Salmonella enterica serovar Typhi and Typhimurium vaccine candidates elicit significant immune responses in mice by intranasal (i.n.) immunization. Because of the proximity of the cribriform plate of the ethmoid bone, we were concerned that Salmonella bacteria delivered i.n. might access the brain. Accordingly, wild-type and attenuated (by single and double mutations) strains of S. enterica serovars Typhimurium and Typhi were recovered at low numbers initially from the olfactory lobe and then from the brain for 3 to 4 days after i.n. immunization. This was independent of invA gene function. Although the presence of bacteria in blood 1 to 3 h after i.n. inoculation was sometimes observed, this was infrequent compared to the frequency of bacteria detected in brain tissues. In confirmation of recent observations by Wickham et al. (M. E. Wickham, N. F. Brown, J. Provias, B. B. Finlay, and B. K. Coombes, BMC Infect. Dis. 7:65, 2007) that oral inoculation with wild-type S. enterica serovar Typhimurium strains lead to bacteria in blood with subsequent colonization of brain tissues with neurological symptoms of disease, we found similar results by using the i.n. and intraperitoneal (i.p.) routes of inoculation for wild-type but not for attenuated strains of S. enterica serovar Typhimurium. In contrast, a highly modified attenuated S. enterica serovar Typhimurium strain was not present in brain tissues when administered at higher doses by the oral, i.n., and i.p. routes than the wild-type strain even though the presence of bacteria in blood was detectable 1 to 3 h after inoculation by each of the three routes. Our results indicate that i.n. and possibly even oral delivery of live Salmonella vaccines may be unsafe although it is possible to reduce this risk by appropriate genetic modifications.
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