RESUMO
Colonization of the upper respiratory tract by pneumococcus is important both as a determinant of disease and for transmission into the population. The immunological mechanisms that contain pneumococcus during colonization are well studied in mice but remain unclear in humans. Loss of this control of pneumococcus following infection with influenza virus is associated with secondary bacterial pneumonia. We used a human challenge model with type 6B pneumococcus to show that acquisition of pneumococcus induced early degranulation of resident neutrophils and recruitment of monocytes to the nose. Monocyte function was associated with the clearance of pneumococcus. Prior nasal infection with live attenuated influenza virus induced inflammation, impaired innate immune function and altered genome-wide nasal gene responses to the carriage of pneumococcus. Levels of the cytokine CXCL10, promoted by viral infection, at the time pneumococcus was encountered were positively associated with bacterial load.
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Coinfecção/imunologia , Influenza Humana/imunologia , Mucosa Nasal/imunologia , Infecções Pneumocócicas/imunologia , Quimiocina CXCL10/imunologia , Quimiotaxia de Leucócito/imunologia , Método Duplo-Cego , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Monócitos/imunologia , Neutrófilos/imunologia , Streptococcus pneumoniaeRESUMO
Rationale: Pneumococcal pneumonia remains a global health problem. Pneumococcal colonization increases local and systemic protective immunity, suggesting that nasal administration of live attenuated Streptococcus pneumoniae (Spn) strains could help prevent infections. Objectives: We used a controlled human infection model to investigate whether nasopharyngeal colonization with attenuated S. pneumoniae strains protected against recolonization with wild-type (WT) Spn (SpnWT). Methods: Healthy adults aged 18-50 years were randomized (1:1:1:1) for nasal administration twice (at a 2-wk interval) with saline solution, WT Spn6B (BHN418), or one of two genetically modified Spn6B strains, SpnA1 (Δfhs/piaA) or SpnA3 (ΔproABC/piaA) (Stage I). After 6 months, participants were challenged with SpnWT to assess protection against the homologous serotype (Stage II). Measurements and Main Results: 125 participants completed both study stages per intention to treat. No serious adverse events were reported. In Stage I, colonization rates were similar among groups: SpnWT, 58.1% (18 of 31); SpnA1, 60% (18 of 30); and SpnA3, 59.4% (19 of 32). Anti-Spn nasal IgG levels after colonization were similar in all groups, whereas serum IgG responses were higher in the SpnWT and SpnA1 groups than in the SpnA3 group. In colonized individuals, increases in IgG responses were identified against 197 Spn protein antigens and serotype 6 capsular polysaccharide using a pangenome array. Participants given SpnWT or SpnA1 in Stage I were partially protected against homologous challenge with SpnWT (29% and 30% recolonization rates, respectively) at stage II, whereas those exposed to SpnA3 achieved a recolonization rate similar to that in the control group (50% vs. 47%, respectively). Conclusions: Nasal colonization with genetically modified live attenuated Spn was safe and induced protection against recolonization, suggesting that nasal administration of live attenuated Spn could be an effective strategy for preventing pneumococcal infections. Clinical trial registered with the ISRCTN registry (ISRCTN22467293).
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Infecções Pneumocócicas , Streptococcus pneumoniae , Adulto , Humanos , Virulência , Nariz , Infecções Pneumocócicas/prevenção & controle , Imunização , Anticorpos Antibacterianos , Imunoglobulina G , Vacinas Pneumocócicas/uso terapêuticoRESUMO
Rationale: Streptococcus pneumoniae serotype 3 (SPN3) is a cause of invasive pneumococcal disease and associated with low carriage rates. Following the introduction of pediatric 13-valent pneumococcal conjugate vaccine (PCV13) programs, SPN3 declines are less than other vaccine serotypes and incidence has increased in some populations coincident with a shift in predominant circulating SPN3 clade, from I to II. A human challenge model provides an effective means for assessing the impact of PCV13 on SPN3 in the upper airway. Objectives: To establish SPN3's ability to colonize the nasopharynx using different inoculum clades and doses, and the safety of an SPN3 challenge model. Methods: In a human challenge study involving three well-characterized and antibiotic-sensitive SPN3 isolates (PFESP306 [clade Ia], PFESP231 [no clade], and PFESP505 [clade II]), inoculum doses (10,000, 20,000, 80,000, and 160,000 cfu/100 µl) were escalated until maximal colonization rates were achieved, with concurrent acceptable safety. Measurement and Main Results: Presence and density of experimental SPN3 nasopharyngeal colonization in nasal wash samples, assessed using microbiological culture and molecular methods, on Days 2, 7, and 14 postinoculation. A total of 96 healthy participants (median age 21, interquartile range 19-25) were inoculated (n = 6-10 per dose group, 10 groups). Colonization rates ranged from 30.0-70.0% varying with dose and isolate. 30.0% (29/96) reported mild symptoms (82.8% [24/29] developed a sore throat); one developed otitis media requiring antibiotics. No serious adverse events occurred. Conclusions: An SPN3 human challenge model is feasible and safe with comparable carriage rates to an established Serotype 6B human challenge model. SPN3 carriage may cause mild upper respiratory symptoms.
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Infecções Pneumocócicas , Streptococcus pneumoniae , Humanos , Criança , Lactente , Adulto Jovem , Adulto , Sorogrupo , Portador Sadio , Vacinas Pneumocócicas/uso terapêutico , Infecções Pneumocócicas/prevenção & controle , Nasofaringe/microbiologia , Antibacterianos/uso terapêutico , Antibacterianos/farmacologiaRESUMO
Rationale: Pneumococcal colonization is key to the pathogenesis of invasive disease but is also immunogenic in young adults, protecting against recolonization. Colonization is rarely detected in older adults, despite high rates of pneumococcal disease.Objectives: To establish experimental human pneumococcal colonization in healthy adults aged 50-84 years, to measure the immune response to pneumococcal challenge, and to assess the protective effect of prior colonization against autologous strain rechallenge.Methods: Sixty-four participants were inoculated with Streptococcus pneumoniae (serotype 6B; 80,000 cfu in each nostril). Colonization was determined by bacterial culture of nasal wash, and humoral immune responses were assessed by anticapsular and antiprotein IgG concentrations.Measurements and Main Results: Experimental colonization was established in 39% of participants (25/64) with no adverse events. Colonization occurred in 47% (9/19) of participants aged 50-59 compared with 21% (3/14) in those aged ≥70 years. Previous pneumococcal polysaccharide vaccination did not protect against colonization. Colonization did not confer serotype-specific immune boosting, with a geometric mean titer (95% confidence interval) of 2.7 µg/ml (1.9-3.8) before the challenge versus 3.0 (1.9-4.7) 4 weeks after colonization (P = 0.53). Furthermore, pneumococcal challenge without colonization led to a drop in specific antibody concentrations from 2.8 µg/ml (2.0-3.9) to 2.2 µg/ml (1.6-3.0) after the challenge (P = 0.006). Antiprotein antibody concentrations increased after successful colonization. Rechallenge with the same strain after a median of 8.5 months (interquartile range, 6.7-10.1) led to recolonization in 5/16 (31%).Conclusions: In older adults, experimental pneumococcal colonization is feasible and safe but demonstrates different immunological outcomes compared with younger adults in previous studies.
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Anticorpos Antibacterianos/imunologia , Portador Sadio/imunologia , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Infecções Assintomáticas , Técnicas de Cultura , Estudos de Viabilidade , Feminino , Humanos , Imunidade Humoral/imunologia , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Cavidade Nasal , Líquido da Lavagem Nasal , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/uso terapêuticoRESUMO
Rationale: Pneumococcal pneumonia remains a global health problem. Colonization of the nasopharynx with Streptococcus pneumoniae (Spn), although a prerequisite of infection, is the main source of exposure and immunological boosting in children and adults. However, our knowledge of how nasal colonization impacts on the lung cells, especially on the predominant alveolar macrophage (AM) population, is limited.Objectives: Using a controlled human infection model to achieve nasal colonization with 6B serotype, we investigated the effect of Spn colonization on lung cells.Methods: We collected BAL from healthy pneumococcal-challenged participants aged 18-49 years. Confocal microscopy and molecular and classical microbiology were used to investigate microaspiration and pneumococcal presence in the lower airways. AM opsonophagocytic capacity was assessed by functional assays in vitro, whereas flow cytometry and transcriptomic analysis were used to assess further changes on the lung cellular populations.Measurements and Main Results: AMs from Spn-colonized individuals exhibited increased opsonophagocytosis to pneumococcus (11.4% median increase) for approximately 3 months after experimental pneumococcal colonization. AMs also had increased responses against other bacterial pathogens. Pneumococcal DNA detected in the BAL samples of Spn-colonized individuals were positively correlated with nasal pneumococcal density (r = 0.71; P = 0.029). Similarly, AM-heightened opsonophagocytic capacity was correlated with nasopharyngeal pneumococcal density (r = 0.61, P = 0.025).Conclusions: Our findings demonstrate that nasal colonization with pneumococcus and microaspiration prime AMs, leading to brisker responsiveness to both pneumococcus and unrelated bacterial pathogens. The relative abundance of AMs in the alveolar spaces, alongside their potential for nonspecific protection, render them an attractive target for novel vaccines.
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Macrófagos Alveolares/imunologia , Nasofaringe/microbiologia , Nariz/microbiologia , Streptococcus pneumoniae/isolamento & purificação , Adolescente , Adulto , Bactérias/imunologia , Humanos , Pessoa de Meia-Idade , Aspiração Respiratória , Adulto JovemRESUMO
Pneumococcal colonization is rarely studied in adults, except as part of family surveys. We report the outcomes of colonization screening in healthy adults (all were nonsmokers without major comorbidities or contact with children aged <5 years) who had volunteered to take part in clinical research. Using nasal wash culture, we detected colonization in 6.5% of volunteers (52 of 795). Serotype 3 was the commonest serotype (10 of 52 isolates). The majority of the remaining serotypes (35 of 52 isolates) were nonvaccine serotypes, but we also identified persistent circulation of serotypes 19A and 19F. Resistance to at least 1 of 6 antibiotics tested was found in 8 of 52 isolates.
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Infecções Pneumocócicas/imunologia , Vacinas Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Vacinas Conjugadas/imunologia , Adulto , Antibacterianos/imunologia , Farmacorresistência Bacteriana/imunologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Sorogrupo , Reino Unido , Adulto JovemRESUMO
RATIONALE: We have previously demonstrated that experimental pneumococcal carriage enhances immunity and protects healthy adults against carriage reacquisition after rechallenge with a homologous strain. OBJECTIVES: To investigate the role of naturally acquired pneumococcal protein and polysaccharide (PS)-specific immunity in protection against carriage acquisition using a heterologous challenge model. METHODS: We identified healthy volunteers that were naturally colonized with pneumococcus and, after clearance of their natural carriage episode, challenged them with a heterologous 6B strain. In another cohort of volunteers we assessed 6BPS-specific, PspA-specific, and PspC-specific IgG and IgA plasma and memory B-cell populations before and 7, 14, and 35 days after experimental pneumococcal inoculation. MEASUREMENTS AND MAIN RESULTS: Heterologous challenge with 6B resulted in 50% carriage among volunteers with previous natural pneumococcal carriage. Protection from carriage was associated with a high number of circulating 6BPS IgG-secreting memory B cells at baseline. There were no associations between protection from carriage and baseline levels of 6BPS IgG in serum or nasal wash, PspA-specific, or PspC-specific memory B cells or plasma cells. In volunteers who did not develop carriage, the number of circulating 6BPS memory B cells decreased and the number of 6BPS plasma cells increased postinoculation. CONCLUSIONS: Our data indicate that naturally acquired PS-specific memory B cells, but not levels of circulating IgG at time of pneumococcal exposure, are associated with protection against carriage acquisition.
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Anticorpos Antibacterianos/imunologia , Linfócitos B/imunologia , Portador Sadio/imunologia , Infecções Pneumocócicas/prevenção & controle , Streptococcus pneumoniae/imunologia , Adolescente , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Nasofaringe/imunologia , Polissacarídeos/imunologia , Adulto JovemRESUMO
Candida species are the most common cause of opportunistic fungal infection worldwide. Here we report the genome sequences of six Candida species and compare these and related pathogens and non-pathogens. There are significant expansions of cell wall, secreted and transporter gene families in pathogenic species, suggesting adaptations associated with virulence. Large genomic tracts are homozygous in three diploid species, possibly resulting from recent recombination events. Surprisingly, key components of the mating and meiosis pathways are missing from several species. These include major differences at the mating-type loci (MTL); Lodderomyces elongisporus lacks MTL, and components of the a1/2 cell identity determinant were lost in other species, raising questions about how mating and cell types are controlled. Analysis of the CUG leucine-to-serine genetic-code change reveals that 99% of ancestral CUG codons were erased and new ones arose elsewhere. Lastly, we revise the Candida albicans gene catalogue, identifying many new genes.
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Candida/fisiologia , Candida/patogenicidade , Evolução Molecular , Genoma Fúngico/genética , Reprodução/genética , Candida/classificação , Candida/genética , Códon/genética , Sequência Conservada , Diploide , Genes Fúngicos/genética , Meiose/genética , Polimorfismo Genético , Saccharomyces/classificação , Saccharomyces/genética , Virulência/genéticaRESUMO
Epidemiological studies report the impact of co-infection with pneumococcus and respiratory viruses upon disease rates and outcomes, but their effect on pneumococcal carriage acquisition and bacterial load is scarcely described. Here, we assess this by combining natural viral infection with controlled human pneumococcal infection in 581 healthy adults screened for upper respiratory tract viral infection before intranasal pneumococcal challenge. Across all adults, respiratory syncytial virus (RSV) and rhinovirus asymptomatic infection confer a substantial increase in secondary infection with pneumococcus. RSV also has a major impact on pneumococcal density up to 9 days post challenge. We also study rates and kinetics of bacterial shedding through the nose and oral route in a subset. High levels of pneumococcal colonization density and nasal inflammation are strongly correlated with increased odds of nasal shedding as opposed to cough shedding. Protection against respiratory viral infections and control of pneumococcal density may contribute to preventing pneumococcal disease and reducing bacterial spread.
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Streptococcus pneumoniae colonization in the upper respiratory tract is linked to pneumococcal disease development, predominantly affecting young children and older adults. As the global population ages and comorbidities increase, there is a heightened concern about this infection. We investigated the immunological responses of older adults to pneumococcal-controlled human infection by analyzing the cellular composition and gene expression in the nasal mucosa. Our comparative analysis with data from a concurrent study in younger adults revealed distinct gene expression patterns in older individuals susceptible to colonization, highlighted by neutrophil activation and elevated levels of CXCL9 and CXCL10. Unlike younger adults challenged with pneumococcus, older adults did not show recruitment of monocytes into the nasal mucosa following nasal colonization. However, older adults who were protected from colonization showed increased degranulation of cluster of differentiation 8+ T cells, both before and after pneumococcal challenge. These findings suggest age-associated cellular changes, in particular enhanced mucosal inflammation, that may predispose older adults to pneumococcal colonization.
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IMPORTANCE: Streptococcus pneumoniae (the pneumococcus) is a bacterial pathogen with the greatest burden of disease in Asia and Africa. The pneumococcal capsular polysaccharide has biological relevance as a major virulence factor as well as public health importance as it is the target for currently licensed vaccines. These vaccines have limited valency, covering up to 23 of the >100 known capsular types (serotypes) with higher valency vaccines in development. Here, we have characterized a new pneumococcal serotype, which we have named 33G. We detected serotype 33G in nasopharyngeal swabs (n = 20) from children and adults hospitalized with pneumonia, as well as healthy children in Mongolia. We show that the genetic, serological, and biochemical properties of 33G differ from existing serotypes, satisfying the criteria to be designated as a new serotype. Future studies should focus on the geographical distribution of 33G and any changes in prevalence following vaccine introduction.
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Infecções Pneumocócicas , Streptococcus pneumoniae , Criança , Humanos , Streptococcus pneumoniae/genética , Infecções Pneumocócicas/microbiologia , Sorogrupo , Vacinas Pneumocócicas , ÁsiaAssuntos
Mãos/microbiologia , Infecções Pneumocócicas/transmissão , Streptococcus pneumoniae/isolamento & purificação , Adolescente , Adulto , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Líquido da Lavagem Nasal/microbiologia , Streptococcus pneumoniae/genética , Adulto JovemRESUMO
BACKGROUND: The SARS-CoV-2 pandemic has caused an unprecedented strain on healthcare systems worldwide, including the United Kingdom National Health Service (NHS). We conducted an observational cohort study of SARS-CoV-2 infection in frontline healthcare workers (HCW) working in an acute NHS Trust during the first wave of the pandemic, to answer emerging questions surrounding SARS-CoV-2 infection, diagnosis, transmission and control. METHODS: Using self-collected weekly saliva and twice weekly combined oropharyngeal/nasopharyngeal (OP/NP) samples, in addition to self-assessed symptom profiles and isolation behaviours, we retrospectively compared SARS-CoV-2 detection by RT-qPCR of saliva and OP/NP samples. We report the association with contemporaneous symptoms and isolation behaviour. RESULTS: Over a 12-week period from 30th March 2020, 40·0% (n = 34/85, 95% confidence interval 31·3-51·8%) HCW had evidence of SARS-CoV-2 infection by surveillance OP/NP swab and/or saliva sample. Symptoms were reported by 47·1% (n = 40) and self-isolation by 25·9% (n = 22) participants. Only 44.1% (n = 15/34) participants with SARS-CoV-2 infection reported any symptoms within 14 days of a positive result and only 29·4% (n = 10/34) reported self-isolation periods. Overall agreement between paired saliva and OP/NP swabs was 93·4% (n = 211/226 pairs) but rates of positive concordance were low. In paired samples with at least one positive result, 35·0% (n = 7/20) were positive exclusively by OP/NP swab, 40·0% (n = 8/20) exclusively by saliva and in only 25·0% (n = 5/20) were the OP/NP and saliva result both positive. CONCLUSIONS: HCW are a potential source of SARS-CoV-2 transmission in hospitals and symptom screening will identify the minority of infections. Without routine asymptomatic SARS-CoV-2 screening, it is likely that HCW with SARS-CoV-2 infection would continue to attend work. Saliva, in addition to OP/NP swab testing, facilitated ascertainment of symptomatic and asymptomatic SARS-CoV-2 infections. Combined saliva and OP/NP swab sampling would improve detection of SARS-CoV-2 for surveillance and is recommended for a high sensitivity strategy.
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COVID-19 , Saliva , Humanos , COVID-19/diagnóstico , SARS-CoV-2 , Estudos de Coortes , Estudos Retrospectivos , Medicina Estatal , Pessoal de Saúde , Manejo de Espécimes , NasofaringeRESUMO
Longitudinal, community-based sampling is important for understanding prevalence and transmission of respiratory pathogens. Using a minimally invasive sampling method, the FAMILY Micro study monitored the oral, nasal and hand microbiota of families for 6 months. Here, we explore participant experiences and opinions. A mixed methods approach was utilised. A quantitative questionnaire was completed after every sampling timepoint to report levels of discomfort and pain, as well as time taken to collect samples. Participants were also invited to discuss their experiences in a qualitative structured exit interview. We received questionnaires from 36 families. Most adults and children >5y experienced no pain (94% and 70%) and little discomfort (73% and 47% no discomfort) regardless of sample type, whereas children ≤5y experienced variable levels of pain and discomfort (48% no pain but 14% hurts even more, whole lot or worst; 38% no discomfort but 33% moderate, severe, or extreme discomfort). The time taken for saliva and hand sampling decreased over the study. We conducted interviews with 24 families. Families found the sampling method straightforward, and adults and children >5y preferred nasal sampling using a synthetic absorptive matrix over nasopharyngeal swabs. It remained challenging for families to fit sampling into their busy schedules. Adequate fridge/freezer space and regular sample pick-ups were found to be important factors for feasibility. Messaging apps proved extremely effective for engaging with participants. Our findings provide key information to inform the design of future studies, specifically that self-sampling at home using minimally invasive procedures is feasible in a family context.
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Dor , Manejo de Espécimes , Adulto , Criança , Humanos , Estudos de Viabilidade , Inquéritos e Questionários , Reino UnidoRESUMO
Streptococcus pneumoniae (pneumococcus) is the most commonly identified bacterial cause of pneumonia and the leading infectious cause of death in children under 5â years of age worldwide. Pneumococcal disease follows a seasonal pattern with increased incidence during winter. Pneumonia burden is also associated with poor air quality. Nasopharyngeal carriage of the bacterium is a pre-requisite of invasive disease. We aimed to determine if susceptibility to nasopharyngeal pneumococcal carriage varied by season and which environmental factors might explain such variation. We also evaluated the influence of sex on susceptibility of carriage. We collated data from five studies in which human volunteers underwent intranasal pneumococcal challenge. Generalised linear mixed-effects models were used to identify factors associated with altered risk of carriage acquisition, specifically climate and air-quality data. During 2011-2017, 374 healthy adults were challenged with type 6B pneumococcus. Odds of carriage were significantly lower in males (OR, 0.61; 95% CI, 0.40-0.92; p=0.02), and higher with cooler temperatures (OR, 0.79; 95% CI, 0.63-0.99; p=0.04). Likelihood of carriage was also associated with lower concentrations of local fine particulate matter concentrations (PM2.5) and increased local rainfall. In contrast to epidemiological series, experimental challenge allowed us to test propensity to acquisition during controlled exposures; immunological explanations for sex and climatic differences should be sought.
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Characterizing the genetic diversity of pathogens within the host promises to greatly improve surveillance and reconstruction of transmission chains. For bacteria, it also informs our understanding of inter-strain competition and how this shapes the distribution of resistant and sensitive bacteria. Here we study the genetic diversity of Streptococcus pneumoniae within 468 infants and 145 of their mothers by deep sequencing whole pneumococcal populations from 3,761 longitudinal nasopharyngeal samples. We demonstrate that deep sequencing has unsurpassed sensitivity for detecting multiple colonization, doubling the rate at which highly invasive serotype 1 bacteria were detected in carriage compared with gold-standard methods. The greater resolution identified an elevated rate of transmission from mothers to their children in the first year of the child's life. Comprehensive treatment data demonstrated that infants were at an elevated risk of both the acquisition and persistent colonization of a multidrug-resistant bacterium following antimicrobial treatment. Some alleles were enriched after antimicrobial treatment, suggesting that they aided persistence, but generally purifying selection dominated within-host evolution. Rates of co-colonization imply that in the absence of treatment, susceptible lineages outcompeted resistant lineages within the host. These results demonstrate the many benefits of deep sequencing for the genomic surveillance of bacterial pathogens.
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Infecções Pneumocócicas , Streptococcus pneumoniae , Criança , Humanos , Streptococcus pneumoniae/genética , Infecções Pneumocócicas/microbiologia , Portador Sadio/epidemiologia , Portador Sadio/microbiologia , Nasofaringe/microbiologia , Sorogrupo , Antibacterianos/farmacologia , Antibacterianos/uso terapêuticoRESUMO
BACKGROUND: Household air pollution from solid fuels increases the risk of childhood pneumonia. Nasopharyngeal carriage of Streptococcus pneumoniae is a necessary step in the development of pneumococcal pneumonia. We aimed to assess the association between exposure to household air pollution and the prevalence and density of S pneumoniae carriage among children. METHODS: The Malawi Streptococcus pneumoniae Carriage and Air Pollution Exposure study was a nested, prospective, observational study of children participating in the cluster randomised controlled Cooking and Pneumonia Study (CAPS) in the Karonga Health and Demographic Surveillance System (HDSS) area in northern Malawi. CAPS compared the effects of a cleaner burning biomass-fuelled cookstove (intervention group) with traditional open-fire cooking (control group) on the incidence of pneumonia in children. Eligible children aged 6 weeks or 6 months (those recruited a 6 weeks were also followed up at age 6 months) were identified by the Karonga HDSS centre. Nasopharyngeal swabs were taken to detect S pneumoniae, and infant exposure to particulate matter with a diameter of ≤2·5 µm (PM2·5) exposure was assessed by use of a MicroPEM device. The primary outcome was the prevalence of nasopharyngeal S pneumoniae carriage in all children aged 6 months, assessed in all children with valid data on PM2·5. The effects of the intervention stoves (intention-to-treat analysis) and PM2·5 (adjusted exposure-response analysis) on the prevalence of S pneumoniae carriage were also assessed in the study children. FINDINGS: Between Nov 15, 2015, and Nov 2, 2017, 485 children were recruited (240 from the intervention group and 245 from the control group). Of all 450 children with available data at age 6 months, 387 (86% [95% CI 82-89]) were positive for S pneumoniae. Geometric mean PM2·5 exposure was 60·3 µg/m3 (95% CI 55·8-65·3) in S pneumoniae-positive children and 47·0 µg/m3 (38·3-57·7) in S pneumoniae-negative children (p=0·044). In the intention-to-treat analysis, a non-significant increase in the risk of S pneumoniae carriage was observed in intervention group children compared with control group children (odds ratio 1·36 [95% CI 0·95-1·94]; p=0·093). In the exposure-response analysis, a significant association between PM2·5 exposure and S pneumoniae carriage was observed; a one unit increase in decile of PM2·5 was found to significantly increase the risk of S pneumoniae carriage by 10% (1·10 [1·01-1·20]; p=0·035), after adjustment for age, sex, 13-valent pneumococcal conjugate vaccination status, season, current use of antibiotics, and MicroPEM run-time. INTERPRETATION: Despite the absence of effect from the intervention cookstove, household air pollution exposure was significantly associated with the prevalence of nasopharyngeal S pneumoniae carriage. These results provide empirical evidence for the potential mechanistic association between exposure to household air pollution and childhood pneumonia. FUNDING: Bill & Melinda Gates Foundation.
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Poluição do Ar em Ambientes Fechados/estatística & dados numéricos , Portador Sadio/epidemiologia , Culinária/métodos , Infecções Pneumocócicas/epidemiologia , Feminino , Humanos , Lactente , Malaui/epidemiologia , Masculino , Nasofaringe/microbiologia , Estudos Prospectivos , Streptococcus pneumoniae/isolamento & purificaçãoRESUMO
BackgroundAlthough recent epidemiological data suggest that pneumococci may contribute to the risk of SARS-CoV-2 disease, cases of coinfection with Streptococcus pneumoniae in patients with coronavirus disease 2019 (COVID-19) during hospitalization have been reported infrequently. This apparent contradiction may be explained by interactions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and pneumococci in the upper airway, resulting in the escape of SARS-CoV-2 from protective host immune responses.MethodsHere, we investigated the relationship of these 2 respiratory pathogens in 2 distinct cohorts of health care workers with asymptomatic or mildly symptomatic SARS-CoV-2 infection identified by systematic screening and patients with moderate to severe disease who presented to the hospital. We assessed the effect of coinfection on host antibody, cellular, and inflammatory responses to the virus.ResultsIn both cohorts, pneumococcal colonization was associated with diminished antiviral immune responses, which primarily affected mucosal IgA levels among individuals with mild or asymptomatic infection and cellular memory responses in infected patients.ConclusionOur findings suggest that S. pneumoniae impair host immunity to SARS-CoV-2 and raise the question of whether pneumococcal carriage also enables immune escape of other respiratory viruses and facilitates reinfection.Trial registrationISRCTN89159899 (FASTER study) and ClinicalTrials.gov NCT03502291 (LAIV study).
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COVID-19 , SARS-CoV-2 , Pessoal de Saúde , Humanos , Imunidade , Streptococcus pneumoniaeRESUMO
Older adults are at increased risk of pneumococcal disease. This work aims to evaluate whether there is any decrease in serum IgG against variants of the antigens Pneumococcal surface protein A (PspA) and Pneumococcal surface protein C (PspC) in healthy adults with increasing age. Levels of IgG against PspA and PspC variants were determined by ELISA in serum samples comparing volunteers 18-30 years of age with volunteers who were 50-70+ before and after an experimental pneumococcal colonization challenge. The serotype 6B strain used in the challenge belongs to a minor group of pneumococcal isolates expressing two PspC variants. There was a decrease in levels of IgG with increasing age for the most common PspA variants and for all PspC variants analyzed. No correlation was found between basal levels of IgG against these antigens and protection against colonization. There was an increase in levels of IgG against PspA variants that are more cross-reactive with the variant expressed by the challenge strain post challenge in younger individuals who became colonized. Since the challenge strain used in our study expresses two different PspC variants, an increase in serum IgG against all PspC variants tested was observed in younger individuals who became colonized. For some of the antigen variants tested, a decrease in serum IgG was observed in young volunteers who were challenged but did not become colonized. Serum IgG antibodies against PspA and PspC variants thus decrease with age in healthy adults, but there is no correlation between levels of IgG against these antigens and protection against human experimental colonization. Though no correlation between naturally induced serum IgG antibodies against PspA and PspC and protection against colonization was observed, these results do not rule out the protective potential of these antigens as vaccines against pneumococcal infections.
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Envelhecimento/imunologia , Anticorpos Antibacterianos/sangue , Proteínas de Bactérias/imunologia , Infecções Pneumocócicas/imunologia , Adolescente , Adulto , Idoso , Anticorpos Antibacterianos/imunologia , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infecções Pneumocócicas/sangueRESUMO
Colonization of the upper respiratory tract with Streptococcus pneumoniae is the precursor of pneumococcal pneumonia and invasive disease. Following exposure, however, it is unclear which human immune mechanisms determine whether a pathogen will colonize. We used a human challenge model to investigate host-pathogen interactions in the first hours and days following intranasal exposure to Streptococcus pneumoniae Using a novel home sampling method, we measured early immune responses and bacterial density dynamics in the nose and saliva after volunteers were experimentally exposed to pneumococcus. Here, we show that nasal colonization can take up to 24 h to become established. Also, the following two distinct bacterial clearance profiles were associated with protection: nasal clearers with immediate clearance of bacteria in the nose by the activity of pre-existent mucosal neutrophils and saliva clearers with detectable pneumococcus in saliva at 1 h post challenge and delayed clearance mediated by an inflammatory response and increased neutrophil activity 24 h post bacterial encounter. This study describes, for the first time, how colonization with a bacterium is established in humans, signifying that the correlates of protection against pneumococcal colonization, which can be used to inform design and testing of novel vaccine candidates, could be valid for subsets of protected individuals.IMPORTANCE Occurrence of lower respiratory tract infections requires prior colonization of the upper respiratory tract with a pathogen. Most bacterial infection and colonization studies have been performed in murine and in vitro models due to the current invasive sampling methodology of the upper respiratory tract, both of which poorly reflect the complexity of host-pathogen interactions in the human nose. Self-collecting saliva and nasal lining fluid at home is a fast, low-cost, noninvasive, high-frequency sampling platform for continuous monitoring of bacterial encounter at defined time points relative to exposure. Our study demonstrates for the first time that, in humans, there are distinct profiles of pneumococcal colonization kinetics, distinguished by speed of appearance in saliva, local phagocytic function, and acute mucosal inflammatory responses, which may either recruit or activate neutrophils. These data are important for the design and testing of novel vaccine candidates.