Dataset Information

O-Serotype Conversion in Salmonella Typhimurium Induces Protective Immune Responses against Invasive Non-Typhoidal Salmonella Infections.

ABSTRACT: Salmonella infections remain a big problem worldwide, causing enteric fever by Salmonella Typhi (or Paratyphi) or self-limiting gastroenteritis by non-typhoidal Salmonella (NTS) in healthy individuals. NTS may become invasive and cause septicemia in elderly or immuno-compromised individuals, leading to high mortality and morbidity. No vaccines are currently available for preventing NTS infection in human. As these invasive NTS are restricted to several O-antigen serogroups including B1, D1, C1, and C2, O-antigen polysaccharide is believed to be a good target for vaccine development. In this study, a strategy of O-serotype conversion was investigated to develop live attenuated S. Typhimurium vaccines against the major serovars of NTS infections. The immunodominant O4 serotype of S. Typhimurium was converted into O9, O7, and O8 serotypes through unmarked chromosomal deletion-insertion mutations. O-serotype conversion was confirmed by LPS silver staining and western blotting. All O-serotype conversion mutations were successfully introduced into the live attenuated S. Typhimurium vaccine S738 (?crp ?cya) to evaluate their immunogenicity in mice model. The vaccine candidates induced high amounts of heterologous O-polysaccharide-specific functional IgG responses. Vaccinated mice survived a challenge of 100 times the 50% lethality dose (LD50) of wild-type S. Typhimurium. Protective efficacy against heterologous virulent Salmonella challenges was highly O-serotype related. Furthermore, broad-spectrum protection against S. Typhimurium, S. Enteritidis, and S. Choleraesuis was observed by co-vaccination of O9 and O7 O-serotype-converted vaccine candidates. This study highlights the strategy of expressing heterologous O-polysaccharides via genetic engineering in developing live attenuated S. Typhimurium vaccines against NTS infections.

SUBMITTER: Li P

PROVIDER: S-EPMC5722840 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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O-Serotype Conversion in Salmonella Typhimurium Induces Protective Immune Responses against Invasive Non-Typhoidal Salmonella Infections.

Li Pei P Liu Qing Q Luo Hongyan H Liang Kang K Yi Jie J Luo Ying Y Hu Yunlong Y Han Yue Y Kong Qingke Q

Frontiers in immunology 20171204

Salmonella infections remain a big problem worldwide, causing enteric fever by Salmonella Typhi (or Paratyphi) or self-limiting gastroenteritis by non-typhoidal Salmonella (NTS) in healthy individuals. NTS may become invasive and cause septicemia in elderly or immuno-compromised individuals, leading to high mortality and morbidity. No vaccines are currently available for preventing NTS infection in human. As these invasive NTS are restricted to several O-antigen serogroups i ...[more]

PMID: 29255460

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Project description:BackgroundNon-typhoidal Salmonella (NTS) are a major cause of bloodstream infection (BSI) in sub-Saharan Africa. This study aimed to assess its longitudinal evolution as cause of BSI, its serotype distribution and its antibiotic resistance pattern in Kisantu, DR Congo.MethodsAs part of a national surveillance network, blood cultures were sampled in patients with suspected BSI admitted to Kisantu referral hospital from 2015-2017. Blood cultures were worked-up according to international standards. Results were compared to similar data from 2007 onwards.ResultsIn 2015-2017, NTS (n = 896) represented the primary cause of BSI. NTS were isolated from 7.6% of 11,764 suspected and 65.4% of 1371 confirmed BSI. In children <5 years, NTS accounted for 9.6% of suspected BSI. These data were in line with data from previous surveillance periods, except for the proportion of confirmed BSI, which was lower in previous surveillance periods. Salmonella Typhimurium accounted for 63.1% of NTS BSI and Salmonella Enteritidis for 36.4%. Of all Salmonella Typhimurium, 36.9% did not express the O5-antigen (i.e. variant Copenhagen). O5-negative Salmonella Typhimurium were rare before 2013, but increased gradually from then onwards. Multidrug resistance was observed in 87.4% of 864 NTS isolates, decreased ciprofloxacin susceptibility in 7.3%, ceftriaxone resistance in 15.7% and azithromycin resistance in 14.9%. A total of 14.2% of NTS isolates, that were all Salmonella Typhimurium, were multidrug resistant and ceftriaxone and azithromycin co-resistant. These Salmonella isolates were called extensively drug resistant. Compared to previous surveillance periods, proportions of NTS isolates with resistance to ceftriaxone and azithromycin and decreased ciprofloxacin susceptibility increased.ConclusionAs in previous surveillance periods, NTS ranked first as the cause of BSI in children. The emergence of O5-negative Salmonella Typhimurium needs to be considered in the light of vaccine development. The high proportions of antibiotic resistance are worrisome.

Project description:Multidrug-resistant non-typhoidal Salmonella (NTS) infection has emerged as a prominent cause of invasive infections in Africa. We investigated the prevalence of ceftriaxone-resistant invasive NTS infections, conducted exploratory analysis of risk factors for resistance, and described antimicrobial use in western Kenya. We conducted a secondary analysis of existing laboratory, epidemiology, and clinical data from three independent projects, a malaria vaccine trial, a central nervous system (CNS) study, and the International Emerging Infections Program morbidity surveillance (surveillance program) during 2009-2014. We calculated odds ratios (OR) with 95% confidence intervals (CI) for ceftriaxone-resistant NTS infections compared with ceftriaxone-susceptible infections. We surveyed hospitals, pharmacies, and animal drug retailers about the availability and use of antimicrobials. In total, 286 invasive NTS infections were identified in the three projects; 43 NTS isolates were ceftriaxone-resistant. The absolute prevalence of ceftriaxone resistance varied among these methodologically diverse projects, with 18% (16/90) of isolates resistant to ceftriaxone in the vaccine trial, 89% (16/18) in the CNS study, and 6% (11/178) in the surveillance program. Invasive ceftriaxone-resistant infections increased over time. Most ceftriaxone-resistant isolates were co-resistant to multiple other antimicrobials. Having an HIV-positive mother (OR = 3.7; CI = 1.2-11.4) and taking trimethoprim-sulfamethoxazole for the current illness (OR = 9.6, CI = 1.2-78.9) were significantly associated with acquiring ceftriaxone-resistant invasive NTS infection. Ceftriaxone and other antibiotics were widely prescribed; multiple issues related to prescription practices and misuse were identified. In summary, ceftriaxone-resistant invasive NTS infection is increasing and limiting treatment options for serious infections. Efforts are ongoing to address the urgent need for improved microbiologic diagnostic capacity and an antimicrobial surveillance system in Kenya.

Project description:BackgroundNon-typhoidal Salmonella (NTS) are a frequent cause of invasive infections in sub-Saharan Africa. They are frequently multidrug resistant (co-resistant to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol), and resistance to third-generation cephalosporin and fluoroquinolone non-susceptibility have been reported. Third-generation cephalosporins and fluoroquinolones are often used to treat invasive NTS infections, but azithromycin might be an alternative. However, data on antibiotic treatment efficacy in invasive NTS infections are lacking. In this study, we aimed to assess the spatiotemporal distribution of antimicrobial resistance in invasive NTS infections in sub-Saharan Africa and to describe the available evidence and recommendations on antimicrobial treatment.MethodsWe conducted a systematic review of all available literature on antimicrobial resistance and treatment in invasive NTS infections. We performed a random effects meta-analysis to assess the temporal distribution of multidrug resistance, third-generation cephalosporin resistance, and fluoroquinolone non-susceptibility. We mapped these data to assess the spatial distribution. We provided a narrative synthesis of the available evidence and recommendations on antimicrobial treatment.ResultsSince 2001, multidrug resistance was observed in 75% of NTS isolates from all sub-Saharan African regions (95% confidence interval, 70-80% and 65-84%). Third-generation cephalosporin resistance emerged in all sub-Saharan African regions and was present in 5% (95% confidence interval, 1-10%) after 2010. Fluoroquinolone non-susceptibility emerged in all sub-Saharan African regions but did not increase over time. Azithromycin resistance was reported in DR Congo. There were no reports on carbapenem resistance. We did not find high-quality evidence on the efficacy of antimicrobial treatment. There were no supranational guidelines. The "Access group" antibiotics ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol and "Watch group" antibiotics ceftriaxone, cefotaxime, and ciprofloxacin were recommended as the first-choice antibiotics in national guidelines or reviews. These also recommended (a switch to) oral fluoroquinolones or azithromycin.ConclusionsIn addition to the widespread multidrug resistance in invasive NTS infections in sub-Saharan Africa, resistance to third-generation cephalosporins and fluoroquinolone non-susceptibility was present in all regions. There was a lack of data on the efficacy of antimicrobial treatment in these infections, and supranational evidence-based guidelines were absent.

Dataset Information

O-Serotype Conversion in Salmonella Typhimurium Induces Protective Immune Responses against Invasive Non-Typhoidal Salmonella Infections.

Publications

O-Serotype Conversion in <i>Salmonella</i> Typhimurium Induces Protective Immune Responses against Invasive Non-Typhoidal <i>Salmonella</i> Infections.

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