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Attenuated Salmonella typhimurium htrA mutants cause fatal infections in mice deficient in NADPH oxidase and destroy NADPH oxidase-deficient macrophage monolayers

Lookup NU author(s): Dr Mbithe Mutunga, Dr Julie Musson, Professor John Robinson, Dr Anjam Khan, Professor Carlos Hormaeche

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Abstract

Salmonella live vaccine strains harbouring mutations in htrA, a stress protein gene, display increased susceptibility to oxidative stress in vitro. This is believed to be connected to their reduced virulence, perhaps due to impaired survival inside phagocytes, although this has never been formally proven. We report that the in vitro phenotype of increased susceptibility to oxidative stress of Salmonella typhimurium htrA mutants newly prepared by transduction is rapidly lost on subculture, with the mutants becoming as resistant as the parent for reasons that remain unclear. However, despite this change, htrA mutants are still attenuated in normal mice. In contrast, they were found to be lethal for gene targeted gp91phox-/- mice deficient in NADPH oxidase, as was a S. typhimurium SPI-2 mutant known to be virulent in gp9lphox-/- mice. Infection with htrA mutants caused little damage to primary bone marrow macrophage cultures from normal mice; conversely, they caused extensive damage to macrophages from gp9lphox-/- mice, with more than 60% reduction in cell numbers 2.5 h after being infected. The parental wild type strain similarly caused extensive damage to macrophages from both normal and gp9lphox-/- mice, whereas an aroA live vaccine strain had no effect on either normal or gp9lphox-/- macrophages. Taken collectively, the present results suggest that htrA is somehow involved in resistance to oxidative stress in vivo, with the avirulence of htrA mutants in mice being due to mechanisms which involve NADPH oxidase and suppression of bacterial growth within macrophages. © 2004 Published by Elsevier Ltd.


Publication metadata

Author(s): Mutunga M, Graham S, De Hormaeche RD, Musson JA, Robinson JH, Mastroeni P, Khan CMA, Hormaeche CE

Publication type: Article

Publication status: Published

Journal: Vaccine

Year: 2004

Volume: 22

Issue: 29-30

Pages: 4124-4131

ISSN (print): 0264-410X

ISSN (electronic): 1873-2518

Publisher: Elsevier Ltd

URL: http://dx.doi.org/10.1016/j.vaccine.2003.10.053

DOI: 10.1016/j.vaccine.2003.10.053

PubMed id: 15364466


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