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* National Research Council–Institute for Biological Sciences, Ottawa, Ontario, Canada;
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada; and
Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
Typhoid fever and gastroenteritis caused by Salmonella enterica species are increasing globally. Pregnancy poses a high risk, but it is unclear how maternal immunity to infection is altered. In mice, susceptible strains die of S. enterica serovar typhimurium (ST) infection within 7 days whereas resistant mice (129x1/SvJ) develop a chronic infection. We found that virulent ST infection during pregnancy, in normally resistant 129x1/SvJ mice, evoked 
100% fetal loss and surprisingly >60% host fatality, with a median survival of 6 days. Splenic bacterial load was 1000-fold higher in pregnant mice. This correlated to a diminished splenic recruitment/expansion of innate immune cells: dendritic cells, neutrophils, and NK cells. In particular, the splenic expansion and activation of NK cells postinfection seen in nonpregnant mice was lacking in pregnancy. Most notably, pregnant-infected mice had decreased production of serum IL-12 and increased IL-6 levels. Moreover, uteroplacental tissue of pregnant-infected mice exhibited an 40-fold increase in IL-6 mRNA expression relative to noninfected placenta, whereas IL-12p40 was not increased. In vivo blocking of IL-6 significantly reduced the splenic bacterial burden in pregnant mice yet failed to prevent fetal loss. Fetal demise correlated to the rapidity of infection; by 14 h, ST expanded to >105 in the placenta and had reached the fetus. Therefore, the preferential placental expansion of ST plausibly altered the inflammatory response toward IL-6 and away from IL-12, reducing the recruitment/activation of splenic innate immune cells. Thus, highly virulent pathogens may use placental invasion to alter systemic host resistance to infection.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by funds from the Canadian Institutes of Health Research–Institute of Infections and Immunity, Canada.
2 Current address: Assisted Human Reproduction Implementation Office, Health Canada, Ottawa, Canada.
3 B.P.-K. and K.G. contributed equally to this work.
4 Address correspondence and reprint requests to Dr. Lakshmi Krishnan, National Research Council–Institute for Biological Sciences, 1200 Montreal Road, Building M-54, Ottawa, Ontario, Canada K1A OR6. E-mail address: Lakshmi.Krishnan{at}nrc-cnrc.gc.ca
5 Abbreviations used in this paper: ST, Salmonella enterica serovar typhimurium; BHI, brain-heart infusion; uNK, uterine NK.
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  H. Albaghdadi, N. Robinson, B. Finlay, L. Krishnan, and S. Sad Selectively Reduced Intracellular Proliferation of Salmonella enterica Serovar Typhimurium within APCs Limits Antigen Presentation and Development of a Rapid CD8 T Cell Response J. Immunol., September 15, 2009; 183(6): 3778 - 3787. [Abstract] [Full Text] [PDF]
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