Abstract
ABSTRACTThe ST313 pathovar of Salmonella enterica serovar Typhimurium contributes to a high burden of invasive disease among African infants and HIV-infected adults. It is characterized by genome degradation (loss of coding capacity) and has increased resistance to antibody-dependent complement-mediated killing compared with enterocolitis-causing strains of S. Typhimurium. Vaccination is an attractive disease-prevention strategy, and leading candidates focus on the induction of bactericidal antibodies. Antibody-resistant strains arising through further gene deletion could compromise such a strategy. Exposing a saturating transposon insertion mutant library of S. Typhimurium to immune serum identified a repertoire of S. Typhimurium genes that, when interrupted, result in increased resistance to serum killing. These genes included several involved in bacterial envelope biogenesis, protein translocation, and metabolism. We generated defined mutant derivatives using S. Typhimurium SL1344 as the host. Based on their initial levels of enhanced resistance to killing, yfgA and sapA mutants were selected for further characterization. The S. Typhimurium yfgA mutant lost the characteristic Salmonella rod-shaped appearance, exhibited increased sensitivity to osmotic and detergent stress, lacked very long lipopolysaccharide, was unable to invade enterocytes, and demonstrated decreased ability to infect mice. In contrast, the S. Typhimurium sapA mutants had similar sensitivity to osmotic and detergent stress and lipopolysaccharide profile and an increased ability to infect enterocytes compared with the wild type, but it had no increased ability to cause in vivo infection. These findings indicate that increased resistance to antibody-dependent complement-mediated killing secondary to genetic deletion is not necessarily accompanied by increased virulence and suggest the presence of different mechanisms of antibody resistance.
Highlights
Nontyphoidal salmonellae (NTS) are a major cause of illness and death worldwide [1]
Case fatality rates of up to 25% [3,4,5]. The majority of this invasive nontyphoidal Salmonella disease is attributable to serovars Typhimurium and Enteritidis, which account for up to 95% of cases in sub-Saharan Africa [4,5,6]
Typhimurium resulted in enhanced survival in serum, we addressed the question as to how this impacts the interaction of the pathogen with host enterocytes in culture and the ability to colonize the host using a mouse model of Salmonella infection
Summary
Nontyphoidal salmonellae (NTS) are a major cause of illness and death worldwide [1]. While gastroenteritis is the most common clinical manifestation of the disease in the developed world, severe, often fatal disseminated disease is dominant in sub-Saharan Africa, with an estimated global burden of mortality in 2010 of 680,000 [2]. Case fatality rates of up to 25% [3,4,5] The majority of this invasive nontyphoidal Salmonella (iNTS) disease is attributable to serovars Typhimurium and Enteritidis, which account for up to 95% of cases in sub-Saharan Africa [4,5,6]. A potential threat to the successful implementation of a vaccination strategy is that further genome modification within the ST313 pathovar could result in adaptation toward enhanced resistance to antibody-mediated killing and subsequently the emergence of potential vaccine escape mutants. Acquisition of such antibody resistance might be accelerated under the selective pressure exerted by an antibody-inducing vaccine. Typhimurium impacts other functions associated with bacterial survival and virulence, so that the trade-offs between serum resistance and viability help to maintain Salmonella in a serum-sensitive state
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
