-
Microbiology Spectrum Dec 2022Metal ions are required by all organisms for the chemical processes that support life. However, in excess they can also exert toxicity within biological systems. During...
Metal ions are required by all organisms for the chemical processes that support life. However, in excess they can also exert toxicity within biological systems. During infection, bacterial pathogens such as Streptococcus pneumoniae are exposed to host-imposed metal intoxication, where the toxic properties of metals, such as copper, are exploited to aid in microbial clearance. However, previous studies investigating the antimicrobial efficacy of copper have reported variable findings. Here, we use a highly copper-sensitive strain of S. pneumoniae, lacking both copper efflux and intracellular copper buffering by glutathione, to investigate how copper stress is managed and where it is encountered during infection. We show that this strain exhibits highly dysregulated copper homeostasis, leading to the attenuation of growth and hyperaccumulation of copper In a murine infection model, whole-tissue copper quantitation and elemental bioimaging of the murine lung revealed that infection with S. pneumoniae resulted in increased copper abundance in specific tissues, with the formation of spatially discrete copper hot spots throughout the lung. While the increased copper was able to reduce the viability of the highly copper-sensitive strain in a pneumonia model, copper levels in professional phagocytes and in a bacteremic model were insufficient to prosecute bacterial clearance. Collectively, this study reveals that host copper is redistributed to sites of infection and can impact bacterial viability in a hypersusceptible strain. However, in wild-type S. pneumoniae, the concerted actions of the copper homeostatic mechanisms are sufficient to facilitate continued viability and virulence of the pathogen. Streptococcus pneumoniae (the pneumococcus) is one of the world's foremost bacterial pathogens. Treatment of both localized and systemic pneumococcal infection is becoming complicated by increasing rates of multidrug resistance globally. Copper is a potent antimicrobial agent used by the mammalian immune system in the defense against bacterial pathogens. However, unlike other bacterial species, this copper stress is unable to prosecute pneumococcal clearance. This study determines how the mammalian host inflicts copper stress on S. pneumoniae and the bacterial copper tolerance mechanisms that contribute to maintenance of viability and virulence and . This work has provided insight into the chemical biology of the host-pneumococcal interaction and identified a potential avenue for novel antimicrobial development.
Topics: Animals; Mice; Anti-Infective Agents; Bacterial Proteins; Copper; Lung; Pneumococcal Infections; Streptococcus pneumoniae
PubMed: 36413018
DOI: 10.1128/spectrum.02495-22 -
FEMS Microbiology Reviews Aug 2021This review provides an overview of the most important novel treatment strategies against Streptococcus pneumoniae infections published over the past 10 years. The... (Review)
Review
This review provides an overview of the most important novel treatment strategies against Streptococcus pneumoniae infections published over the past 10 years. The pneumococcus causes the majority of community-acquired bacterial pneumonia cases, and it is one of the prime pathogens in bacterial meningitis. Over the last 10 years, extensive research has been conducted to prevent severe pneumococcal infections, with a major focus on (i) boosting the host immune system and (ii) discovering novel antibacterials. Boosting the immune system can be done in two ways, either by actively modulating host immunity, mostly through administration of selective antibodies, or by interfering with pneumococcal virulence factors, thereby supporting the host immune system to effectively overcome an infection. While several of such experimental therapies are promising, few have evolved to clinical trials. The discovery of novel antibacterials is hampered by the high research and development costs versus the relatively low revenues for the pharmaceutical industry. Nevertheless, novel enzymatic assays and target-based drug design, allow the identification of targets and the development of novel molecules to effectively treat this life-threatening pathogen.
Topics: Anti-Bacterial Agents; Humans; Pneumococcal Infections; Streptococcus pneumoniae; Virulence Factors
PubMed: 33399826
DOI: 10.1093/femsre/fuaa072 -
The Cochrane Database of Systematic... Jan 2015Approximately 450,000 children worldwide die of pneumococcal infections each year. The development of bacterial resistance to antimicrobials adds to the difficulty of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Approximately 450,000 children worldwide die of pneumococcal infections each year. The development of bacterial resistance to antimicrobials adds to the difficulty of treatment of diseases and emphasizes the need for a preventive approach. Newborn vaccination schedules could substantially reduce the impact of pneumococcal disease in immunized children, but do not have an effect on the morbidity and mortality of infants less than three months of age. Pneumococcal vaccination during pregnancy may be a way of preventing pneumococcal disease during the first months of life before the pneumococcal vaccine administered to the infant starts to produce protection.
OBJECTIVES
To assess the effect of pneumococcal vaccination during pregnancy for preventing infant infection.
SEARCH METHODS
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2014) and reference lists of retrieved studies.
SELECTION CRITERIA
Randomized controlled trials in pregnant women comparing pneumococcal vaccine with placebo or doing nothing, or with another vaccine to prevent infant infections.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We contacted study authors for additional information.
MAIN RESULTS
Seven trials were included, but only six trials (919 participants) contributed data. There was no evidence that pneumococcal vaccination during pregnancy reduces the risk of neonatal infection (risk ratio (RR) 0.66; 95% confidence interval (CI) 0.30 to 1.46; two trials, 241 pregnancies, low quality evidence). Although the data suggest an effect in reducing pneumococcal colonization in infants by 16 months of age (average RR 0.33; 95% CI 0.11 to 0.98; one trial, 56 pregnancies), there was no evidence of this effect in infants at two to three months of age (average RR 1.13; 95% CI 0.46 to 2.78; two trials, 146 pregnancies, low quality evidence) or by six to seven months of age (average RR 0.67, 95% CI 0.22 to 2.08; two trials, 148 pregnancies, low quality evidence). None of the trials included in this review reported neonatal death as a result of pneumococcal infection.Neonatal antibody levels were reported as geometric mean and 95% CI. There were inconsistent results between studies. Two studies showed significantly higher immunoglobulin G (IgG) levels in cord blood in the pneumococcal vaccine group when compared with the control group for all serotypes. In contrast, another trial showed no difference in neonatal antibody levels between the pneumococcal vaccine group and the control group.Maternal antibody levels were also reported as geometric mean and 95% CI. One study showed significantly higher IgG levels in maternal serum in women immunized with pneumococcal vaccine when compared with control vaccine regardless of any serotypes. Another study showed significantly higher maternal antibody levels only for serotype 14, but no evidence of an effect for other serotypes.The percentage of women with seroprotection was measured in one trial at delivery and at 12 months post-delivery. At delivery, results favored the intervention group for serotype 6 (RR 1.49, 95% CI 1.31 to 1.69), serotype 14 (RR 1.40, 95% CI 1.25 to 1.56) and serotype 19 (RR 2.29, 95% CI 1.89 to 2.76). There were no group differences seen at 12 months post-delivery for serotypes 6 or 14 (RR 1.06, 95% CI 1.00 to 1.12 and RR 1.06, 95% CI 0.98 to 1.15, respectively), but results favored the intervention group for serotype 19 (RR 1.59, 95% CI 1.37 to 1.85).No significant difference for tenderness at the injection site between women who received pneumococcal vaccine and those who received control vaccine (average RR 3.20; 95% CI 0.32 to 31.54; two trials, 130 women).The overall quality of evidence is low for primary outcomes. Most outcomes had wide confidence intervals crossing the line of no effect, and most of the included trials had small numbers of participants and few events which led to downgrading evidence for imprecision of findings.
AUTHORS' CONCLUSIONS
There is insufficient evidence to assess whether pneumococcal vaccination during pregnancy could reduce infant infections.
Topics: Female; Gestational Age; Humans; Infant; Infant, Newborn; Pneumococcal Infections; Pneumococcal Vaccines; Pregnancy; Randomized Controlled Trials as Topic; Vaccination
PubMed: 25613573
DOI: 10.1002/14651858.CD004903.pub4 -
PloS One 2017Welders are more susceptible to pneumococcal pneumonia. The mechanisms are yet unclear. Pneumococci co-opt the platelet activating factor receptor (PAFR) to infect... (Comparative Study)
Comparative Study
Welders are more susceptible to pneumococcal pneumonia. The mechanisms are yet unclear. Pneumococci co-opt the platelet activating factor receptor (PAFR) to infect respiratory epithelial cells. We previously reported that exposure of respiratory cells to welding fumes (WF), upregulates PAFR-dependent pneumococcal infection. The signaling pathway for this response is unknown, however, in intestinal cells, hypoxia-inducible factor-1 α (HIF 1α) is reported to mediate PAFR-dependent infection. We sought to assess whether oxidative stress plays a role in susceptibility to pneumococcal infection via the platelet activating factor receptor. We also sought to evaluate the suitability of nasal epithelial PAFR expression in welders as a biomarker of susceptibility to infection. Finally, we investigated the generalisability of the effect of welding fumes on pneumococcal infection and growth using a variety of different welding fume samples. Nasal epithelial PAFR expression in welders and controls was analysed by flow cytometry. WF were collected using standard methodology. The effect of WF on respiratory cell reactive oxygen species production, HIF-1α expression, and pneumococcal infection was determined using flow cytometry, HIF-1α knockdown and overexpression, and pneumococcal infection assays. We found that nasal PAFR expression is significantly increased in welders compared with controls and that WF significantly increased reactive oxygen species production, HIF-1α and PAFR expression, and pneumococcal infection of respiratory cells. In unstimulated cells, HIF-1α knockdown decreased PAFR expression and HIF-1α overexpression increased PAFR expression. However, in knockdown cells pneumococcal infection was paradoxically increased and in overexpressing cells infection was unaffected. Nasal epithelial PAFR expression may be used as a biomarker of susceptibility to pneumococcal infection in order to target individuals, particularly those at high risk such as welders, for the pneumococcal vaccine. Expression of HIF-1α in unexposed respiratory cells inhibits basal pneumococcal infection via PAFR-independent mechanisms.
Topics: Adolescent; Adult; Case-Control Studies; Follow-Up Studies; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Middle Aged; Occupational Exposure; Oxidative Stress; Platelet Membrane Glycoproteins; Pneumococcal Infections; Prognosis; Reactive Oxygen Species; Receptors, G-Protein-Coupled; Respiratory Mucosa; Streptococcus pneumoniae; Welding; Young Adult
PubMed: 28278175
DOI: 10.1371/journal.pone.0173569 -
PloS One 2024The Ukrainian Ministerial Order (UMO) recommends pneumococcal vaccine (PCV) in risk groups but not free-of-charge resulting in coverage <5% (crude estimation). In 2022,...
BACKGROUND
The Ukrainian Ministerial Order (UMO) recommends pneumococcal vaccine (PCV) in risk groups but not free-of-charge resulting in coverage <5% (crude estimation). In 2022, the vaccination calendar will include PCV for children <5years. Doctors' pneumococcal knowledge, attitudes and practices (КAP) are paramount to successful roll-out but unexplored. We surveyed doctors aiming to assess their KAP to address gaps and misconceptions and support PCV implementation.
METHODS
In March 2021, we selected and surveyed primary care doctors using simple random sampling and structured self-administered online questionnaire. We measured attitudes (importance, effectiveness, safety) and practices using 5-point Likert-type questions. We defined pneumococcal disease (PD) knowledge as low/moderate (<80%) and high (≥80%), PCV and overall knowledge as low (≤50%) and moderate/high (51-100%) and PCV attitudes and practices as negative/neutral (1.0-3.4) and positive (3.5-5.0). We calculated prevalence ratios (PRs) and 95% confidence intervals (95%CI) using Poisson regression.
RESULTS
The response rate was 46% (286/628). Females represented 85% (243/285); the median age was 47 (interquartile range: 33-59, N = 281) years. Twenty-six percent (72/277) had high PD knowledge associated with age (>47 years: PR = 0.52, 95%CI: 0.30-0.90) and child-related UMO awareness (PR = 1.78, 95%CI: 1.04-3.08); 65% (182/278) had moderate/high PCV knowledge associated with positive attitudes towards PCV effectiveness (PR = 2.08, 95%CI: 1.20-3.59). Overall knowledge was moderate/high in 69% (188/271); 83% (220/265) had positive PCV attitudes; 52% (135/258) had positive practices associated with female sex (PR = 2.11, 95%CI: 1.09-4.09), positive attitudes (PR = 3.40, 95%CI: 1.23-9.39) and perception of vaccine supply as medium/big barrier (PR = 1.66, 95%CI: 1.02-2.72).
CONCLUSION
We observed moderate pneumococcal knowledge, especially in older doctors, positive PCV attitudes and neutral practices. Females and doctors with positive attitudes recommended PCV more. For successful PCV implementation, we recommend proper planning and prior educational activities targeting patients and primary care doctors, especially older males, to improve knowledge, introduce PCV and address concerns while ensuring uninterrupted vaccine supply.
Topics: Humans; Female; Male; Ukraine; Pneumococcal Infections; Health Knowledge, Attitudes, Practice; Pneumococcal Vaccines; Adult; Physicians, Primary Care; Vaccination; Middle Aged; Surveys and Questionnaires; Attitude of Health Personnel
PubMed: 38843200
DOI: 10.1371/journal.pone.0304346 -
Clinical Infectious Diseases : An... Sep 2022The Streptococcus pneumoniae capsule is regarded as indispensable in bacteremia. We report an infant with a ventricular septal defect and infective endocarditis caused...
The Streptococcus pneumoniae capsule is regarded as indispensable in bacteremia. We report an infant with a ventricular septal defect and infective endocarditis caused by nontypeable S. pneumoniae. In-depth investigation confirmed a deficient capsule yet favored pneumococcal fitness for causing infective endocarditis, rather than a host immune disorder, as the cause of infective endocarditis in this case.
Topics: Endocarditis; Endocarditis, Bacterial; Humans; Infant; Pneumococcal Infections; Pneumonia; Streptococcus pneumoniae
PubMed: 35134152
DOI: 10.1093/cid/ciac079 -
Antioxidants & Redox Signaling May 2020Up until recently, metabolism has scarcely been referenced in terms of immunology. However, emerging evidence has shown that immune cells undergo an adaptation of... (Review)
Review
Up until recently, metabolism has scarcely been referenced in terms of immunology. However, emerging evidence has shown that immune cells undergo an adaptation of metabolic processes, known as the metabolic switch. This switch is key to the activation, and sustained inflammatory phenotype in immune cells, which includes the production of cytokines and reactive oxygen species (ROS) that underpin infectious diseases, respiratory and cardiovascular disease, neurodegenerative disease, as well as cancer. There is a burgeoning body of evidence that immunometabolism and redox biology drive infectious diseases. For example, influenza A virus (IAV) utilizes endogenous ROS production NADPH oxidase (NOX)2-containing NOXs and mitochondria to circumvent antiviral responses. These evolutionary conserved processes are promoted by glycolysis, the pentose phosphate pathway, and the tricarboxylic acid (TCA) cycle that drive inflammation. Such metabolic products involve succinate, which stimulates inflammation through ROS-dependent stabilization of hypoxia-inducible factor-1α, promoting interleukin-1β production by the inflammasome. In addition, itaconate has recently gained significant attention for its role as an anti-inflammatory and antioxidant metabolite of the TCA cycle. The molecular mechanisms by which immunometabolism and ROS promote viral and bacterial pathology are largely unknown. This review will provide an overview of the current paradigms with an emphasis on the roles of immunometabolism and ROS in the context of IAV infection and secondary complications due to bacterial infection such as . Molecular targets based on metabolic cell processes and ROS generation may provide novel and effective therapeutic strategies for IAV and associated bacterial superinfections.
Topics: Animals; Anti-Inflammatory Agents; Humans; Influenza, Human; Orthomyxoviridae Infections; Oxidative Stress; Pneumococcal Infections; Reactive Oxygen Species; Respiratory Tract Diseases
PubMed: 32008371
DOI: 10.1089/ars.2020.8028 -
Vaccine Jan 2020Pneumococcal carriage is a prerequisite for pneumococcal disease. Little is known about whether social contact frequency and intensity are associated with pneumococcal...
BACKGROUND
Pneumococcal carriage is a prerequisite for pneumococcal disease. Little is known about whether social contact frequency and intensity are associated with pneumococcal carriage. In Fiji, indigenous iTaukei have higher prevalence of pneumococcal carriage compared with Fijians of Indian Descent (FID). We hypothesised that contact differences may contribute to ethnic differences in pneumococcal carriage prevalence and density.
METHODS
In 2015, young infants (5-8 weeks), toddlers (12-23 months), children (2-6 years), and caregivers from Suva and surrounding areas, participated in a cross-sectional survey (n = 2014), three years post pneumococcal conjugate vaccine introduction. Demographic and contact data, and nasopharyngeal swabs were collected. Pneumococci were detected, and quantified using quantitative real-time PCR, with molecular serotyping by microarray. Associations between ethnicity, contact, and pneumococcal carriage and density were estimated using multivariable generalised estimating equation regression models.
RESULTS
iTaukei participants had larger household sizes, higher pneumococcal carriage rates, more contacts, and more frequent contacts of longer duration, compared with FID. The odds of vaccine-type carriage increased by 28% (95% CI 8-53%) P < 0.01 in association with physical contact with 7-14 year old children. iTaukei ethnicity was associated with vaccine-type carriage (aOR) 1.73; 95% CI 1.06-2.82, P = 0.03) and non-vaccine type carriage (aOR 5.98; 95% CI 4.47-8.00, P < 0.01). Ethnicity and contact were not associated with pneumococcal density.
CONCLUSIONS
iTaukei had greater frequency and intensity of contact compared with FID. Physical contact was associated with pneumococcal carriage. Observed differences in pneumococcal nasopharyngeal carriage prevalence between iTaukei and FID were not explained by differences in social contact patterns by ethnicity.
Topics: Adolescent; Adult; Carrier State; Child; Child, Preschool; Cross-Sectional Studies; Ethnicity; Female; Fiji; Humans; Infant; Male; Middle Aged; Nasopharynx; Pneumococcal Infections; Pneumococcal Vaccines; Prevalence; Serotyping; Streptococcus pneumoniae
PubMed: 31668367
DOI: 10.1016/j.vaccine.2019.10.030 -
PloS One 2014Infection with Streptococcus pneumoniae is a major cause of childhood morbidity and mortality worldwide, especially in low income countries where pneumococcal conjugate... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Infection with Streptococcus pneumoniae is a major cause of childhood morbidity and mortality worldwide, especially in low income countries where pneumococcal conjugate vaccines (PCVs) are still underused. In countries where PCVs have been introduced, much of their efficacy has resulted from their impact on nasopharyngeal carriage in vaccinated children. Understanding the epidemiology of carriage for S. pneumoniae and other common respiratory bacteria in developing countries is crucial for implementing appropriate vaccination strategies and evaluating their impact.
METHODS AND FINDINGS
We have systematically reviewed published studies reporting nasopharyngeal or oropharyngeal carriage of S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Neisseria meningitidis in children and adults in low and lower-middle income countries. Studies reporting pneumococcal carriage for healthy children <5 years of age were selected for a meta-analysis. The prevalences of carriage for S. pneumoniae, H. influenzae, and M. catarrhalis were generally higher in low income than in lower-middle income countries and were higher in young children than in adults. The prevalence of S. aureus was high in neonates. Meta-analysis of data from young children before the introduction of PCVs showed a pooled prevalence estimate of 64.8% (95% confidence interval, 49.8%-76.1%) in low income countries and 47.8% (95% confidence interval, 44.7%-50.8%) in lower-middle income countries. The most frequent serotypes were 6A, 6B, 19A, 19F, and 23F.
CONCLUSIONS
In low and lower-middle income countries, pneumococcal carriage is frequent, especially in children, and the spectrum of serotypes is wide. However, because data are limited, additional studies are needed to adequately assess the impact of PCV introduction on carriage of respiratory bacteria in these countries.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carrier State; Child; Child, Preschool; Developing Countries; Humans; Income; Infant; Infant, Newborn; Middle Aged; Pneumococcal Infections; Pneumococcal Vaccines; Prevalence; Respiratory Tract Infections; Risk Factors; Serogroup; Streptococcus pneumoniae; Vaccination; Young Adult
PubMed: 25084351
DOI: 10.1371/journal.pone.0103293 -
Proceedings of the National Academy of... Jun 2016Immunization strategies against commensal bacterial pathogens have long focused on eradicating asymptomatic carriage as well as disease, resulting in changes in the...
Immunization strategies against commensal bacterial pathogens have long focused on eradicating asymptomatic carriage as well as disease, resulting in changes in the colonizing microflora with unknown future consequences. Additionally, current vaccines are not easily adaptable to sequence diversity and immune evasion. Here, we present a "smart" vaccine that leverages our current understanding of disease transition from bacterial carriage to infection with the pneumococcus serving as a model organism. Using conserved surface proteins highly expressed during virulent transition, the vaccine mounts an immune response specifically against disease-causing bacterial populations without affecting carriage. Aided by a delivery technology capable of multivalent surface display, which can be adapted easily to a changing clinical picture, results include complete protection against the development of pneumonia and sepsis during animal challenge experiments with multiple, highly variable, and clinically relevant pneumococcal isolates. The approach thus offers a unique and dynamic treatment option readily adaptable to other commensal pathogens.
Topics: Animals; Antibodies, Bacterial; Biofilms; Humans; Mice; Pneumococcal Infections; Pneumococcal Vaccines
PubMed: 27274071
DOI: 10.1073/pnas.1603007113