Dynamics of relapsing and chronic Salmonella infection

Kranz, Denise-Carina; Pabst, Oliver (Thesis advisor); Pradel, Gabriele (Thesis advisor); Hornef, Mathias (Thesis advisor)

Aachen : RWTH Aachen University (2020, 2021)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2020


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, chronic carriers are not resistant to antibiotics. Indeed, the pathogen survives stress conditions such as antibiotic treatment via colonization of niches, which enables it to evade the host immune defence in a non-growing, dormant state. In such a "persister state", the pathogen is antibiotic-tolerant and able to survive drug therapy. After termination of the antibiosis, Salmonella can start to regrow and cause relapsing infection. These asymptomatic, chronically infected patients are high-risk factors since they shed the pathogen in their faeces resulting in spread and maintenance of Salmonella in the human population. This thesis aimed to obtain new insights into the dynamics during the Salmonella infection processes. A typhoid relapse mouse model was used to understand the mechanisms resulting in chronic carriage and relapsing infection. Mixed infections with nucleotide-tagged Salmonella Typhimurium, so called Wildtype isogenic tagged Salmonella strains (WITS), were used to predict routes of the pathogens‘ dissemination in order to identify bottlenecks in the infection process, e.g. host immune response. The data obtained in this thesis demonstrate that infection and colonization differ between the organs and that infection of gut-associated organs (mesenteric lymph nodes and Peyer`s Patches) occurs independent from that of systemic compartments like liver and spleen. The results obtained identified at least three individual anatomical sites where Salmonella is able to persist and from where relapse infections might originate. CD11c+-cells were identified as reservoirs for Salmonella and relapse infections were blocked by depletion of this cell type. Furthermore, the findings suggest a minor role of the adaptive immunity in the dissemination of Salmonella to systemic sites that influences the colonisation and spread to these compartments in an age-dependent manner. In addition, this study emphasized to establish a method for the identification of growing and persisting cells in given/non-defined samples to bypass the biased sampling via conventional plating methods, which are limited to the detection of viable, actively growing bacteria. This study supports the understanding of the dynamics of relapsing infection and provides information necessary for the development of effective therapeutic strategies against (persisting) Salmonella Typhi and S. Paratyphi A.