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MSphere Jan 2024causes bacillary dysentery and is responsible for a high burden of disease globally. Several studies have emphasized the value of functional antibody activity to...
causes bacillary dysentery and is responsible for a high burden of disease globally. Several studies have emphasized the value of functional antibody activity to understand immunity and correlates of protection. The anti-microbial function of local (mucosal) antibodies and their contribution to preventing infection remain unknown. The goal of this study was to identify the functional humoral immune effectors elicited by two live oral vaccine candidates, WRSs2 and WRSs3. Complement-dependent bactericidal [serum bactericidal antibody (SBA)/bactericidal antibody (BA)] and opsonophagocytic killing antibody (OPKA) activity were determined in sera and stool extracts as indicators of systemic and local anti-microbial immunity. High levels of SBA/BA and OPKA were detected in serum as well as in fecal extracts from volunteers who received a single dose of WRSs2 and WRSs3. Functional antibody activity peaked on days 10 and 14 post-vaccination in fecal and serum samples, respectively. Bactericidal and OPKA titers were closely associated. Peak fold rises in functional antibody titers in serum and fecal extracts were also associated. Antibody activity interrogated in IgG and IgA purified from stool fractions identified IgG as the primary driver of mucosal bactericidal and OPKA activity, with minimal functional activity of IgA alone, highlighting an underappreciated role for IgG in bacterial clearance in the mucosa. The combination of IgG and IgA in equal proportions enhanced bactericidal and OPKA titers hinting at a co-operative or synergistic action. Our findings provide insight into the functional anti-microbial capacity of vaccine-induced mucosal IgG and IgA and propose an operative local humoral effector of protective immunity.IMPORTANCEThere is an urgent need for a safe, effective, and affordable vaccine against . Understanding the immunological underpinning of infection and the make-up of protective immunity is critical to achieve the best approach to prevent illness caused by this mucosal pathogen. We measured the complement-dependent bactericidal and opsonophagocytic antibody killing in serum and stool extracts from adult volunteers vaccinated with live oral vaccine candidates WRSs2 and WRSs3. For the first time, we detected functional antibody responses in stool samples that were correlated with those in sera. Using purified stool IgA and IgG fractions, we found that functional activity was mediated by IgG, with some help from IgA. These findings provide insight into the functional anti-microbial capacity of vaccine-induced mucosal IgG and IgA and support future studies to identify potential markers of protective mucosal immunity.
Topics: Adult; Humans; Shigella sonnei; Dysentery, Bacillary; Antibodies, Bacterial; Shigella; Immunization; Vaccination; Vaccines; Mucous Membrane; Immunoglobulin G; Immunoglobulin A
PubMed: 38132716
DOI: 10.1128/msphere.00419-23 -
Clinical Microbiology and Infection :... Nov 2017Shigella sonnei is a globally important diarrhoeal pathogen tracked through the surveillance network PulseNet Latin America and Caribbean (PNLA&C), which participates in...
OBJECTIVES
Shigella sonnei is a globally important diarrhoeal pathogen tracked through the surveillance network PulseNet Latin America and Caribbean (PNLA&C), which participates in PulseNet International. PNLA&C laboratories use common molecular techniques to track pathogens causing foodborne illness. We aimed to demonstrate the possibility and advantages of transitioning to whole genome sequencing (WGS) for surveillance within existing networks across a continent where S. sonnei is endemic.
METHODS
We applied WGS to representative archive isolates of S. sonnei (n = 323) from laboratories in nine PNLA&C countries to generate a regional phylogenomic reference for S. sonnei and put this in the global context. We used this reference to contextualise 16 S. sonnei from three Argentinian outbreaks, using locally generated sequence data. Assembled genome sequences were used to predict antimicrobial resistance (AMR) phenotypes and identify AMR determinants.
RESULTS
S. sonnei isolates clustered in five Latin American sublineages in the global phylogeny, with many (46%, 149 of 323) belonging to previously undescribed sublineages. Predicted multidrug resistance was common (77%, 249 of 323), and clinically relevant differences in AMR were found among sublineages. The regional overview showed that Argentinian outbreak isolates belonged to distinct sublineages and had different epidemiologic origins.
CONCLUSIONS
Latin America contains novel genetic diversity of S. sonnei that is relevant on a global scale and commonly exhibits multidrug resistance. Retrospective passive surveillance with WGS has utility for informing treatment, identifying regionally epidemic sublineages and providing a framework for interpretation of prospective, locally sequenced outbreaks.
Topics: Caribbean Region; DNA, Bacterial; Disease Outbreaks; Drug Resistance, Bacterial; Dysentery, Bacillary; Foodborne Diseases; Humans; Latin America; Public Health Surveillance; Retrospective Studies; Shigella sonnei; Whole Genome Sequencing
PubMed: 28389276
DOI: 10.1016/j.cmi.2017.03.021 -
Emerging Infectious Diseases Jul 2018Whole-genome sequencing unveiled host and environment-related insights to Shigella sonnei transmission within cyclic epidemics during 2000-2012 in Israel. The Israeli...
Whole-genome sequencing unveiled host and environment-related insights to Shigella sonnei transmission within cyclic epidemics during 2000-2012 in Israel. The Israeli reservoir contains isolates belonging to S. sonnei lineage III but of different origin, shows loss of tetracycline resistance genes, and little genetic variation within the O antigen: highly relevant for Shigella vaccine development.
Topics: Disease Outbreaks; Dysentery, Bacillary; Evolution, Molecular; Genome, Bacterial; Humans; Israel; Public Health Surveillance; Shigella sonnei; Whole Genome Sequencing
PubMed: 29912703
DOI: 10.3201/eid2407.171313 -
Nature Communications Jan 2023Shigella sonnei, the main cause of bacillary dysentery in high-income countries, has become increasingly resistant to antibiotics. We monitored the antimicrobial...
Shigella sonnei, the main cause of bacillary dysentery in high-income countries, has become increasingly resistant to antibiotics. We monitored the antimicrobial susceptibility of 7121 S. sonnei isolates collected in France between 2005 and 2021. We detected a dramatic increase in the proportion of isolates simultaneously resistant to ciprofloxacin (CIP), third-generation cephalosporins (3GCs) and azithromycin (AZM) from 2015. Our genomic analysis of 164 such extensively drug-resistant (XDR) isolates identified 13 different clusters within CIP-resistant sublineage 3.6.1, which was selected in South Asia ∼15 years ago. AZM resistance was subsequently acquired, principally through IncFII (pKSR100-like) plasmids. The last step in the development of the XDR phenotype involved various extended-spectrum beta-lactamase genes (bla, bla, bla, bla, and bla) carried by different plasmids (IncFII, IncI1, IncB/O/K/Z) or even integrated into the chromosome, and encoding resistance to 3GCs. This rapid emergence of XDR S. sonnei, including an international epidemic strain, is alarming, and good laboratory-based surveillance of shigellosis will be crucial for informed decision-making and appropriate public health action.
Topics: Humans; Anti-Bacterial Agents; Azithromycin; beta-Lactamases; Ciprofloxacin; Dysentery, Bacillary; France; Microbial Sensitivity Tests; Plasmids; Shigella sonnei; Drug Resistance, Multiple, Bacterial
PubMed: 36709320
DOI: 10.1038/s41467-023-36222-8 -
PLoS Neglected Tropical Diseases Apr 2017Although, Shigella encephalopathy, a serious extra-intestinal complication of shigellosis, significantly increases the risks of death, data are very limited on...
BACKGROUND
Although, Shigella encephalopathy, a serious extra-intestinal complication of shigellosis, significantly increases the risks of death, data are very limited on predicting factors particularly related to electrolyte profiles in children below five years of age with Shigella encephalopathy. Our objective was to determine the clinical as well as laboratory predicting factors and outcome of children with Shigella encephalopathy.
METHODOLOGY/PRINCIPAL FINDINGS
In this unmatched case-control design, children aged 2-59 months having a positive stool culture for Shigella and who had their serum electrolytes been done from July 2012 to June 2015 were studied. Children with Shigella encephalopathy, defined as having abnormal mentation, constituted the cases, and those without encephalopathy constituted the controls. During the study period, we identified a total of 541 children less than five years of age, who had Shigella in their stool culture. Only 139 children fulfilled the study criteria and among them 69 were cases and 70 were controls. The cases more often had fatal outcome compared to the controls (7% vs. 0%, P = 0.02). In logistic regression analysis, the cases were independently associated with shorter duration (1.2 ± 0.4 days) of diarrhea prior to admission, dehydrating diarrhea, sepsis and hyponatremia (p<0.05 for all). Among 139 Shigella isolates, S. flexneri (88/139, 63%) and S. sonnei(34/139, 24%) were the dominant species. S. dysenteriae was not isolated throughout the study period. S.sonnei was more frequently isolated from the cases (24/69, 35%) than the controls (10/70, 14%), whereas the isolation of S. flexneri was comparable between the groups (40/69, 58% vs 48/70, 69%). A total of 94 (67.6%) isolates were resistant to trimethoprim-sulphamethoxazole, 84 (60.4%) to ciprofloxacin, 66/138 (48%) to ampicillin, 5 (3.5%) to ceftriaxone, 17 (12.2%) to mecillinum and 35 (25%) to azithromycin.
CONCLUSIONS/SIGNIFICANCE
The case-fatality-rate was significantly higher among the children with Shigella encephalopathy compared to those without encephalopathy. Early identification and aggressive management of simple risk factors for Shigella encephalopathy may help to reduce morbidity and deaths in such children especially in resource-limited settings.
Topics: Anti-Bacterial Agents; Bangladesh; Brain Diseases; Case-Control Studies; Child, Preschool; Drug Resistance, Bacterial; Dysentery, Bacillary; Female; Humans; Infant; Male; Risk Factors; Shigella dysenteriae; Shigella flexneri; Shigella sonnei; Survival Analysis; Treatment Outcome
PubMed: 28453565
DOI: 10.1371/journal.pntd.0005561 -
The Journal of Antimicrobial... Mar 2016We aimed to quantify the impact of fluoroquinolone resistance on the clinical outcome of paediatric shigellosis patients treated with fluoroquinolones in southern...
OBJECTIVES
We aimed to quantify the impact of fluoroquinolone resistance on the clinical outcome of paediatric shigellosis patients treated with fluoroquinolones in southern Vietnam. Such information is important to inform therapeutic management for infections caused by this increasingly drug-resistant pathogen, responsible for high morbidity and mortality in young children globally.
METHODS
Clinical information and bacterial isolates were derived from a randomized controlled trial comparing gatifloxacin with ciprofloxacin for the treatment of paediatric shigellosis. Time-kill experiments were performed to evaluate the impact of MIC on the in vitro growth of Shigella and Cox regression modelling was used to compare clinical outcome between treatments and Shigella species.
RESULTS
Shigella flexneri patients treated with gatifloxacin had significantly worse outcomes than those treated with ciprofloxacin. However, the MICs of fluoroquinolones were not significantly associated with poorer outcome. The presence of S83L and A87T mutations in the gyrA gene significantly increased MICs of fluoroquinolones. Finally, elevated MICs and the presence of the qnrS gene allowed Shigella to replicate efficiently in vitro in high concentrations of ciprofloxacin.
CONCLUSIONS
We found that below the CLSI breakpoint, there was no association between MIC and clinical outcome in paediatric shigellosis infections. However, S. flexneri patients had worse clinical outcomes when treated with gatifloxacin in this study regardless of MIC. Additionally, Shigella harbouring the qnrS gene are able to replicate efficiently in high concentrations of ciprofloxacin and we hypothesize that such strains possess a competitive advantage against fluoroquinolone-susceptible strains due to enhanced shedding and transmission.
Topics: Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; DNA, Bacterial; Drug Resistance, Bacterial; Dysentery, Bacillary; Female; Fluoroquinolones; Humans; Infant; Male; Microbial Sensitivity Tests; Randomized Controlled Trials as Topic; Sequence Analysis, DNA; Shigella flexneri; Shigella sonnei; Treatment Failure; Vietnam
PubMed: 26679253
DOI: 10.1093/jac/dkv400 -
PloS One 2019Shigella species remains a major diarrhoeagenic agent, affecting mostly children, with global high incidence and high mortality rate specially in developing areas....
Shigella species remains a major diarrhoeagenic agent, affecting mostly children, with global high incidence and high mortality rate specially in developing areas. Although azithromycin is recommended for treatment of shigellosis, there are currently no CLSI susceptibility breakpoints, accordingly no routine antimicrobial susceptibility test is performed in the clinical laboratory. The purpose of this study was to estimate the prevalence, resistance profile and molecular epidemiology of azithromycin non-susceptible Shigella strains in Israel during a three year period. Shigella isolates (n = 1,170) referred to the National Reference Center during 2014-2016, were included in this study. Serotyping was performed by slide agglutination. Resistance genes, mph(A) and erm(B), were identified by PCR and the phenotype profile was determined by broth microdilution (BMD). Genetic relatedness was assessed by wgMLST. Decreased susceptibility to azithromycin (DSA) phenotype and genotype were detected in various Shigella species and serotypes related to diverse genetic backgrounds and antimicrobial profiles: 6% (26/423) of Shigella flexneri and 2% (16/747) of Shigella sonnei displayed DSA (MIC16 mg/L). Correlation of this phenotype with the presence of mph(A) and erm(B) genes was confirmed. All DSA-strains displayed resistance to ≥3 different antimicrobial classes. Among DSA-strains, 14% were resistant to quinolones and 5% displayed resistance to ceftriaxone. Most of these strains (32/42) were isolated from children in the southern and central regions of Israel. Clonality and significant relatedness was confirmed by PFGE and wgMLST. The presence of macrolide resistance genes among the different species and lineages reflects the transmissible nature of these genes. The emergence of DSA-Shigella reinforces the necessity to establish clinical breakpoints that would warrant routine testing, reporting and surveillance for this drug of choice.
Topics: Azithromycin; Drug Resistance, Bacterial; Dysentery, Bacillary; Genes, Bacterial; Genotype; Humans; Israel; Shigella flexneri; Shigella sonnei
PubMed: 31626667
DOI: 10.1371/journal.pone.0221458 -
Antimicrobial Agents and Chemotherapy Apr 2018Infection by spp. is a common cause of dysentery in Southeast Asia. Antimicrobials are thought to be beneficial for treatment; however, antimicrobial resistance in...
Infection by spp. is a common cause of dysentery in Southeast Asia. Antimicrobials are thought to be beneficial for treatment; however, antimicrobial resistance in spp. is becoming widespread. We aimed to assess the frequency and mechanisms associated with decreased susceptibility to azithromycin in Southeast Asian isolates and use these data to assess appropriate susceptibility breakpoints. isolates recovered in Vietnam and Laos were screened for susceptibility to azithromycin (15 μg) by disc diffusion and MIC. Phenotypic resistance was confirmed by PCR amplification of macrolide resistance loci. We compared the genetic relationships and plasmid contents of azithromycin-resistant isolates using whole-genome sequences. From 475 available spp. isolated in Vietnam and Laos between 1994 and 2012, 6/181 isolates (3.3%, MIC ≥ 16 g/liter) and 16/294 isolates (5.4%, MIC ≥ 32 g/liter) were phenotypically resistant to azithromycin. PCR amplification confirmed a resistance mechanism in 22/475 (4.6%) isolates ( in 19 isolates and in 3 isolates). The susceptibility data demonstrated the acceptability of the (MIC ≥ 16 g/liter, zone diameter ≤ 15 mm) and (MIC ≥ 32 g/liter, zone diameter ≤ 11 mm) breakpoints with a <3% discrepancy. Phylogenetic analysis demonstrated that decreased susceptibility has arisen sporadically in Vietnamese isolates on at least seven occasions between 2000 and 2009 but failed to become established. While the proposed susceptibility breakpoints may allow better recognition of resistant isolates, additional studies are required to assess the impact on the clinical outcome. The potential emergence of azithromycin resistance highlights the need for alternative options for management of infections in countries where is endemic.
Topics: Anti-Bacterial Agents; Asia, Southeastern; Azithromycin; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Dysentery, Bacillary; Microbial Sensitivity Tests; Phylogeny; Shigella; Shigella flexneri; Shigella sonnei
PubMed: 29378707
DOI: 10.1128/AAC.01748-17 -
Emerging Infectious Diseases Sep 2016Shigellae are sensitive indicator species for studying trends in the international transmission of antimicrobial-resistant Enterobacteriaceae. Orthodox Jewish...
Shigellae are sensitive indicator species for studying trends in the international transmission of antimicrobial-resistant Enterobacteriaceae. Orthodox Jewish communities (OJCs) are a known risk group for shigellosis; Shigella sonnei is cyclically epidemic in OJCs in Israel, and sporadic outbreaks occur in OJCs elsewhere. We generated whole-genome sequences for 437 isolates of S. sonnei from OJCs and non-OJCs collected over 22 years in Europe (the United Kingdom, France, and Belgium), the United States, Canada, and Israel and analyzed these within a known global genomic context. Through phylogenetic and genomic analysis, we showed that strains from outbreaks in OJCs outside of Israel are distinct from strains in the general population and relate to a single multidrug-resistant sublineage of S. sonnei that prevails in Israel. Further Bayesian phylogenetic analysis showed that this strain emerged approximately 30 years ago, demonstrating the speed at which antimicrobial drug-resistant pathogens can spread widely through geographically dispersed, but internationally connected, communities.
Topics: Anti-Bacterial Agents; Community-Acquired Infections; Disease Outbreaks; Drug Resistance, Multiple, Bacterial; Dysentery, Bacillary; Genes, Bacterial; Genome, Bacterial; Global Health; History, 20th Century; History, 21st Century; Humans; Jews; Microbial Sensitivity Tests; Population Surveillance; Risk Factors; Shigella sonnei; Travel; Whole Genome Sequencing
PubMed: 27532625
DOI: 10.3201/eid2209.151953 -
The Journal of Infectious Diseases Dec 2021We demonstrated in a randomized placebo-controlled trial that WRSS1, a live oral Shigella sonnei vaccine candidate, is safe in Bangladeshi adults and children, and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
We demonstrated in a randomized placebo-controlled trial that WRSS1, a live oral Shigella sonnei vaccine candidate, is safe in Bangladeshi adults and children, and elicits antigen-specific antibodies. Here, we describe functional antibody and innate immune responses to WRSS1.
METHODS
Adults (18-39 years) and children (5-9 years) received 3 doses of 3 × 105 or 3 × 106 colony forming units (CFU) of WRSS1 or placebo, 4 weeks apart; children additionally received 3 × 104 CFU. Blood and stool were collected at baseline and 7 days after each dose. Functional antibodies were measured using serum bactericidal antibody (SBA) assay. Cytokine/chemokine concentrations were measured in lymphocyte cultures. Host defense peptides LL-37, HBD-1, and HD-5 were analyzed in plasma and stool.
RESULTS
Children showed increased SBA titers over baseline after the third dose of 3 × 106 CFU (P = .048). Significant increases of Th-17 and proinflammatory cytokines (TNF-α, G-CSF, MIP-1β), and reduction of anti-inflammatory and Th2 cytokines (IL-10, IL-13, GM-CSF) were observed in children. Plasma HBD-1 and LL-37 decreased in children after vaccination but were increased/unchanged in adults.
CONCLUSIONS
Functional antibodies and Th1/Th17 cytokine responses in children may serve as important indicators of immunogenicity and protective potential of WRSS1. Clinical Trials Registration: NCT01813071.
Topics: Adolescent; Adult; Antibodies, Bacterial; Bangladesh; Child; Child, Preschool; Cytokines; Dysentery, Bacillary; Female; Humans; Immunity, Innate; Immunity, Mucosal; Male; Shigella Vaccines; Shigella sonnei; Vaccines, Attenuated; Young Adult
PubMed: 34374425
DOI: 10.1093/infdis/jiab395