Serum resistance, gallium nitrate tolerance and extrapulmonary dissemination are linked to heme consumption in a bacteremic strain of Acinetobacter baumannii.
Bacteremia caused by Acinetobacter baumannii is a highly lethal complication of hospital-acquired pneumonia. In the present study, we investigated the serum resistance, gallium nitrate tolerance and heme consumption of A. baumannii strain LAC-4 which was recently reported to display high virulence in a mouse pneumonia model with extrapulmonary dissemination leading to fatal bacteremia. This strain showed enhanced growth in mouse and fetal bovine serum that was independent of complement and was not observed with regular growth media. The LAC-4 strain was found to possess a high tolerance to gallium nitrate (GaN), whereas serum synergized with GaN in inhibiting A. baumannii strain ATCC 17978. We found that LAC-4 contains a heme oxygenase gene and expresses a highly efficient heme consumption system. This system can be fully blocked in vitro and in vivo by gallium protoporphyrin IX (GaPPIX). Inhibition of heme consumption by GaPPIX completely abrogated the growth advantage of LAC-4 in serum as well as its tolerance to GaN. More importantly, GaPPIX treatment of mice intranasally infected with LAC-4 prevented extrapulmonary dissemination and death. Thus, we propose that heme provides an additional source of iron for LAC-4 to bypass iron restriction caused by serum transferrin, lactoferrin or free gallium salts. Heme consumption systems in A. baumannii may constitute major virulence factors for lethal bacteremic isolates.
Human Health Therapeutics Portfolio, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada.
Louis
L
de Léséleuc
Human Health Therapeutics Portfolio, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada.
Greg
G
Harris
Human Health Therapeutics Portfolio, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada.
Rhonda
R
KuoLee
Department of Biological Sciences, California State University, Los Angeles, CA, USA.
H Howard
HH
Xu
Human Health Therapeutics Portfolio, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada; Department of Biology, Brock University, St. Catharines, Ontario, Canada. Electronic address: wangxue.chen@nrc.gc.ca.
Wangxue
W
Chen
D000151:Acinetobacter Infections / Q000382:microbiology*; D040981:Acinetobacter baumannii / Q000187:drug effects / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D016470:Bacteremia / Q000382:microbiology*; D001770:Blood Bactericidal Activity; D002417:Cattle; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D005260:Female; D005708:Gallium / Q000633:toxicity*; D006418:Heme / Q000378:metabolism*; D006801:Humans; D008810:Mice, Inbred C57BL; D018410:Pneumonia, Bacterial / Q000150:complications / Q000382:microbiology*; D044967:Serum / Q000382:microbiology
D006418:Heme; D005708:Gallium; C027235:gallium nitrate
Acinetobacter baumannii; Heme; Mice; Pneumonia; Virulence