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Reverse transcriptase inhibitors prevent liver abscess formation during Escherichia coli bloodstream infection
Karthik Hullahalli1,2, Katherine G Dailey1,2, Yuko Hasegawa1,2
1Department of Microbiology, Harvard Medical School, Boston, MA 02115.
Abstract:
The presence of bacteria in the bloodstream is associated with severe clinical outcomes. In mice, intravenous inoculation of Escherichia coli 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 E. coli 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 E. coli 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.
Insights
Bacterial bloodstream infections can cause liver abscesses. Researchers found that inhibiting endogenous retroviruses (ERVs) with reverse transcriptase inhibitors prevents abscess formation and reduces bacterial load.
Area of Science:
- Microbiology
- Immunology
- Genetics
Background:
- Bacterial bloodstream infections are linked to severe outcomes.
- Liver abscesses, characterized by necrosis and high bacterial loads, form after *Escherichia coli* inoculation in mice.
- Susceptibility to liver abscesses varies among mouse strains, with underlying host factors being unclear.
Purpose of the Study:
- To investigate host factors influencing liver abscess formation.
- To explore the role of endogenous retroviruses (ERVs) in bacterial bloodstream infections.
- To evaluate the therapeutic potential of reverse transcriptase inhibitors against liver abscesses.
Main Methods:
- Hepatic transcriptome profiling in mice with varying liver abscess susceptibility.
- Analysis of endogenous retroviral (ERV) transcript induction following *E. coli* infection.
- Administration of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) post-infection to assess impact on abscess formation and bacterial burden.
Main Results:
- ERV transcripts were significantly induced in the liver by *E. coli* infection.
- ERV expression levels positively correlated with the frequency of liver abscess formation.
- A single dose of NRTI administered post-infection completely prevented abscess formation and reduced bacterial burden by 100,000-fold.
- NRTIs were shown to inhibit abscess formation by preventing tissue necrosis.
Conclusions:
- Endogenous reverse transcriptases play a critical role in driving inflammatory responses during bacterial bloodstream infections, leading to abscess formation.
- Nucleoside/nucleotide reverse transcriptase inhibitors demonstrate high efficacy in preventing bacterial liver abscesses, suggesting a novel therapeutic strategy.
- Further research into the impact of reverse transcription on inflammation in infectious diseases like sepsis is warranted.
