Genomic Variability of Serial Human Isolates of Salmonella enterica Serovar Typhimurium Associated with Prolonged Carriage

Abstract

c Salmonella enterica serovar Typhimurium is an important foodborne human pathogen that often causes self-limiting but severe gastroenteritis. Prolonged excretion of S. Typhimurium after the infection can lead to secondary transmissions. However, little is known about within-host genomic variation in bacteria associated with asymptomatic shedding. Genomes of 35 longitudinal isolates of S. Typhimurium recovered from 11 patients (children and adults) with culture-confirmed gastroenteritis were sequenced. There were three or four isolates obtained from each patient. Single nucleotide polymorphisms (SNPs) were analyzed in these isolates, which were recovered between 1 and 279 days after the initial diagnosis. Limited genomic variation (5 SNPs or fewer) was associated with short-and long-term carriage of S. Typhimurium. None of the isolates was shown to be due to reinfection. SNPs occurred randomly, and the majority of the SNPs were nonsynonymous. Two nonsense mutations were observed. A nonsense mutation in flhC rendered the isolate nonmotile, whereas the significance of a nonsense mutation in yihV is unknown. The estimated mutation rate is 1.49 ؋ 10 ؊6 substitution per site per year. S. Typhimurium isolates excreted in stools following acute gastroenteritis in children and adults demonstrated limited genomic variability over time, regardless of the duration of carriage. These findings have important implications for the detection of possible transmission events suspected by public health genomic surveillance of S. Typhimurium infections. Nontyphoid Salmonella (NTS) infections generally result in a short-term, self-limiting gastroenteritis. However, NTS can be excreted continually and asymptomatically in stools for many weeks, even after the initial diarrheal episode has been resolved. Children are the more common carriers, especially children under the age of 3 years (1, 2). Fecal shedding of NTS after an intestinal infection can last for up to 4 weeks in adults and 7 weeks in children (3). In a very small proportion of cases, carriage can last for a year after the initial onset of the disease (3). Carriers excrete large numbers of bacteria in their feces and can facilitate the transmission of Salmonella to other hosts by contaminating water and food sources. The persistence of fecal shedding in asymptomatic patients can have a duration similar to that for patients with clinical disease (4). Antibiotic treatment of NTS disease is rarely indicated, as it does not assist in clearance of infection but may increase the duration of asymptomatic shedding (4).Salmonella enterica serovar Typhimurium is one of the leading causes of NTS gastroenteritis in humans in Australia and other countries. Salmonellosis is a notifiable disease in all Australian states and territories. In the state of New South Wales (NSW), the notification rate has been around 50 cases per 100,000 population (5). Sequencing of S. Typhimurium genomes or analyses of tandem repeats within the genome have increasingly been employed for tracking community ou...

Persistent Infection and Long-Term Carriage of Typhoidal and Nontyphoidal Salmonellae

“…Although this is a relatively low SNP rate, we were able to demonstrate that in independent cases, SNPs were found to be nonsynonymous substitutions or nonsense mutations in global virulence regulatory genes, including dksA, rpoS, hilD, melR, rfc, and barA, which may infer a pleotropic change in the transcriptional landscape of persistent Salmonella infection (154). Similarly, a nonsense mutation in another global regulator, flhC, encoding a master regulator of flagellum biogenesis, was reported by Octavia and colleagues for a 55-day S. Typhimurium persistence case (264). Moreover, we demonstrated that recrudescent isolates may harbor different compositions of plasmids and bacteriophages, suggesting loss and/or horizontal acquisition of mobile genetic elements during prolonged infection within the human host (154).…”

“…A similar SNP substitution rate was found in patients who were persistently infected with invasive S. Typhimurium pv. ST313 in sub-Saharan Africa (263) or in S. Typhimurium associated with short-and long-term carriage, which showed an estimated mutation rate of 1.49 ϫ 10 Ϫ6 substitutions per site per year (264). Although this is a relatively low SNP rate, we were able to demonstrate that in independent cases, SNPs were found to be nonsynonymous substitutions or nonsense mutations in global virulence regulatory genes, including dksA, rpoS, hilD, melR, rfc, and barA, which may infer a pleotropic change in the transcriptional landscape of persistent Salmonella infection (154).…”

Campylobacteriosis, Salmonellosis, Yersiniosis, and Listeriosis as Zoonotic Foodborne Diseases: A Review

“…After the disappearance of symptoms, Salmonella may still reside in the intestines of an adult for 4 weeks, and in children for up to 7 weeks. A small number of people demonstrates an asymptomatic carrier state of pathogenic bacteria for a year after the disappearance of symptoms [ 111 ]. In the majority of cases, nontyphoid salmonellosis does not require hospitalisation, and only fluid therapy is necessary in the cases associated with severe diarrhea.…”

Evolution of Variable Number Tandem Repeats and Its Relationship with Genomic Diversity in Salmonella Typhimurium

“…Typhimurium isolates with no apparent adaptive values. For example, Octavia et al (2015b) analyzed the genomic variation of serial S . Typhimurium isolates in human infection related with prolonged carriage and found that the majority of SNPs observed were located in coding regions, most of which were nsSNPs in the genes involved with metabolism.…”