title: Pregnancy impairs the innate immune resistance to Salmonella typhimurium leading to rapid fatal infection.
abstract: 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 (129 x 1/SvJ) develop a chronic infection. We found that virulent ST infection during pregnancy, in normally resistant 129 x 1/SvJ mice, evoked approximately 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 approximately 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 >10(5) 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.
authors.affiliation: National Research Council-Institute for Biological Sciences, Ottawa, Ontario, Canada.
authors.forename: Branka
authors.initials: B
authors.lastname: Pejcic-Karapetrovic
authors.forename: Komal
authors.initials: K
authors.lastname: Gurnani
authors.forename: Marsha S
authors.initials: MS
authors.lastname: Russell
authors.forename: B Brett
authors.initials: BB
authors.lastname: Finlay
authors.forename: Subash
authors.initials: S
authors.lastname: Sad
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Krishnan
mesh_terms: D000818:Animals; D020964:Embryo Loss / Q000276:immunology* / Q000382:microbiology; D005260:Female; D007113:Immunity, Innate / Q000276:immunology*; D018664:Interleukin-12 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D007700:Kinetics; D008297:Male; D051379:Mice; D011247:Pregnancy; D012480:Salmonella Infections / Q000276:immunology* / Q000382:microbiology; D012486:Salmonella typhimurium / Q000276:immunology* / Q000472:pathogenicity*; D013154:Spleen / Q000276:immunology; D013997:Time Factors
chemical_list: D015850:Interleukin-6; D018664:Interleukin-12