A Superoxide-HypersusceptibleSalmonella entericaSerovar Typhimurium Mutant Is Attenuated but Regains Virulence in p47phox−/−Mice

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Abstract
Salmonella entericaserovar Typhimurium is a gram-negative, facultative intracellular pathogen that predominantly invades mononuclear phagocytes and is able to establish persistent infections. One of the innate defense mechanisms of phagocytic cells is the production of reactive oxygen species, including superoxide.S. entericaserovar Typhimurium has evolved mechanisms to resist such radicals, and these mechanisms could be decisive in its ability to survive and replicate within macrophages. Recently, we described a superoxide-hypersusceptibleS. entericaserovar Typhimurium mutant strain, DLG294, that carries a transposon insspJ, resulting in the lack of expression of SspJ, which is necessary for resistance against superoxide and replication within macrophages. Here we show that DLG294, which is a 14028s derivative, hardly induced any granulomatous lesions in the livers upon subcutaneous infection of C3H/HeN (Ityr) mice with 3 × 104bacteria and that its bacterial counts were reduced by 3 log units compared to those of wild-typeS. entericaserovar Typhimurium 14028s on day 5 after infection. In contrast, DLG294 replicated like wild-typeS. entericaserovar Typhimurium 14028s and induced a phenotypically similar liver pathology in p47phox−/−mice, which are deficient in the p47phoxsubunit of the NADPH oxidase complex and which do not produce superoxide. Consistent with these results, DLG294 reached bacterial counts identical to those of wild-typeS. entericaserovar Typhimurium 14028s in bone marrow-derived macrophages from p47phox−/−mice and in X-CGD PLB-985 cells at 24 h after challenge. These results indicate that SspJ plays a role in the bacterium's resistance to oxidative stress and in the survival and replication ofS. entericaserovar Typhimurium both in vitro and in vivo.