A low gastric pH mouse model to evaluate live attenuated bacterial vaccines.
The low pH of the stomach serves as a barrier to ingested microbes and must be overcome or bypassed when delivering live bacteria for vaccine or probiotic applications. Typically, the impact of stomach acidity on bacterial survival is evaluated in vitro, as there are no small animal models to evaluate these effects in vivo. To better understand the effect of this low pH barrier to live attenuated Salmonella vaccines, which are often very sensitive to low pH, we investigated the value of the histamine mouse model for this application. A low pH gastric compartment was transiently induced in mice by the injection of histamine. This resulted in a gastric compartment of approximately pH 1.5 that was capable of distinguishing between acid-sensitive and acid-resistant microbes. Survival of enteric microbes during gastric transit in this model directly correlated with their in vitro acid resistance. Because many Salmonella enterica serotype Typhi vaccine strains are sensitive to acid, we have been investigating systems to enhance the acid resistance of these bacteria. Using the histamine mouse model, we demonstrate that the in vivo survival of S. Typhi vaccine strains increased approximately 10-fold when they carried a sugar-inducible arginine decarboxylase system. We conclude that this model will be a useful for evaluating live bacterial preparations prior to clinical trials.
Center for Infectious Diseases and Vaccinology, The Biodesign Institute, Arizona State University, Tempe, Arizona, United States of America.
Karen E
KE
Brenneman
Center for Infectious Diseases and Vaccinology, The Biodesign Institute, Arizona State University, Tempe, Arizona, United States of America.
Crystal
C
Willingham
Center for Infectious Diseases and Vaccinology, The Biodesign Institute, Arizona State University, Tempe, Arizona, United States of America.
Jacquelyn A
JA
Kilbourne
Center for Infectious Diseases and Vaccinology, The Biodesign Institute, Arizona State University, Tempe, Arizona, United States of America ; School of Life Sciences, Arizona State University, Tempe, Arizona, United States of America.
Roy
R
Curtiss
Center for Infectious Diseases and Vaccinology, The Biodesign Institute, Arizona State University, Tempe, Arizona, United States of America.
Kenneth L
KL
Roland
D000818:Animals; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D002262:Carboxy-Lyases / Q000096:biosynthesis / Q000235:genetics; D004926:Escherichia coli / Q000276:immunology / Q000502:physiology; D005260:Female; D005744:Gastric Acid; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D050296:Microbial Viability; D022562:Salmonella Vaccines / Q000276:immunology*; D012485:Salmonella typhi / Q000276:immunology / Q000502:physiology; D014435:Typhoid Fever / Q000517:prevention & control; D014613:Vaccines, Attenuated / Q000276:immunology*; D014734:Vibrio cholerae / Q000502:physiology
D001426:Bacterial Proteins; D022562:Salmonella Vaccines; D014613:Vaccines, Attenuated; D006632:Histamine; D002262:Carboxy-Lyases; C019722:arginine decarboxylase