Host control of persistent Salmonella infection
Parasitology and Biology of Tropical Infectious Disease Pathogens
Final Report Abstract
Enteric (typhoid) fever is a systemic disease caused by infections with Salmonella Typhi or Salmonella Paratyphi A. More than 21 million cases of enteric fever are reported annually causing around 161000 deaths per year (WHO). A major complication in Salmonella infected patients despite a prolonged antibiotic therapy is the development of chronic, asymptomatic carriers. However, the Salmonella in chronic carriers are not resistant to antibiotics. Rather, the pathogen survives stress conditions via colonization of niches, which enables it to evade the antimicrobial effect of the antibiotic treatment and host immune defense in a nongrowing, dormant state. In such a “persister state”, the pathogen is antibiotic-tolerant and able to survive drug therapy. In this project, we performed mixed infections with genome-tagged Salmonella starins that we refer to as WITS library. Each strain in the WITS library has identical biological properties but can be identified by PCR/sequencing. Analyzing the WITS composition in different compartments allows describing dynamics of the infection process, to interrogate routes of Salmonella invasion and define sites of Salmonella persistence. Contrasting WITS distributions in neonate and adult mice, we propose that Salmonella uses different routes of invasion in very young and older mice. In adult mice, the mucosal compartments MLN and PP, showed similar Salmonella/WITS populations indicating shared routes of invasion and/or early dissemination and exchange of WITS between both organs. In contrast no such similarity was apparent in neonate mice. We speculate that these differences might foremost reflect divergent routes of initial Salmonella invasion in neonate and adult mice, potentially including the M cell route in the adult but not neonate mouse. Extending the approach of mixed infections to a model of Salmonella relapse/persistence, we observed that Salmonella can establish independent sites of persistence. Whereas relapsing populations in spleen and liver appeared highly similar, mucosal compartments showed largely unrelated WITS populations. Persistence at these sites seemed to require CD11cexpressing host cells. Depletion of CD11c-expressing cells but not IFNγ neutralization abolished Salmonella relapse in the antibiotic/relapse model. We are exploring further cell depletion models to pin point the exact CD11c+ cell types involved. Our results support the understanding of the dynamics of relapsing infection and guide future approaches to define and eventually better treat chronic/persisting Salmonella infections.
