA:DNA hybrids that signal through nucleic acid sensors to amplify inflammatory responses and drive proinflammatory cytokine production. NRTIs, by blocking ERV-encoded reverse transcriptases, diminish these inflammatory responses. Successful completion of this project will lead to the development of a new paradigm in innate immunity and bacterial pathogenesis, as it would suggest that elements encoding reverse transcriptases, which comprise 40% of our genomes, may be central yet unappreciated amplifiers of inflammatory responses. In turn, these observations would reveal that reverse transcriptase inhibitors, which represent a large class of clinically approved drugs, may be powerful agents in the fight against bacterial infections and sepsis.