期刊
JOURNAL OF INFECTIOUS DISEASES
卷 211, 期 8, 页码 1296-1305出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiu593
关键词
Acinetobacter baumannii; virulence; pathogenesis; bloodstream; mouse
资金
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01 AI072219, R21 AI101750, R01 AI1081719, R56 AI104751, R41 AI106375]
- Cleveland Department of Veterans Affairs
- Veterans Affairs Merit Review Program [1I01BX001974]
- VISN 10 Geriatric Research Education and Clinical Center
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI081719, R21AI101750, R56AI104751, R41AI106375, R01AI072219] Funding Source: NIH RePORTER
- Veterans Affairs [I01BX001974] Funding Source: NIH RePORTER
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.
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