Reverse transcriptase inhibitors prevent liver abscess formation during Escherichia coli bloodstream infection

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 4; p. e2319162121
• Main Authors: Hullahalli, Karthik, Dailey, Katherine G, Hasegawa, Yuko, Johnson, Welkin E, Waldor, Matthew K
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.01.2024
• Series: Brief Report
• Subjects: Abscesses; Animals; Bacteria; Bacterial Infections - drug therapy; Biological Sciences; Clinical outcomes; E coli; Endogenous Retroviruses; Escherichia coli; Escherichia coli - genetics; Escherichia coli Infections - genetics; Hepatocytes; Immune system; Infections; Infectious diseases; Inflammation; Inhibitors; Inoculation; Liver; Liver Abscess - drug therapy; Liver Abscess - genetics; Mice; Necrosis; Necrosis - genetics; Nucleotides; Reverse Transcriptase Inhibitors - pharmacology; Reverse transcription; RNA-directed DNA polymerase; Sepsis; Sepsis - drug therapy; Transcriptomes; reverse transcriptase inhibitors; bloodstream infection; liver abscess; endogenous retroviruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2319162121

The presence of bacteria in the bloodstream is associated with severe clinical outcomes. In mice, intravenous inoculation of can lead to the formation of macroscopic abscesses in the liver. Abscesses are regions of severe necrosis and consist of millions of bacteria surrounded by inflammatory immune cells. Liver abscess susceptibility varies widely across strains of mice, but the host factors governing this variation are unknown. Here, we profiled hepatic transcriptomes in mice with varying susceptibility to liver abscess formation. We found that transcripts from endogenous retroviruses (ERVs) are robustly induced in the liver by infection and ERV expression positively correlates with the frequency of abscess formation. Hypothesizing that ERV-encoded reverse transcriptase may generate cytoplasmic DNA and heighten inflammatory responses, we tested whether nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) influence abscess formation. Strikingly, a single NRTI dose administered immediately following inoculation prevented abscess formation, leading to a concomitant 100,000-fold reduction in bacterial burden. We provide evidence that NRTIs inhibit abscess formation by preventing the tissue necrosis that facilitates bacterial replication. Together, our findings suggest that endogenous reverse transcriptases drive inflammatory responses during bacterial bloodstream infection to drive abscess formation. The high efficacy of NRTIs in preventing abscess formation suggests that the consequences of reverse transcription on inflammation should be further examined, particularly in infectious diseases where inflammation drives negative clinical outcomes, such as sepsis.