| DOI | Resolve DOI: https://doi.org/10.1093/infdis/jiu593 |
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| Author | Search for: Bruhn, Kevin W.; Search for: Pantapalangkoor, Paul; Search for: Nielsen, Travis; Search for: Tan, Brandon; Search for: Junus, Justin; Search for: Hujer, Kristine M.; Search for: Wright, Meredith S.; Search for: Bonomo, Robert A.; Search for: Adams, Mark D.; Search for: Chen, Wangxue1; Search for: Spellberg, Brad |
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| Affiliation | - National Research Council of Canada. Human Health Therapeutics
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| Format | Text, Article |
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| Subject | Acinetobacter baumannii; bacteremia; bacterial clearance; bacterial strain; bacterial virulence; bacterium identification; bacterium isolate; cell transport; growth rate; host pathogen interaction; in vitro study; in vivo study; inoculation; molecular dynamics; Acinetobacter infection; C3H mouse; immunology; innate immunity; macrophage; microbiology; multidrug resistance; neutrophil; organismal interaction; virulence; antiinfective agent; virulence factor; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Mice, Inbred C3H; Microbial Interactions |
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| Abstract | 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. |
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| Publication date | 2014-11-05 |
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| In | |
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| Language | English |
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| Peer reviewed | Yes |
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| NPARC number | 21275670 |
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| Export citation | Export as RIS |
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| Report a correction | Report a correction (opens in a new tab) |
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| Record identifier | 0d80185e-99e2-4f8f-a22d-89ac8dd31b1c |
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| Record created | 2015-07-14 |
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| Record modified | 2020-04-22 |
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