The contribution of accessory toxins of Vibrio cholerae O1 El Tor to the proinflammatory response in a murine pulmonary cholera model.
The contribution of accessory toxins to the acute inflammatory response to Vibrio cholerae was assessed in a murine pulmonary model. Intranasal administration of an El Tor O1 V. cholerae strain deleted of cholera toxin genes (ctxAB) caused diffuse pneumonia characterized by infiltration of PMNs, tissue damage, and hemorrhage. By contrast, the ctxAB mutant with an additional deletion in the actin-cross-linking repeats-in-toxin (RTX) toxin gene (rtxA) caused a less severe pathology and decreased serum levels of proinflammatory molecules interleukin (IL)-6 and murine macrophage inflammatory protein (MIP)-2. These data suggest that the RTX toxin contributes to the severity of acute inflammatory responses. Deletions within the genes for either hemagglutinin/protease (hapA) or hemolysin (hlyA) did not significantly affect virulence in this model. Compound deletion of ctxAB, hlyA, hapA, and rtxA created strain KFV101, which colonized the lung but induced pulmonary disease with limited inflammation and significantly reduced serum titers of IL-6 and MIP-2. 100% of mice inoculated with KFV101 survive, compared with 20% of mice inoculated with the ctxAB mutant. Thus, the reduced virulence of KFV101 makes it a prototype for multi-toxin deleted vaccine strains that could be used for protection against V. cholerae without the adverse effects of the accessory cholera toxins.
Fullner
Karla Jean
KJ
Departments of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Morton 6-626, Chicago, IL 60611, USA. k-fullner@northwestern.edu
Boucher
John C
JC
Hanes
Martha A
MA
Haines
G Kenneth
GK
Meehan
Brian M
BM
Walchle
Cynthia
C
Sansonetti
Philippe J
PJ
Mekalanos
John J
JJ
D000818:Animals; D001427:Bacterial Toxins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism; D002771:Cholera / Q000276:immunology / Q000473:pathology*; D004195:Disease Models, Animal; D017353:Gene Deletion; D007249:Inflammation / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D051379:Mice; D015996:Survival Rate; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014734:Vibrio cholerae / Q000145:classification / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D014774:Virulence / Q000235:genetics
D001427:Bacterial Toxins; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha