Prolonged infection of non-typhoid Salmonella serovars in humans is not well-characterized and only poorly understood. To better understand this manifestation, we have analyzed 48,757 Salmonella cases reported to the National Salmonella Reference Center, 1995-2012. Persistent infection was defined as patients who have submitted at least two positive Salmonella isolates of the same serovar with a minimal interval of 30 days between the first and the last isolate. Altogether, we identified 1056 cases of persistent infections comprising 2.1% of all reported Salmonellosis cases in Israel. A case-control study showed that the mean persistent period was 151 days, the majority (93.3%) of the persistently infected patients was immunocompetent and that 62.3% of the patients were symptomatic with relapsing diarrhea. To the best of our knowledge, this is the first study describing a prolonged symptomatic non-typhoidal Salmonella infection in humans.
Whole genome sequencing of 22 S. Typhimurium isolates from 11 cases of persistent infection demonstrated very high sequence similarity between isolates originated from the same patient, confirming continuous infection, but also revealed SNPs and changes in the composition of mobile genetic elements including plasmids and phages. This indicates that Salmonella genome during persistence is dynamic and horizontal gene exchange with the microbiota occurs inside the host. Virulence and phenotypic studies, in-vitro and in-vivo, using tissue culture and the mouse models demonstrated in multiple cases differences in the virulence between earlier and later isolates from the same patients, indicating that genetic changes during persistent can enhance Salmonella pathogenicity and affect host-pathogen interactions.
