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Pharmacological Research Jan 2021Resolution failure of exacerbated inflammation triggered by Influenza A virus (IAV) prevents return of pulmonary homeostasis and survival, especially when associated...
Resolution failure of exacerbated inflammation triggered by Influenza A virus (IAV) prevents return of pulmonary homeostasis and survival, especially when associated with secondary pneumococcal infection. Therapeutic strategies based on pro-resolving molecules have great potential against acute inflammatory diseases. Angiotensin-(1-7) [Ang-(1-7)] is a pro-resolving mediator that acts on its Mas receptor (MasR) to promote resolution of inflammation. We investigated the effects of Ang-(1-7) and the role of MasR in the context of primary IAV infection and secondary pneumococcal infection and evaluated pulmonary inflammation, virus titers and bacteria counts, and pulmonary damage. Therapeutic treatment with Ang-(1-7) decreased neutrophil recruitment, lung injury, viral load and morbidity after a primary IAV infection. Ang-(1-7) induced apoptosis of neutrophils and efferocytosis of these cells by alveolar macrophages, but had no direct effect on IAV replication in vitro. MasR-deficient (MasR) mice were highly susceptible to IAV infection, displaying uncontrolled inflammation, increased viral load and greater lethality rate, as compared to WT animals. Ang-(1-7) was not protective in MasR mice. Interestingly, Ang-(1-7) given during a sublethal dose of IAV infection greatly reduced morbidity associated with a subsequent S. pneumoniae infection, as seen by decrease in the magnitude of neutrophil influx, number of bacteria in the blood leading to a lower lethality. Altogether, these results show that Ang-(1-7) is highly protective against severe primary IAV infection and protects against secondary bacterial infection of the lung. These effects are MasR-dependent. Mediators of resolution of inflammation, such as Ang-(1-7), should be considered for the treatment of pulmonary viral infections.
Topics: A549 Cells; Angiotensin I; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cytokines; Dogs; Humans; Influenza A virus; Lung; Madin Darby Canine Kidney Cells; Male; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Peptide Fragments; Peroxidase; Phagocytosis; Pneumococcal Infections; Pneumonia, Viral; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Streptococcus pneumoniae; Mice
PubMed: 33171305
DOI: 10.1016/j.phrs.2020.105292 -
Bulletin of Experimental Biology and... Sep 2023The aim of the study was to evaluate the activity of Raphamin in a model of non-lethal pneumococcal infection caused by Streptococcus pneumoniae 3 in BALB/c mice. The...
The aim of the study was to evaluate the activity of Raphamin in a model of non-lethal pneumococcal infection caused by Streptococcus pneumoniae 3 in BALB/c mice. The drug or placebo was administered intragastrically 3 days prior to infection, 2 h before and 2 h post infection, and then for 3 full days, alone or in combination with antibiotic (amoxicil-lin/clavulanic acid). Raphamin monotherapy significantly decreased bacterial load in the lungs in comparison with placebo (p<0.05) which was comparable to the effect in antibiotic alone or combined with Raphamin. Raphamin prevented reproduction of Streptococcus pneumoniae in the lower respiratory tract and its combination with the antibiotic was safe and did not reduce the efficacy of amoxicillin/clavulanic acid.
Topics: Mice; Animals; Pneumococcal Infections; Streptococcus pneumoniae; Anti-Bacterial Agents; Amoxicillin-Potassium Clavulanate Combination; Clavulanic Acid
PubMed: 37861906
DOI: 10.1007/s10517-023-05919-7 -
PloS One 2024While the 23-valent pneumococcal polysaccharide vaccine (PPV23) has demonstrated its role in preventing severe pneumococcal disease, its impact on more non-specific...
BACKGROUND
While the 23-valent pneumococcal polysaccharide vaccine (PPV23) has demonstrated its role in preventing severe pneumococcal disease, its impact on more non-specific conditions like acute respiratory tract infection (ARI) and lower respiratory tract infections (LRTI) remains unclear. We aimed to investigate the role of PPV23 in prevention of presentations for ARI and LRTI and related antibiotic prescriptions among older adults in primary care.
METHODS
Using a nationwide general practice dataset, we followed a cohort of regularly attending patients aged ≥65 years from 1 January 2014 until 31 December 2018 for presentations for ARI, LRTI, and related antibiotic prescriptions. Associations between PPV23 receipt and each outcome were assessed using a multiple failures survival model to estimate hazard ratios (HR) adjusted for age, sex, socioeconomic status, and various health measures.
RESULTS
A cohort of 75,264 patients aged ≥65 years (mean 75.4, 56% female) in 2014 was followed. The incidence of presentations for ARI, ARI-related antibiotic prescription, LRTI, and LRTI-related antibiotic prescription was 157.6, 76.0, 49.6, and 24.3 per 1000 person-years, respectively. Recent PPV23 vaccine receipt was associated with a small reduction in ARI presentations (adjusted HR vaccinated vs. unvaccinated 0.96; 95%CI 0.94-0.98; p = 0.002); however, there was no reduction in ARI-related antibiotic prescription, LRTI presentation, nor LRTI-related antibiotic prescription (adjusted HR were 0.99[95%CI 0.96-1.03], 1.04[95%CI 0.99-1.09], 1.07[95%CI 1.00-1.14]).
CONCLUSION
PPV23 vaccination in older adults may result in a small reduction in the incidence of total ARI presentations in primary care. However, the effect is small and residual confounding cannot be excluded.
Topics: Humans; Female; Aged; Male; Anti-Bacterial Agents; Respiratory Tract Infections; Streptococcus pneumoniae; Vaccination; Pneumococcal Vaccines; Primary Health Care; Pneumococcal Infections
PubMed: 38635814
DOI: 10.1371/journal.pone.0299924 -
Frontiers in Immunology 2022During the past decades, with the implementation of pneumococcal polysaccharide vaccine (PPV) and pneumococcal conjugate vaccines (PCVs), a dramatic reduction in vaccine...
During the past decades, with the implementation of pneumococcal polysaccharide vaccine (PPV) and pneumococcal conjugate vaccines (PCVs), a dramatic reduction in vaccine type diseases and transmissions has occurred. However, it is necessary to develop a less expensive, serotype-independent pneumococcal vaccine due to the emergence of nonvaccine-type pneumococcal diseases and the limited effect of vaccines on colonization. As next-generation vaccines, conserved proteins, such as neuraminidase A (NanA), elongation factor Tu (Tuf), and pneumolysin (Ply), are promising targets against pneumococcal infections. Here, we designed and constructed a novel fusion protein, NanAT1-TufT1-PlyD4, using the structural and functional domains of full-length NanA, Tuf and Ply proteins with suitable linkers based on bioinformatics analysis and molecular cloning technology. Then, we tested whether the protein protected against focal and lethal pneumococcal infections and examined its potential protective mechanisms. The fusion protein NanAT1-TufT1-PlyD4 consists of 627 amino acids, which exhibits a relatively high level of thermostability, high stability, solubility and a high antigenic index without allergenicity. The purified fusion protein was used to subcutaneously immunize C57BL/6 mice, and NanAT1-TufT1-PlyD4 induced a strong and significant humoral immune response. The anti-NanAT1-TufT1-PlyD4 specific IgG antibody assays increased after the first immunization and reached the highest value at the 35th day. The results from experiments showed that anti-NanAT1-TufT1-PlyD4 antisera could inhibit the adhesion of to A549 cells. In addition, immunization with NanAT1-TufT1-PlyD4 significantly reduced colonization in the lung and decreased the damage to the lung tissues induced by infection. After challenge with a lethal dose of serotype 3 (NC_WCSUH32403), a better protection effect was observed with NanAT1-TufT1-PlyD4-immunized mice than with the separate full-length proteins and the adjuvant control; the survival rate was 50%, which met the standard of the marketed vaccine. Moreover, we showed that the humoral immune response and the Th1, Th2 and Th17-cellular immune pathways are involved in the immune protection of NanAT1-TufT1-PlyD4 to the host. Collectively, our results support that the novel fusion protein NanAT1-TufT1-PlyD4 exhibits extensive immune stimulation and is effective against pneumococcal challenges, and these properties are partially attributed to humoral and cellular-mediated immune responses.
Topics: Mice; Animals; Streptococcus pneumoniae; Antibodies, Bacterial; Mice, Inbred C57BL; Pneumococcal Vaccines; Pneumococcal Infections
PubMed: 36389808
DOI: 10.3389/fimmu.2022.1043293 -
Vaccine Nov 2021Pneumococcal infection is a leading cause of disability and death globally. The Hong Kong Government has launched two programmes for pneumococcal vaccination - The...
BACKGROUND
Pneumococcal infection is a leading cause of disability and death globally. The Hong Kong Government has launched two programmes for pneumococcal vaccination - The Vaccination Subsidy Scheme (VSS) and the Government Vaccination Programme (GVP). This study aimed to examine the enabling factors, obstacles and perception of pneumococcal vaccination, and their association with its uptake in a general Chinese population.
METHODS
We performed a population-based, telephone survey in the general public aged 65 or above via simple random sampling. A validated survey based on the Health Belief Model (HBM) was used. Their socio-demographic information; history of previous participation in the GVP or VSS; and self-perceived health status were captured. Binary logistic regression models were constructed to examine the factors independently associated with vaccination.
RESULTS
A total of 1,000 respondents were enrolled in the study, with 402 (40.2%) respondents having intention to join the GVP/VSS in 12 months. Respondents with long-term medical consultant and medication (adjusted odds ratios [aOR] = 1.541, 95% confidence interval (CI): 1.008-2.356, p = 0.046); high levels of perceived susceptibility of infections (aOR = 3.624, 95 %CI: 2.318-5.665, p < 0.001); high levels of perceived benefits of vaccine (aOR = 1.699, 95 %CI: 1.153-2.504, p < 0.001); recommendations from government (aOR = 8.025, 95 %CI: 4.771-13.497, p < 0.001) or physicians (aOR = 7.399, 95 %CI: 3.472-15.764, p = 0.008); and high levels of self-efficacy (aOR = 3.045, 95 %CI: 1.458-6.362, p = 0.003) were more likely to have intention to participate in the vaccination programme.
CONCLUSIONS
The acceptance rate of pneumococcal vaccination programme remained suboptimal in the population. The government and physicians should be involved in the promotion of pneumococcal vaccination and GVP/VSS by increasing perceived benefits and self-efficacy, and reducing barriers towards vaccination among the target population. More studies are required to confirm our findings in other settings.
Topics: Aged; Cross-Sectional Studies; Health Knowledge, Attitudes, Practice; Humans; Pneumococcal Infections; Pneumococcal Vaccines; Surveys and Questionnaires; Vaccination
PubMed: 34711437
DOI: 10.1016/j.vaccine.2021.10.024 -
Pediatric Nephrology (Berlin, Germany) Jan 2023Pneumococcal infections are common in children with nephrotic syndrome. Knowledge of the commonly available serotypes and antibiotic susceptibility will help in...
BACKGROUND
Pneumococcal infections are common in children with nephrotic syndrome. Knowledge of the commonly available serotypes and antibiotic susceptibility will help in prevention and appropriate management of pneumococcal sepsis, especially in resource-limited countries.
METHODS
Demographic, clinical, and laboratory data on children with nephrotic syndrome and pneumococcal infections were extracted from the electronic medical records.
RESULTS
Sixty-three isolates of pneumococci obtained from 60 children with nephrotic syndrome, over a period of 14 years, were included in the study. This represented 18% of all pneumococcal infections occurring in children during the same period. Commonly available vaccines covered up to 58% of all the serotypes causing infection. Severe disease, with shock, intensive care admission and/or meningitis, was observed in 38% children and mortality was observed in 10%. Resistance to commonly used antibiotics was not observed, except for erythromycin.
CONCLUSIONS
Pneumococcal sepsis was observed to be common in children with nephrotic syndrome and results in significant morbidity and mortality. Commonly used antibiotics were observed to be effective in management of the infections.
Topics: Child; Humans; Infant; Nephrotic Syndrome; Developing Countries; Pneumococcal Infections; Streptococcus pneumoniae; Bacteremia; Anti-Bacterial Agents; Pneumococcal Vaccines
PubMed: 35425998
DOI: 10.1007/s00467-022-05550-0 -
Emerging Infectious Diseases Nov 2019Increased nasopharyngeal pneumococcal (Streptococcus pneumoniae) colonization density has been associated with invasive pneumococcal disease, but factors that increase...
Increased nasopharyngeal pneumococcal (Streptococcus pneumoniae) colonization density has been associated with invasive pneumococcal disease, but factors that increase pneumococcal density are poorly understood. We evaluated pneumococcal densities in nasopharyngeal samples from asymptomatic young children from Peru and their association with subsequent acute respiratory illness (ARI). Total pneumococcal densities (encompassing all present serotypes) during asymptomatic periods were significantly higher when a respiratory virus was detected versus when no virus was detected (p<0.001). In adjusted analyses, increased pneumococcal density was significantly associated with the risk for a subsequent ARI (p<0.001), whereas asymptomatic viral detection alone was associated with lower risk for subsequent ARI. These findings suggest that interactions between viruses and pneumococci in the nasopharynx during asymptomatic periods might have a role in onset of subsequent ARI. The mechanisms for these interactions, along with other potentially associated host and environmental factors, and their role in ARI pathogenesis and pneumococcal transmission require further elucidation.
Topics: Asymptomatic Diseases; Child; Child, Preschool; Coinfection; Female; Humans; Male; Nasopharynx; Pneumococcal Infections; Public Health Surveillance; Respiratory Tract Infections; Risk Assessment; Risk Factors; Streptococcus pneumoniae
PubMed: 31625844
DOI: 10.3201/eid2511.190157 -
Cell Reports Mar 2024Pneumolysin (Ply) is an indispensable cholesterol-dependent cytolysin for pneumococcal infection. Although Ply-induced disruption of pneumococci-containing endosomal...
Pneumolysin (Ply) is an indispensable cholesterol-dependent cytolysin for pneumococcal infection. Although Ply-induced disruption of pneumococci-containing endosomal vesicles is a prerequisite for the evasion of endolysosomal bacterial clearance, its potent activity can be a double-edged sword, having a detrimental effect on bacterial survivability by inducing severe endosomal disruption, bactericidal autophagy, and scaffold epithelial cell death. Thus, Ply activity must be maintained at optimal levels. We develop a highly sensitive assay to monitor endosomal disruption using NanoBiT-Nanobody, which shows that the pneumococcal sialidase NanA can fine-tune Ply activity by trimming sialic acid from cell-membrane-bound glycans. In addition, oseltamivir, an influenza A virus sialidase inhibitor, promotes Ply-induced endosomal disruption and cytotoxicity by inhibiting NanA activity in vitro and greater tissue damage and bacterial clearance in vivo. Our findings provide a foundation for innovative therapeutic strategies for severe pneumococcal infections by exploiting the duality of Ply activity.
Topics: Humans; Neuraminidase; Streptococcus pneumoniae; Streptolysins; Pneumococcal Infections; Bacterial Proteins
PubMed: 38483905
DOI: 10.1016/j.celrep.2024.113962 -
Quality of Life Research : An... Feb 2022Streptococcus pneumoniae infections remain a significant source of morbidity and mortality worldwide. The purpose of this review was to summarize the impact of... (Review)
Review
PURPOSE
Streptococcus pneumoniae infections remain a significant source of morbidity and mortality worldwide. The purpose of this review was to summarize the impact of pneumococcal disease on health state utilities (HSU) in the acute phase of illness.
METHODS
We searched MEDLINE, EMBASE, EconLit, the Health Technology Assessment Database, the National Health Economic Evaluation Database, and Tufts Cost-Effectiveness Registry (up to January 2020) for primary studies. Eligible studies elicited HSU estimates using preference-based instruments for the acute phase of infection of pneumococcal syndromes including acute otitis media, pneumonia/lower respiratory tract infections, bacteremia/sepsis, and meningitis. Two reviewers independently conducted screening, data extraction and quality appraisal.
RESULTS
We screened 10,178 studies, of which 26 met our inclusion criteria. Cohort sizes ranged from 8 to 2060 respondents. The most frequently studied syndrome was pneumonia (n = 17), followed by acute otitis media (n = 9), meningitis (n = 7) and bacteremia/sepsis (n = 4). Overall, each syndrome was associated with a substantial impact on HSU. Bacteremia/sepsis (range: - 0.331 to 0.992) and meningitis (range: - 0.330 to 0.977) were generally associated with the lowest HSU, followed by pneumonia (range: - 0.054 to 0.998) and acute otitis media (range: 0.064 to 0.970). HSU estimates varied considerably by treatment setting, elicitation method and type of respondent. The only study to compare pneumococcal infections to non-pneumococcal infections in the same population revealed significantly lower HSU estimates among pneumococcal infections.
CONCLUSIONS
Pneumococcal syndromes are associated with decreased HSU estimates. Given the considerable heterogeneity in methods and source populations as well as study quality, care should be taken to select the most appropriate estimates.
Topics: Cost-Benefit Analysis; Humans; Infant; Otitis Media; Pneumococcal Infections; Quality of Life; Streptococcus pneumoniae
PubMed: 34273067
DOI: 10.1007/s11136-021-02941-y -
Factors associated with pneumococcal carriage and density in infants and young children in Laos PDR.PloS One 2019Nasopharyngeal carriage of Streptococcus pneumoniae (the pneumococcus) is a precursor to pneumococcal disease. Several host and environmental factors have been...
Nasopharyngeal carriage of Streptococcus pneumoniae (the pneumococcus) is a precursor to pneumococcal disease. Several host and environmental factors have been associated with pneumococcal carriage, however few studies have examined the relationship between host factors and pneumococcal carriage density. We sought to identify risk factors for pneumococcal carriage and density using data from cross-sectional pneumococcal carriage surveys conducted in the Lao People's Democratic Republic before and after the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13). Nasopharyngeal swabs were collected infants from aged 5-8 weeks old (n = 999) and children aged 12-23 months (n = 1,010), pneumococci detected by quantitative PCR, and a risk factor questionnaire completed. Logistic and linear regression models were used to evaluate associations between participant characteristics and pneumococcal carriage and density. In infants aged 5-8 weeks, living in a household with two or more children under the age of five years (aOR 1.97; 95% CI 1.39-2.79) and low family income (aOR 1.64; 95% CI 0.99-2.72) were positively associated with pneumococcal carriage. For children aged 12-23 months, upper respiratory tract infection (URTI) symptoms (aOR 2.64; 95% CI 1.97-3.53), two or more children under five in the household (aOR 2.40; 95% CI 1.80-3.20), and rural residence (aOR 1.84, 95% CI 1.35-2.50) were positively associated with pneumococcal carriage. PCV13 vaccination was negatively associated with carriage of PCV13 serotypes (aOR 0.60; 95% CI 0.44-0.83). URTI symptoms (p < 0.001), current breastfeeding (p = 0.005), rural residence (p = 0.012), and delivery by Caesarean section (p = 0.035) were associated with higher mean pneumococcal density in pneumococcal carriers (both age groups combined). This study provides new data on pneumococcal carriage and density in a high disease burden setting in southeast Asia.
Topics: Carrier State; Child, Preschool; Cross-Sectional Studies; Female; Humans; Infant; Infant, Newborn; Laos; Male; Nasopharynx; Pneumococcal Infections; Pneumococcal Vaccines; Risk Factors; Serogroup; Serotyping; Streptococcus pneumoniae; Vaccines, Conjugate
PubMed: 31661527
DOI: 10.1371/journal.pone.0224392