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EMBO Molecular Medicine Nov 2020Cholesterol-dependent cytolysins (CDCs) are essential virulence factors for many human pathogens like Streptococcus pneumoniae (pneumolysin, PLY), Streptococcus pyogenes...
Cholesterol-dependent cytolysins (CDCs) are essential virulence factors for many human pathogens like Streptococcus pneumoniae (pneumolysin, PLY), Streptococcus pyogenes (streptolysin O, SLO), and Listeria monocytogenes (Listeriolysin, LLO) and induce cytolysis and inflammation. Recently, we identified that pneumococcal PLY interacts with the mannose receptor (MRC-1) on specific immune cells thereby evoking an anti-inflammatory response at sublytic doses. Here, we identified the interaction sites between MRC-1 and CDCs using computational docking. We designed peptides from the CTLD4 domain of MRC-1 that binds to PLY, SLO, and LLO, respectively. In vitro, the peptides blocked CDC-induced cytolysis and inflammatory cytokine production by human macrophages. Also, they reduced PLY-induced damage of the epithelial barrier integrity as well as blocked bacterial invasion into the epithelium in a 3D lung tissue model. Pre-treatment of human DCs with peptides blocked bacterial uptake via MRC-1 and reduced intracellular bacterial survival by targeting bacteria to autophagosomes. In order to use the peptides for treatment in vivo, we developed calcium phosphate nanoparticles (CaP NPs) as peptide nanocarriers for intranasal delivery of peptides and enhanced bioactivity. Co-administration of peptide-loaded CaP NPs during infection improved survival and bacterial clearance in both zebrafish and mice models of pneumococcal infection. We suggest that MRC-1 peptides can be employed as adjunctive therapeutics with antibiotics to treat bacterial infections by countering the action of CDCs.
Topics: Animals; Bacterial Proteins; Humans; Inflammation; Lectins, C-Type; Mannose Receptor; Mannose-Binding Lectins; Mice; Peptides; Pneumococcal Infections; Receptors, Cell Surface; Zebrafish
PubMed: 32985105
DOI: 10.15252/emmm.202012695 -
Frontiers in Immunology 2023Extensive efforts have been made toward improving effective strategies for pneumococcal vaccination, focusing on evaluating the potential of multivalent protein-based...
Development of a bivalent protein-based vaccine candidate against invasive pneumococcal diseases based on novel pneumococcal surface protein A in combination with pneumococcal histidine triad protein D.
Extensive efforts have been made toward improving effective strategies for pneumococcal vaccination, focusing on evaluating the potential of multivalent protein-based vaccines and overcoming the limitations of pneumococcal polysaccharide-based vaccines. In this study, we investigated the protective potential of mice co-immunization with the pneumococcal PhtD and novel rPspA proteins against pneumococcal sepsis infection. The formulations of each antigen alone or in combination were administered intraperitoneally with alum adjuvant into BALB/c mice three times at 14-day intervals. The production of antigen-specific IgG, IgG1 and IgG2a subclasses, and IL-4 and IFN-γ cytokines, were analyzed. Two complement- and opsonophagocytic-mediated killing activities of raised antibodies on day 42 were also assessed. Finally, the protection against an intraperitoneal challenge with 10 CFU/mouse of multi-drug resistance of ATCC49619 was investigated. Our findings showed a significant increase in the anti-PhtD and anti-rPspA sera IgG levels in the immunized group with the PhtD+rPspA formulation compared to each alone. Moreover, the results demonstrated a synergistic effect with a 6.7- and 1.3- fold increase in anti-PhtD and anti-rPspA IgG1, as well as a 5.59- and 1.08- fold increase in anti-PhtD and anti-rPspA IgG2a, respectively. Co-administration of rPspA+PhtD elicited a mixture of Th-2 and Th-1 immune responses, more towards Th-2. In addition, the highest complement-mediated killing activity was observed in the sera of the immunized group with PhtD+rPspA at 1/16 dilution, and the opsonophagocytic activity was increased from 74% to 86.3%. Finally, the survival rates showed that mice receiving the rPspA+PhtD formulation survived significantly longer (100%) than those receiving protein alone or PBS and exhibited the strongest clearance with a 2 log decrease in bacterial load in the blood 24h after challenge compared to the control group. In conclusion, the rPspA+PhtD formulation can be considered a promising bivalent serotype-independent vaccine candidate for protection against invasive pneumococcal infection in the future.
Topics: Animals; Mice; Streptococcus pneumoniae; Pneumococcal Infections; Vaccines
PubMed: 37680628
DOI: 10.3389/fimmu.2023.1187773 -
BMC Infectious Diseases Jan 2023The introduction of PCV13 to the Malawi infant immunization schedule in 2011 has been associated with reduced disease from Streptococcus pneumoniae. Improved...
INTRODUCTION
The introduction of PCV13 to the Malawi infant immunization schedule in 2011 has been associated with reduced disease from Streptococcus pneumoniae. Improved understanding of serotypes with high invasive potential can guide future vaccination interventions. We aimed to estimate pneumococcal serotypes associated with acute respiratory infection (ARI) and invasive pneumococcal disease (IPD) in hospitalized children in Blantyre, Malawi.
METHODS
We analysed data from healthy children under 5 years in the community in Blantyre and children admitted to Queen Elizabeth Central Hospital with ARI between 2015 and 2018. Nasopharyngeal swabs from children were tested for S. pneumoniae and serotyped by latex agglutination if positive. We analysed culture-positive blood and cerebrospinal fluid samples from admitted children between 2012 and 2018 to identify cases of IPD after the introduction of PCV13. We calculated the age-adjusted odds ratio (OR) of carriage for S. pneumoniae vaccine serotypes (VT) comparing those with ARI to healthy children. We also calculated age-adjusted ORs comparing serotypes causing IPD to carriage in the community with OR > 1 indicating high invasive potential.
RESULTS
Serotypes 5 (OR 24.73 [95% CI 7.90-78.56] p < 0.001), 1 (OR 23.38 [95% CI 9.75-56.06] p < 0.001), and 6B (OR 4.73 [95% CI 1.66-11.64] p = 0.001) had high invasive potential. Serotype 6B was no longer significant (OR 1.34 [95% CI 0.07-6.87] p = 0.777) in a sensitivity analysis accounting for year of recruitment. The prevalence of S. pneumoniae carriage in the community was 72.6% [95% CI 71.3-74.0] (3078/4238) and 23.4% (719/3078) of positive community samples were VT. The carriage prevalence in those hospitalised with ARI was 45.5% [95% CI 42.1-48.9] (389/855) and 43.8% of hospital attendees reported antibiotic use prior to admission. We did not identify significant associations with carriage of any serotypes in those with ARI.
CONCLUSIONS
Pneumococcal serotypes 5 and 1 are associated with high invasive potential. Despite high community pneumococcal carriage, pre-hospital antibiotic usage likely reduces pneumococcal detection among children admitted in this setting and further research is needed to investigate serotypes associated with ARI. Data from this study can guide future preventative vaccination strategies in Malawi.
Topics: Infant; Child; Humans; Child, Preschool; Serogroup; Malawi; Carrier State; Nasopharynx; Streptococcus pneumoniae; Pneumococcal Infections; Pneumococcal Vaccines; Respiratory Tract Infections; Anti-Bacterial Agents
PubMed: 36703117
DOI: 10.1186/s12879-023-08022-4 -
The Journal of International Medical... Oct 2022In developing countries, the pneumococcal conjugate vaccine (PCV) has not been incorporated into the national immunization schedule, and the vaccination rate is low....
OBJECTIVES
In developing countries, the pneumococcal conjugate vaccine (PCV) has not been incorporated into the national immunization schedule, and the vaccination rate is low. This study aimed to examine parental knowledge, attitudes, and barriers to children receiving the PCV in Jordan.
METHODS
This was a questionnaire-based cross-sectional study. The online survey was written in Arabic and consisted of three main sections. The questionnaire was distributed via social media platforms, such as Facebook, Twitter, and WhatsApp.
RESULTS
In total, 720 responses were analyzed. Only 149 (20.7%) of the parents' children were vaccinated with the PCV. However, almost half 356 (49.4%) of the respondents were willing to vaccinate their children. Most (563, 78.1%) parents stated that the vaccine would protect their children from pneumococcal disease. More than two thirds (516, 71.6%) of them strongly agreed or agreed that the cost of the PCV is high. Parents who had vaccinated their children had a higher monthly income than parents who had not vaccinated their children.
CONCLUSIONS
This study shows a lack of knowledge regarding pneumococcal infection and the PCV among Jordanian parents. This is the main barrier to vaccinating children. Therefore, improving parental knowledge would increase the rate of vaccination among Jordanian children.
Topics: Child; Cross-Sectional Studies; Humans; Infant; Jordan; Parents; Pneumococcal Infections; Pneumococcal Vaccines; Surveys and Questionnaires; Vaccination; Vaccines, Conjugate
PubMed: 36200323
DOI: 10.1177/03000605221128151 -
PLoS Pathogens Aug 2019Human zinc deficiency increases susceptibility to bacterial infection. Although zinc supplementation therapies can reduce the impact of disease, the molecular basis for...
Human zinc deficiency increases susceptibility to bacterial infection. Although zinc supplementation therapies can reduce the impact of disease, the molecular basis for protection remains unclear. Streptococcus pneumoniae is a major cause of bacterial pneumonia, which is prevalent in regions of zinc deficiency. We report that dietary zinc levels dictate the outcome of S. pneumoniae infection in a murine model. Dietary zinc restriction impacts murine tissue zinc levels with distribution post-infection altered, and S. pneumoniae virulence and infection enhanced. Although the activation and infiltration of murine phagocytic cells was not affected by zinc restriction, their efficacy of bacterial control was compromised. S. pneumoniae was shown to be highly sensitive to zinc intoxication, with this process impaired in zinc restricted mice and isolated phagocytic cells. Collectively, these data show how dietary zinc deficiency increases sensitivity to S. pneumoniae infection while revealing a role for zinc as a component of host antimicrobial defences.
Topics: Animals; Dietary Supplements; Disease Models, Animal; Female; Lung Diseases; Mice; Pneumococcal Infections; Streptococcus pneumoniae; Virulence; Zinc
PubMed: 31437249
DOI: 10.1371/journal.ppat.1007957 -
MSphere Jul 2020(the pneumococcus) carriage is commonly used to measure effects of pneumococcal vaccines. Based on findings from culture-based studies, the World Health Organization...
(the pneumococcus) carriage is commonly used to measure effects of pneumococcal vaccines. Based on findings from culture-based studies, the World Health Organization recommends both nasopharyngeal (NP) and oropharyngeal (OP) sampling for detecting adult carriage. Given evidence of potential confounding by other streptococci, we evaluated molecular methods for pneumococcal identification and serotyping from 250 OP samples collected from adults in Fiji, using paired NP samples for comparison. Samples were screened using quantitative PCR (qPCR), as well as pneumococcal identification and serotyping conducted by DNA microarray. A subset of OP samples were characterized by latex sweep agglutination and multiplex PCR. Alternate qPCR assays ( and ) for pneumococcal identification were evaluated. The qPCR was less specific and had poor positive predictive value (PPV) in OP samples (88% and 26%, respectively) compared with NP samples (95% and 64%, respectively). Using additional targets and/or improved qPCR specificity in OP, although the PPV (42 to 53%) was still poor. Using microarray, we found that 102/107 (95%) of OP samples contained nonpneumococcal streptococci with partial or divergent complements of pneumococcal capsule genes. We explored 91 colonies isolated from 11 OP samples using various techniques, including multiplex PCR, latex agglutination, and microarray. We found that nonpneumococcal streptococci contribute to false positives in pneumococcal serotyping and may also contribute to spurious identification by qPCR. Our results highlight that molecular approaches should include multiple loci to minimize false-positive results when testing OP samples. Regardless of method, pneumococcal identification and serotyping results from OP samples should be interpreted with caution. (the pneumococcus) is a significant global pathogen. Accurate identification and serotyping are vital. In contrast with World Health Organization recommendations based on culture methods, we demonstrate that pneumococcal identification and serotyping with molecular methods are affected by sample type. Results from oropharyngeal samples from adults were often inaccurate. This is particularly important for assessment of vaccine impact using carriage studies, particularly in low- and middle-income countries where there are significant barriers for disease surveillance.
Topics: Adult; Carrier State; False Positive Reactions; Female; Humans; Male; Microarray Analysis; Molecular Diagnostic Techniques; Oropharynx; Pneumococcal Infections; Predictive Value of Tests; Real-Time Polymerase Chain Reaction; Serotyping; Specimen Handling; Streptococcus pneumoniae
PubMed: 32727860
DOI: 10.1128/mSphere.00478-20 -
Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease.The Cochrane Database of Systematic... Mar 2021Sickle cell disease (SCD) is a group of inherited disorders that result in haemoglobin abnormalities and other complications. Injury to the spleen, among other factors,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Sickle cell disease (SCD) is a group of inherited disorders that result in haemoglobin abnormalities and other complications. Injury to the spleen, among other factors, contribute to persons with SCD being particularly susceptible to infection. Infants and very young children are especially vulnerable. The 'Co-operative Study of Sickle Cell Disease' observed an incidence rate for pneumococcal septicaemia of 10 per 100 person-years in children under the age of three years. Vaccines, including customary pneumococcal vaccines, may be of limited use in this age group. Therefore, prophylactic penicillin regimens may be advisable for this population. This is an update of a Cochrane Review which was first published in 2002, and previously updated, most recently in 2017. OBJECTIVES: To compare the effects of antibiotic prophylaxis against pneumococcus in children with SCD receiving antibiotic prophylaxis compared to those without in relation to: 1. incidence of Streptococcus pneumoniae infection; 2. mortality (as reported in the included studies); 3. drug-related adverse events (as reported in the included studies) to the individual and the community; 4. the impact of discontinuing at various ages on incidence of infection and mortality.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which is comprised of references identified from comprehensive electronic database searches and also two clinical trials registries: ClinicalTrials.gov and the WHO International Registry Platform (not in 2020 given access issues relating to Covid-19 pandemic). Additionally, we carried out hand searching of relevant journals and abstract books of conference proceedings. Date of the most recent search: 25 January 2021.
SELECTION CRITERIA
All randomised or quasi-randomised controlled trials comparing prophylactic antibiotics to prevent pneumococcal infection in children with SCD with placebo, no treatment or a comparator drug.
DATA COLLECTION AND ANALYSIS
The standard methodological procedures expected by Cochrane were used. Both authors independently extracted data and assessed trial quality. The authors used the GRADE criteria to assess the certainty of the evidence.
MAIN RESULTS
Six trials were identified by the searches, of which three trials were eligible for inclusion. A total of 880 children, who were between three months to five years of age at randomization were included. The included studies were conducted in centres in the USA and in Kingston, Jamaica. In trials that investigated initiation of penicillin on risk of pneumococcal infection, the odds ratio was 0.37 (95% confidence interval 0.16 to 0.86) (two trials, 457 children) (low-certainty evidence), while for withdrawal the odds ratio was 0.49 (95% confidence interval 0.09 to 2.71) (one trial, 400 children) (low-certainty evidence). Adverse drug effects were rare and minor. Rates of pneumococcal infection were found to be relatively low in children over the age of five years. Overall, the certainty of the evidence for all outcomes was judged to be low. The results from the risk of bias assessment undertaken identified two domains in which the risk of bias was considered to be high, these were incomplete outcome data (attrition bias) (two trials) and allocation concealment (selection bias) (one trial). Domains considered to have a low risk of bias for all three trials were selective reporting (reporting bias) and blinding (performance and detection bias).
AUTHORS' CONCLUSIONS
The evidence examined was determined to be of low certainty and suggests that prophylactic penicillin significantly reduces risk of pneumococcal infection in children with homozygous SCD, and is associated with minimal adverse reactions. Further research may help to determine the ideal age to safely withdraw penicillin.
Topics: Age Factors; Anemia, Sickle Cell; Antibiotic Prophylaxis; Bias; Child, Preschool; Hemoglobin SC Disease; Homozygote; Humans; Incidence; Infant; Medication Adherence; Penicillins; Pneumococcal Infections; Randomized Controlled Trials as Topic; Streptococcus pneumoniae; beta-Thalassemia
PubMed: 33724440
DOI: 10.1002/14651858.CD003427.pub5 -
Frontiers in Immunology 2020C-reactive protein (CRP) binds to several species of bacterial pathogens including . Experiments in mice have revealed that one of the functions of CRP is to protect...
C-reactive protein (CRP) binds to several species of bacterial pathogens including . Experiments in mice have revealed that one of the functions of CRP is to protect against pneumococcal infection by binding to pneumococci and activating the complement system. For protection, however, CRP must be injected into mice within a few hours of administering pneumococci, that is, CRP is protective against early-stage infection but not against late-stage infection. It is assumed that CRP cannot protect if pneumococci got time to recruit complement inhibitor factor H on their surface to become complement attack-resistant. Since the conformation of CRP is altered under inflammatory conditions and altered CRP binds to immobilized factor H also, we hypothesized that in order to protect against late-stage infection, CRP needed to change its structure and that was not happening in mice. Accordingly, we engineered CRP molecules (E-CRP) which bind to factor H on pneumococci but do not bind to factor H on any host cell in the blood. We found that E-CRP, in cooperation with wild-type CRP, was protective regardless of the timing of administering E-CRP into mice. We conclude that CRP acts via two different conformations to execute its anti-pneumococcal function and a model for the mechanism of action of CRP is proposed. These results suggest that pre-modified CRP, such as E-CRP, is therapeutically beneficial to decrease bacteremia in pneumococcal infection. Our findings may also have implications for infections with antibiotic-resistant pneumococcal strains and for infections with other bacterial species that use host proteins to evade complement-mediated killing.
Topics: Animals; C-Reactive Protein; Complement Factor H; Disease Models, Animal; Humans; Male; Mice; Mice, Inbred C57BL; Pneumococcal Infections; Protein Conformation; Protein Engineering; Streptococcus pneumoniae
PubMed: 33117400
DOI: 10.3389/fimmu.2020.586669 -
Journal of Thrombosis and Haemostasis :... Jun 2022Severe acute respiratory syndrome coronavirus 2 infection is associated with an increased incidence of thrombosis.
BACKGROUND
Severe acute respiratory syndrome coronavirus 2 infection is associated with an increased incidence of thrombosis.
OBJECTIVES
By studying the fibrin network structure of coronavirus disease 2019 (COVID-19) patients, we aimed to unravel pathophysiological mechanisms that contribute to this increased risk of thrombosis. This may contribute to optimal prevention and treatment of COVID-19 related thrombosis.
PATIENTS/METHODS
In this case-control study, we collected plasma samples from intensive care unit (ICU) patients with COVID-19, with and without confirmed thrombosis, between April and December 2020. Additionally, we collected plasma from COVID-19 patients admitted to general wards without thrombosis, from ICU patients with pneumococcal infection, and from healthy controls. Fibrin fiber diameters and fibrin network density were quantified in plasma clots imaged with stimulated emission depletion microscopy and confocal microscopy. Finally, we determined the sensitivity to fibrinolysis.
RESULTS
COVID-19 ICU patients (n = 37) and ICU patients with pneumococcal disease (n = 7) showed significantly higher fibrin densities and longer plasma clot lysis times than healthy controls (n = 7). No differences were observed between COVID-19 ICU patients with and without thrombosis, or ICU patients with pneumococcal infection. At a second time point, after diagnosis of thrombosis or at a similar time point in patients without thrombosis, we observed thicker fibers and longer lysis times in COVID-19 ICU patients with thrombosis (n = 19) than in COVID-19 ICU patients without thrombosis (n = 18).
CONCLUSIONS
Our results suggest that severe COVID-19 is associated with a changed fibrin network structure and decreased susceptibility to fibrinolysis. Because these changes were not exclusive to COVID-19 patients, they may not explain the increased thrombosis risk.
Topics: COVID-19; Case-Control Studies; Fibrin; Fibrin Clot Lysis Time; Fibrinolysis; Humans; Intensive Care Units; Pneumococcal Infections; Thrombosis
PubMed: 35316570
DOI: 10.1111/jth.15708 -
JAMA Network Open Jun 2022An association between pneumococcal nasopharyngeal carriage and invasive pneumococcal disease (IPD) has been previously established. However, it is unclear whether the...
Association of Nonpharmaceutical Interventions During the COVID-19 Pandemic With Invasive Pneumococcal Disease, Pneumococcal Carriage, and Respiratory Viral Infections Among Children in France.
IMPORTANCE
An association between pneumococcal nasopharyngeal carriage and invasive pneumococcal disease (IPD) has been previously established. However, it is unclear whether the decrease in IPD incidence observed after implementation of nonpharmaceutical interventions (NPIs) during the COVID-19 pandemic was associated with concomitant changes in pneumococcal carriage and respiratory viral infections.
OBJECTIVE
To assess changes in IPD incidence after the implementation of NPIs during the COVID-19 pandemic and examine their temporal association with changes in pneumococcal carriage rate and respiratory viral infections (specifically respiratory syncytial virus [RSV] and influenza cases) among children in France.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study used interrupted time series analysis of data from ambulatory and hospital-based national continuous surveillance systems of pneumococcal carriage, RSV and influenza-related diseases, and IPD between January 1, 2007, and March 31, 2021. Participants included 11 944 children younger than 15 years in France.
EXPOSURES
Implementation of NPIs during the COVID-19 pandemic.
MAIN OUTCOMES AND MEASURES
The estimated fraction of IPD change after implementation of NPIs and the association of this change with concomitant changes in pneumococcal carriage rate and RSV and influenza cases among children younger than 15 years. The estimated fraction of change was analyzed using a quasi-Poisson regression model.
RESULTS
During the study period, 5113 children (median [IQR] age, 1.0 [0.6-4.0] years; 2959 boys [57.9%]) had IPD, and 6831 healthy children (median [IQR] age, 1.5 [0.9-3.9] years; 3534 boys [51.7%]) received a swab test. Data on race and ethnicity were not collected. After NPI implementation, IPD incidence decreased by 63% (95% CI, -82% to -43%; P < .001) and was similar for non-13-valent pneumococcal conjugate vaccine serotypes with both high disease potential (-63%; 95% CI, -77% to -48%; P < .001) and low disease potential (-53%; 95% CI, -70% to -35%; P < .001). The overall pneumococcal carriage rate did not significantly change after NPI implementation (-12%; 95% CI, -37% to 12%; P = .32), nor did the carriage rate for non-PCV13 serotypes with high disease potential (-26%; 95% CI, -100% to 52%; P = .50) or low disease potential (-7%; 95% CI, -34% to 20%; P = .61). After NPI implementation, the estimated number of influenza cases decreased by 91% (95% CI, -74% to -97%; P < .001), and the estimated number of RSV cases decreased by 74% (95% CI, -55% to -85%; P < .001). Overall, the decrease in influenza and RSV cases accounted for 53% (95% CI, -28% to -78%; P < .001) and 40% (95% CI, -15% to -65%; P = .002) of the decrease in IPD incidence during the NPI period, respectively. The decrease in IPD incidence was not associated with pneumococcal carriage, with carriage accounting for only 4% (95% CI, -7% to 15%; P = .49) of the decrease.
CONCLUSIONS AND RELEVANCE
In this cohort study of data from multiple national continuous surveillance systems, a decrease in pediatric IPD incidence occurred after the implementation of NPIs in France; this decrease was associated with a decrease in viral infection cases rather than pneumococcal carriage rate. The association between pneumococcal carriage and IPD was potentially modified by changes in the number of RSV and influenza cases, suggesting that interventions targeting respiratory viruses, such as immunoprophylaxis or vaccines for RSV and influenza, may be able to prevent a large proportion of pediatric IPD cases.
Topics: COVID-19; Child; Cohort Studies; Humans; Infant; Influenza Vaccines; Influenza, Human; Male; Pandemics; Pneumococcal Infections; Streptococcus pneumoniae; Viruses
PubMed: 35763298
DOI: 10.1001/jamanetworkopen.2022.18959