Role of Salmonella typhimurium virulence in differentially modulating immune response and host susceptibility during pregnancy

Abstract

Pregnancy poses a high risk to many infections but it is unclear how maternal immunity is modulated by pathogen virulence. Typhoid fever and gastroenteritis caused by Salmonella enterica species are increasing globally and pregnancy poses a high risk. In 129X1Sv/J mice, Salmonella enterica serovar typhimurium (ST) infection normally leads to a systemic chronic disease. However, pregnant 129X1Sv/J mice succumb rapidly to ST infection. We aimed to decipher the host and/or pathogen-associated immune mechanisms that contribute to the loss of resistance to ST in pregnancy. Infection of pregnant mice with virulent wild-type ST promoted profound pathogen proliferation in the placenta, leading to loss of placental integrity by 72 hours. Severe systemic disease in pregnant hosts was associated with an acute increase in serum inflammatory cytokines/chemokines (ex. G-CSF, IL6, I-309). This correlated to increased placental expression of inflammatory cytokines, (G-CSF, IL-6, TNFalpha) and massive infiltration of polymorphonuclear cells (neutrophils) to the infected placental tissue. Contrastingly, even a high dose of the avirulent ST aroA mutant did not induce fetal loss or maternal illness, despite massive placental infection. This correlated to an anti-inflammatory cytokine signature (increased splenic IL10 and reduced systemic and placental inflammation) evoked by the aroA mutant. Thus, pathogen virulence rather than absolute bacterial burden critically influences the quality and/or quantity of the cytokine/cellular response to infection. This study provides a mechanistic insight as to why pregnant hosts are highly vulnerable to food and water borne pathogens, and may facilitate the development of potential therapeutics. ST infection in pregnancy also provides a convenient model to address the role of inflammation in placental pathology.