Kevin W Bruhn1, Paul Pantapalangkoor1, Travis Nielsen1, Brandon Tan1, Justin Junus1, Kristine M Hujer2, Meredith S Wright3, Robert A Bonomo4, Mark D Adams3, Wangxue Chen5, Brad Spellberg6. 1. Department of Molecular Microbiology and Immunology. 2. Department of Medicine Department of Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Ohio. 3. Department of J. Craig Venter Institute, La Jolla, California. 4. Department of Medicine Department of Pharmacology Department of Molecular Biology and Microbiology, Case Western Reserve University Department of Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Ohio. 5. Department of Human Health Therapeutics, National Research Council Canada, Ottawa, Ontario. 6. Department of Medicine, Division of Infectious Diseases, Keck School of Medicine, University of Southern California, Los Angeles.
Abstract
BACKGROUND: Acinetobacter baumannii is one of the most antibiotic-resistant pathogens. Defining mechanisms driving pathogenesis is critical to enable new therapeutic approaches. METHODS: We studied virulence differences across a diverse panel of A. baumannii clinical isolates during murine bacteremia to elucidate host-microbe interactions that drive outcome. RESULTS: We identified hypervirulent strains that were lethal at low intravenous inocula and achieved very high early, and persistent, blood bacterial densities. Virulent strains were nonlethal at low inocula but lethal at 2.5-fold higher inocula. Finally, relatively avirulent (hypovirulent) strains were nonlethal at 20-fold higher inocula and were efficiently cleared by early time points. In vivo virulence correlated with in vitro resistance to complement and macrophage uptake. Depletion of complement, macrophages, and neutrophils each independently increased bacterial density of the hypovirulent strain but insufficiently to change lethality. However, disruption of all 3 effector mechanisms enabled early bacterial densities similar to hypervirulent strains, rendering infection 100% fatal. CONCLUSIONS: The lethality of A. baumannii strains depends on distinct stages. Strains resistant to early innate effectors are able to establish very high early bacterial blood density, and subsequent sustained bacteremia leads to Toll-like receptor 4-mediated hyperinflammation and lethality. These results have important implications for translational efforts to develop therapies that modulate host-microbe interactions.
BACKGROUND:Acinetobacter baumannii is one of the most antibiotic-resistant pathogens. Defining mechanisms driving pathogenesis is critical to enable new therapeutic approaches. METHODS: We studied virulence differences across a diverse panel of A. baumannii clinical isolates during murinebacteremia to elucidate host-microbe interactions that drive outcome. RESULTS: We identified hypervirulent strains that were lethal at low intravenous inocula and achieved very high early, and persistent, blood bacterial densities. Virulent strains were nonlethal at low inocula but lethal at 2.5-fold higher inocula. Finally, relatively avirulent (hypovirulent) strains were nonlethal at 20-fold higher inocula and were efficiently cleared by early time points. In vivo virulence correlated with in vitro resistance to complement and macrophage uptake. Depletion of complement, macrophages, and neutrophils each independently increased bacterial density of the hypovirulent strain but insufficiently to change lethality. However, disruption of all 3 effector mechanisms enabled early bacterial densities similar to hypervirulent strains, rendering infection 100% fatal. CONCLUSIONS: The lethality of A. baumannii strains depends on distinct stages. Strains resistant to early innate effectors are able to establish very high early bacterial blood density, and subsequent sustained bacteremia leads to Toll-like receptor 4-mediated hyperinflammation and lethality. These results have important implications for translational efforts to develop therapies that modulate host-microbe interactions.
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