Publications by authors named "Robert S Heyderman"

200 Publications

Acute bacterial meningitis.

Curr Opin Neurol 2021 Mar 26. Epub 2021 Mar 26.

Francis Crick Institute NIHR Mucosal Pathogens Research Unit, Department of Infection, Division of Infection and Immunity, University College London, London, UK.

Purpose Of Review: Community-acquired bacterial meningitis is a continually changing disease. This review summarises both dynamic epidemiology and emerging data on pathogenesis. Updated clinical guidelines are discussed, new agents undergoing clinical trials intended to reduce secondary brain damage are presented.

Recent Findings: Conjugate vaccines are effective against serotype/serogroup-specific meningitis but vaccine escape variants are rising in prevalence. Meningitis occurs when bacteria evade mucosal and circulating immune responses and invade the brain: directly, or across the blood-brain barrier. Tissue damage is caused when host genetic susceptibility is exploited by bacterial virulence. The classical clinical triad of fever, neck stiffness and headache has poor diagnostic sensitivity, all guidelines reflect the necessity for a low index of suspicion and early Lumbar puncture. Unnecessary cranial imaging causes diagnostic delays. cerebrospinal fluid (CSF) culture and PCR are diagnostic, direct next-generation sequencing of CSF may revolutionise diagnostics. Administration of early antibiotics is essential to improve survival. Dexamethasone partially mitigates central nervous system inflammation in high-income settings. New agents in clinical trials include C5 inhibitors and daptomycin, data are expected in 2025.

Summary: Clinicians must remain vigilant for bacterial meningitis. Constantly changing epidemiology and emerging pathogenesis data are increasing the understanding of meningitis. Prospects for better treatments are forthcoming.
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http://dx.doi.org/10.1097/WCO.0000000000000934DOI Listing
March 2021

CSF Levels of Elongation Factor Tu Is Associated With Increased Mortality in Malawian Adults With Meningitis.

Front Cell Infect Microbiol 2020 11;10:603623. Epub 2020 Dec 11.

UCL Respiratory, Division of Medicine, University College London, London, United Kingdom.

Background: Mortality from bacterial meningitis, predominately caused by , exceeds 50% in sub-Saharan African countries with high HIV prevalence. Underlying causes of high mortality are poorly understood. We examined the host and pathogen proteome in the CSF of adults with proven pneumococcal meningitis (PM), testing if there was an association between differentially expressed proteins and outcome.

Materials/methods: CSF proteomes were analyzed by quantitative Mass-Spectrometry. Spectra were identified using the Swissprot human and TIGR4 pneumococcal protein libraries. Proteins were quantitated and analyzed against mortality. Unique proteins in PM were identified against published normal CSF proteome. Random-Forest models were used to test for protein signatures discriminating outcome. Proteins of interest were tested for their effects on growth and neutrophil opsonophagocytic killing of .

Results: CSF proteomes were available for 57 Adults with PM (median age 32 years, 60% male, 70% HIV-1 co-infected, mortality 63%). Three hundred sixty individual human and 23 pneumococcal proteins were identified. Of the human protein hits, 30% were not expressed in normal CSF, and these were strongly associated with inflammation and primarily related to neutrophil activity. No human protein signature predicted outcome. However, expression of the essential protein Elongation Factor Tu (EF-Tu) was significantly increased in CSF of non-survivors [False Discovery Rate (q) <0.001]. Expression of EF-Tu was negatively cocorrelated against expression of Neutrophil defensin (r 0.4 p p < 0.002), but not against complement proteins C3 or Factor H. , addition of EF-Tu protein impaired neutrophil killing in CSF.

Conclusions: Excessive EF-Tu protein in CSF was associated with reduced survival in meningitis in a high HIV prevalence population. We show EF-Tu may inhibit neutrophil mediated killing of in CSF. Further mechanistic work is required to better understand how avoids essential innate immune responses during PM through production of excess EF-Tu.
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http://dx.doi.org/10.3389/fcimb.2020.603623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759504PMC
December 2020

The histone demethylase KDM6B fine-tunes the host response to Streptococcus pneumoniae.

Nat Microbiol 2021 02 21;6(2):257-269. Epub 2020 Dec 21.

G5 Chromatin and Infection, Institut Pasteur, Paris, France.

Streptococcus pneumoniae is a natural colonizer of the human respiratory tract and an opportunistic pathogen. Although epithelial cells are among the first to encounter pneumococci, the cellular processes and contribution of epithelial cells to the host response are poorly understood. Here, we show that a S. pneumoniae serotype 6B ST90 strain, which does not cause disease in a murine infection model, induces a unique NF-κB signature response distinct from an invasive-disease-causing isolate of serotype 4 (TIGR4). This signature is characterized by activation of p65 and requires a histone demethylase KDM6B. We show, molecularly, that the interaction of the 6B strain with epithelial cells leads to chromatin remodelling within the IL-11 promoter in a KDM6B-dependent manner, where KDM6B specifically demethylates histone H3 lysine 27 dimethyl. Remodelling of the IL-11 locus facilitates p65 access to three NF-κB sites that are otherwise inaccessible when stimulated by IL-1β or TIGR4. Finally, we demonstrate through chemical inhibition of KDM6B with GSK-J4 inhibitor and through exogenous addition of IL-11 that the host responses to the 6B ST90 and TIGR4 strains can be interchanged both in vitro and in a murine model of infection in vivo. Our studies therefore reveal how a chromatin modifier governs cellular responses during infection.
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http://dx.doi.org/10.1038/s41564-020-00805-8DOI Listing
February 2021

Electronic data capture for large scale typhoid surveillance, household contact tracing, and health utilisation survey: Strategic Typhoid Alliance across Africa and Asia.

Wellcome Open Res 2020 1;5:66. Epub 2020 Dec 1.

Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi.

Electronic data capture systems (EDCs) have the potential to achieve efficiency and quality in collection of multisite data. We quantify the volume, time, accuracy and costs of an EDC using large-scale census data from the STRATAA consortium, a comprehensive programme assessing population dynamics and epidemiology of typhoid fever in Malawi, Nepal and Bangladesh to inform vaccine and public health interventions. A census form was developed through a structured iterative process and implemented using Open Data Kit Collect running on Android-based tablets. Data were uploaded to Open Data Kit Aggregate, then auto-synced to MySQL-defined database nightly. Data were backed-up daily from three sites centrally, and auto-reported weekly. Pre-census materials' costs were estimated. Demographics of 308,348 individuals from 80,851 households were recorded within an average of 14.7 weeks range (13-16) using 65 fieldworkers. Overall, 21.7 errors (95% confidence interval: 21.4, 22.0) per 10,000 data points were found: 13.0 (95% confidence interval: 12.6, 13.5) and 24.5 (95% confidence interval: 24.1, 24.9) errors on numeric and text fields respectively. These values meet standard quality threshold of 50 errors per 10,000 data points. The EDC's total variable cost was estimated at US$13,791.82 per site. In conclusion, the EDC is robust, allowing for timely and high-volume accurate data collection, and could be adopted in similar epidemiological settings.
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http://dx.doi.org/10.12688/wellcomeopenres.15811.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471626PMC
December 2020

Benefits of enhanced infection prophylaxis at antiretroviral therapy initiation by cryptococcal antigen status.

AIDS 2021 03;35(4):585-594

MRC CTU at UCL, Institute of Clinical Trials and Methodology, UCL, London, UK.

Objectives: To assess baseline prevalence of cryptococcal antigen (CrAg) positivity; and its contribution to reductions in all-cause mortality, deaths from cryptococcus and unknown causes, and new cryptococcal disease in the REALITY trial.

Design: Retrospective CrAg testing of baseline and week-4 plasma samples in all 1805 African adults/children with CD4+ cell count less than 100 cells/μl starting antiretroviral therapy who were randomized to receive 12-week enhanced-prophylaxis (fluconazole 100 mg/day, azithromycin, isoniazid, cotrimoxazole) vs. standard-prophylaxis (cotrimoxazole).

Methods: Proportional hazards models were used to estimate the relative impact of enhanced-prophylaxis vs. standard-cotrimoxazole on all, cryptococcal and unknown deaths, and new cryptococcal disease, through 24 weeks, by baseline CrAg positivity.

Results: Excluding 24 (1.4%) participants with active/prior cryptococcal disease at enrolment (all treated for cryptococcal disease), 133/1781 (7.5%) participants were CrAg-positive. By 24 weeks, 105 standard-cotrimoxazole vs. 78 enhanced-prophylaxis participants died. Of nine standard-cotrimoxazole and three enhanced-prophylaxis cryptococcal deaths, seven and two, respectively, were CrAg-positive at baseline. Among deaths of unknown cause, only 1/46 standard-cotrimoxazole and 1/28 enhanced-prophylaxis were CrAg-positive at baseline. There was no evidence that relative reductions in new cryptococcal disease associated with enhanced-prophylaxis varied between baseline CrAg-positives [hazard-ratio = 0.36 (95% confidence interval 0.13-0.98), incidence 19.5 vs. 56.5/100 person-years] and CrAg-negatives [hazard-ratio = 0.33 (0.03-3.14), incidence 0.3 vs. 0.9/100 person-years; Pheterogeneity = 0.95]; nor for all deaths, cryptococcal deaths or unknown deaths (Pheterogeneity > 0.3).

Conclusion: Relative reductions in cryptococcal disease/death did not depend on CrAg status. Deaths of unknown cause were unlikely to be cryptococcus-related; plausibly azithromycin contributed to their reduction. Findings support including 100 mg fluconazole in an enhanced-prophylaxis package at antiretroviral therapy initiation where CrAg screening is unavailable/impractical.
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http://dx.doi.org/10.1097/QAD.0000000000002781DOI Listing
March 2021

Streptococcal Serine-Rich Repeat Proteins in Colonization and Disease.

Front Microbiol 2020 30;11:593356. Epub 2020 Oct 30.

NIHR Mucosal Pathogens Research Unit, Division of Infection and Immunity, University College London, London, United Kingdom.

Glycosylation of proteins, previously thought to be absent in prokaryotes, is increasingly recognized as important for both bacterial colonization and pathogenesis. For mucosal pathobionts, glycoproteins that function as cell wall-associated adhesins facilitate interactions with mucosal surfaces, permitting persistent adherence, invasion of deeper tissues and transition to disease. This is exemplified by and , which can switch from being relatively harmless members of the mucosal tract microbiota to bona fide pathogens that cause life-threatening diseases. As part of their armamentarium of virulence factors, streptococci encode a family of large, glycosylated serine-rich repeat proteins (SRRPs) that facilitate binding to various tissue types and extracellular matrix proteins. This minireview focuses on the roles of and SRRPs in persistent colonization and the transition to disease. The potential of utilizing SRRPs as vaccine targets will also be discussed.
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http://dx.doi.org/10.3389/fmicb.2020.593356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661464PMC
October 2020

Evaluation of Pneumococcal Serotyping of Nasopharyngeal-Carriage Isolates by Latex Agglutination, Whole-Genome Sequencing (PneumoCaT), and DNA Microarray in a High-Pneumococcal-Carriage-Prevalence Population in Malawi.

J Clin Microbiol 2020 Dec 17;59(1). Epub 2020 Dec 17.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi.

Accurate assessment of the serotype distribution associated with pneumococcal colonization and disease is essential for evaluating and formulating pneumococcal vaccines and for informing vaccine policy. For this reason, we evaluated the concordance between pneumococcal serotyping results by latex agglutination, whole-genome sequencing (WGS) with PneumoCaT, and DNA microarray for samples from community carriage surveillance in Blantyre, Malawi. Nasopharyngeal swabs were collected according to WHO recommendations between 2015 and 2017 by using stratified random sampling among study populations. Participants included healthy children 3 to 6 years old (vaccinated with the 13-valent pneumococcal conjugate vaccine [PCV13] as part of the Expanded Program on Immunization [EPI]), healthy children 5 to 10 years old (age-ineligible for PCV13), and HIV-infected adults (18 to 40 years old) on antiretroviral therapy (ART). For phenotypic serotyping, we used a 13-valent latex kit (Statens Serum Institut [SSI], Denmark). For genomic serotyping, we applied the PneumoCaT pipeline to whole-genome sequence libraries. For molecular serotyping by microarray, we used the BUGS Bioscience Senti-SP microarray. A total of 1,347 samples were analyzed. Concordance was 90.7% (95% confidence interval [CI], 89.0 to 92.2%) between latex agglutination and PneumoCaT, 95.2% (95% CI, 93.9 to 96.3%) between latex agglutination and the microarray, and 96.6% (95% CI, 95.5 to 97.5%) between the microarray and PneumoCaT. By detecting additional vaccine serotype (VT) pneumococci carried at low relative abundances (median, 8%), the microarray increased VT detection by 31.5% over that by latex serotyping. To conclude, all three serotyping methods were highly concordant in identifying dominant serotypes. Latex serotyping is accurate in identifying vaccine serotypes and requires the least expertise and resources for field implementation and analysis. However, WGS, which adds population structure, and microarray, which adds multiple-serotype carriage, should be considered at regional reference laboratories for investigating the importance of vaccine serotypes at low relative abundances in transmission and disease.
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http://dx.doi.org/10.1128/JCM.02103-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771446PMC
December 2020

Bacterial genome-wide association study of hyper-virulent pneumococcal serotype 1 identifies genetic variation associated with neurotropism.

Commun Biol 2020 Oct 8;3(1):559. Epub 2020 Oct 8.

Parasites and Microbes Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK.

Hyper-virulent Streptococcus pneumoniae serotype 1 strains are endemic in Sub-Saharan Africa and frequently cause lethal meningitis outbreaks. It remains unknown whether genetic variation in serotype 1 strains modulates tropism into cerebrospinal fluid to cause central nervous system (CNS) infections, particularly meningitis. Here, we address this question through a large-scale linear mixed model genome-wide association study of 909 African pneumococcal serotype 1 isolates collected from CNS and non-CNS human samples. By controlling for host age, geography, and strain population structure, we identify genome-wide statistically significant genotype-phenotype associations in surface-exposed choline-binding (P = 5.00 × 10) and helicase proteins (P = 1.32 × 10) important for invasion, immune evasion and pneumococcal tropism to CNS. The small effect sizes and negligible heritability indicated that causation of CNS infection requires multiple genetic and other factors reflecting a complex and polygenic aetiology. Our findings suggest that certain pathogen genetic variation modulate pneumococcal survival and tropism to CNS tissue, and therefore, virulence for meningitis.
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http://dx.doi.org/10.1038/s42003-020-01290-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545184PMC
October 2020

How Does Blood-Retinal Barrier Breakdown Relate to Death and Disability in Pediatric Cerebral Malaria?

J Infect Dis 2020 Aug 26. Epub 2020 Aug 26.

Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool, a member of Liverpool Health Partners, Liverpool, UK.

Background: In cerebral malaria, the retina can be used to understand disease pathogenesis. The mechanisms linking sequestration, brain swelling and death remain poorly understood. We hypothesized that retinal vascular leakage would be associated with brain swelling.

Methods: We used retinal angiography to study blood-retinal barrier integrity. We analyzed retinal leakage, histopathology, brain MRI, and associations with death and neurological disability in prospective cohorts of Malawian children with cerebral malaria.

Results: Three types of retinal leakage were seen: Large focal leak (LFL), punctate leak (PL) and vessel leak. LFL and PL were associated with death (OR 13.20, 95%CI 5.21-33.78 and 8.58, 2.56-29.08 respectively), and brain swelling (p<0.05). Vessel leak and macular non-perfusion were associated with neurological disability (3.71, 1.26-11.02 and 9.06, 1.79-45.90). LFL was observed as an evolving retinal hemorrhage. A core of fibrinogen and monocytes was found in 39 (93%) white-centered hemorrhages.

Conclusions: Blood-retina barrier breakdown occurs in three patterns in cerebral malaria. Associations between LFL, brain swelling, and death suggest that the rapid accumulation of cerebral hemorrhages, with accompanying fluid egress, may cause fatal brain swelling. Vessel leak from barrier dysfunction, and non-perfusion were not associated with severe brain swelling, but with neurological deficits, suggesting hypoxic injury in survivors.
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http://dx.doi.org/10.1093/infdis/jiaa541DOI Listing
August 2020

Intestinal Perforations Associated With a High Mortality and Frequent Complications During an Epidemic of Multidrug-resistant Typhoid Fever in Blantyre, Malawi.

Clin Infect Dis 2020 Jul;71(Supplement_2):S96-S101

Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi.

Background: Typhoid fever remains a major source of morbidity and mortality in low-income settings. Its most feared complication is intestinal perforation. However, due to the paucity of diagnostic facilities in typhoid-endemic settings, including microbiology, histopathology, and radiology, the etiology of intestinal perforation is frequently assumed but rarely confirmed. This poses a challenge for accurately estimating burden of disease.

Methods: We recruited a prospective cohort of patients with confirmed intestinal perforation in 2016 and performed enhanced microbiological investigations (blood and tissue culture, plus tissue polymerase chain reaction [PCR] for Salmonella Typhi). In addition, we used a Poisson generalized linear model to estimate excess perforations attributed to the typhoid epidemic, using temporal trends in S. Typhi bloodstream infection and perforated abdominal viscus at Queen Elizabeth Central Hospital from 2008-2017.

Results: We recruited 23 patients with intraoperative findings consistent with intestinal perforation. 50% (11/22) of patients recruited were culture or PCR positive for S. Typhi. Case fatality rate from typhoid-associated intestinal perforation was substantial at 18% (2/11). Our statistical model estimates that culture-confirmed cases of typhoid fever lead to an excess of 0.046 perforations per clinical typhoid fever case (95% CI, .03-.06). We therefore estimate that typhoid fever accounts for 43% of all bowel perforation during the period of enhanced surveillance.

Conclusions: The morbidity and mortality associated with typhoid abdominal perforations are high. By placing clinical outcome data from a cohort in the context of longitudinal surgical registers and bacteremia data, we describe a valuable approach to adjusting estimates of the burden of typhoid fever.
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http://dx.doi.org/10.1093/cid/ciaa405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388708PMC
July 2020

The Surveillance for Enteric Fever in Asia Project (SEAP), Severe Typhoid Fever Surveillance in Africa (SETA), Surveillance of Enteric Fever in India (SEFI), and Strategic Typhoid Alliance Across Africa and Asia (STRATAA) Population-based Enteric Fever Studies: A Review of Methodological Similarities and Differences.

Clin Infect Dis 2020 Jul;71(Supplement_2):S102-S110

Department of Medicine, University of Cambridge, Cambridge, United Kingdom.

Building on previous multicountry surveillance studies of typhoid and others salmonelloses such as the Diseases of the Most Impoverished program and the Typhoid Surveillance in Africa Project, several ongoing blood culture surveillance studies are generating important data about incidence, severity, transmission, and clinical features of invasive Salmonella infections in sub-Saharan Africa and South Asia. These studies are also characterizing drug resistance patterns in their respective study sites. Each study answers a different set of research questions and employs slightly different methodologies, and the geographies under surveillance differ in size, population density, physician practices, access to healthcare facilities, and access to microbiologically safe water and improved sanitation. These differences in part reflect the heterogeneity of the epidemiology of invasive salmonellosis globally, and thus enable generation of data that are useful to policymakers in decision-making for the introduction of typhoid conjugate vaccines (TCVs). Moreover, each study is evaluating the large-scale deployment of TCVs, and may ultimately be used to assess post-introduction vaccine impact. The data generated by these studies will also be used to refine global disease burden estimates. It is important to ensure that lessons learned from these studies not only inform vaccination policy, but also are incorporated into sustainable, low-cost, integrated vaccine-preventable disease surveillance systems.
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http://dx.doi.org/10.1093/cid/ciaa367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388711PMC
July 2020

Influenza-like illness is associated with high pneumococcal carriage density in Malawian children.

J Infect 2020 10 22;81(4):549-556. Epub 2020 Jul 22.

Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.

Background: High pneumococcal carriage density is a risk factor for invasive pneumococcal disease (IPD) and transmission, but factors that increase pneumococcal carriage density are still unclear.

Methods: We undertook a cross-sectional study to evaluate the microbial composition, cytokine levels and pneumococcal carriage densities in samples from children presenting with an influenza-like illness (ILI) and asymptomatic healthy controls (HC).

Results: The proportion of children harbouring viral organisms (Relative risk (RR) 1.4, p = 0.0222) or ≥ 4 microbes at a time (RR 1.9, p < 0.0001), was higher in ILI patients than HC. ILI patients had higher IL-8 levels in nasal aspirates than HC (median [IQR], 265.7 [0 - 452.3] vs. 0 [0 - 127.3] pg/ml; p = 0.0154). Having an ILI was associated with higher pneumococcal carriage densities compared to HC (RR 4.2, p < 0.0001).

Conclusion: These findings suggest that children with an ILI have an increased propensity for high pneumococcal carriage density. This could in part contribute to increased susceptibility to IPD and transmission in the community.
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http://dx.doi.org/10.1016/j.jinf.2020.06.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375306PMC
October 2020

The global meningitis genome partnership.

J Infect 2020 10 29;81(4):510-520. Epub 2020 Jun 29.

WHO, Geneva, Switzerland.

Genomic surveillance of bacterial meningitis pathogens is essential for effective disease control globally, enabling identification of emerging and expanding strains and consequent public health interventions. While there has been a rise in the use of whole genome sequencing, this has been driven predominately by a subset of countries with adequate capacity and resources. Global capacity to participate in surveillance needs to be expanded, particularly in low and middle-income countries with high disease burdens. In light of this, the WHO-led collaboration, Defeating Meningitis by 2030 Global Roadmap, has called for the establishment of a Global Meningitis Genome Partnership that links resources for: N. meningitidis (Nm), S. pneumoniae (Sp), H. influenzae (Hi) and S. agalactiae (Sa) to improve worldwide co-ordination of strain identification and tracking. Existing platforms containing relevant genomes include: PubMLST: Nm (31,622), Sp (15,132), Hi (1935), Sa (9026); The Wellcome Sanger Institute: Nm (13,711), Sp (> 24,000), Sa (6200), Hi (1738); and BMGAP: Nm (8785), Hi (2030). A steering group is being established to coordinate the initiative and encourage high-quality data curation. Next steps include: developing guidelines on open-access sharing of genomic data; defining a core set of metadata; and facilitating development of user-friendly interfaces that represent publicly available data.
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http://dx.doi.org/10.1016/j.jinf.2020.06.064DOI Listing
October 2020

Pan-GWAS of Streptococcus agalactiae Highlights Lineage-Specific Genes Associated with Virulence and Niche Adaptation.

mBio 2020 06 9;11(3). Epub 2020 Jun 9.

NIHR Mucosal Pathogens Research Unit, Division of Infection and Immunity, University College London, London, United Kingdom.

(group B streptococcus; GBS) is a colonizer of the gastrointestinal and urogenital tracts, and an opportunistic pathogen of infants and adults. The worldwide population of GBS is characterized by clonal complexes (CCs) with different invasive potentials. CC17, for example, is a hypervirulent lineage commonly associated with neonatal sepsis and meningitis, while CC1 is less invasive in neonates and more commonly causes invasive disease in adults with comorbidities. The genetic basis of GBS virulence and the extent to which different CCs have adapted to different host environments remain uncertain. We have therefore applied a pan-genome-wide association study (GWAS) approach to 1,988 GBS strains isolated from different hosts and countries. Our analysis identified 279 CC-specific genes associated with virulence, disease, metabolism, and regulation of cellular mechanisms that may explain the differential virulence potential of particular CCs. In CC17 and CC23, for example, we have identified genes encoding pilus, quorum-sensing proteins, and proteins for the uptake of ions and micronutrients which are absent in less invasive lineages. Moreover, in CC17, carriage and disease strains were distinguished by the allelic variants of 21 of these CC-specific genes. Together our data highlight the lineage-specific basis of GBS niche adaptation and virulence. GBS is a leading cause of mortality in newborn babies in high- and low-income countries worldwide. Different strains of GBS are characterized by different degrees of virulence, where some are harmlessly carried by humans or animals and others are much more likely to cause disease.The genome sequences of almost 2,000 GBS samples isolated from both animals and humans in high- and low- income countries were analyzed using a pan-genome-wide association study approach. This allowed us to identify 279 genes which are associated with different lineages of GBS, characterized by a different virulence and preferred host. Additionally, we propose that the GBS now carried in humans may have first evolved in animals before expanding clonally once adapted to the human host.These findings are essential to help understand what is causing GBS disease and how the bacteria have evolved and are transmitted.
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http://dx.doi.org/10.1128/mBio.00728-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373188PMC
June 2020

High residual carriage of vaccine-serotype Streptococcus pneumoniae after introduction of pneumococcal conjugate vaccine in Malawi.

Nat Commun 2020 05 6;11(1):2222. Epub 2020 May 6.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi.

There are concerns that pneumococcal conjugate vaccines (PCVs) in sub-Saharan Africa sub-optimally interrupt Streptococcus pneumoniae vaccine-serotype (VT) carriage and transmission. Here we assess PCV carriage using rolling, prospective nasopharyngeal carriage surveys between 2015 and 2018, 3.6-7.1 years after Malawi's 2011 PCV13 introduction. Carriage decay rate is analysed using non-linear regression. Despite evidence of reduction in VT carriage over the study period, there is high persistent residual carriage. This includes among PCV-vaccinated children 3-5-year-old (16.1% relative reduction from 19.9% to 16.7%); PCV-unvaccinated children 6-8-year-old (40.5% reduction from 26.4% to 15.7%); HIV-infected adults 18-40-years-old on antiretroviral therapy (41.4% reduction from 15.2% to 8.9%). VT carriage prevalence half-life is similar among PCV-vaccinated and PCV-unvaccinated children (3.26 and 3.34 years, respectively). Compared with high-income settings, there is high residual VT carriage 3.6-7.1 years after PCV introduction. Rigorous evaluation of strategies to augment vaccine-induced control of carriage, including alternative schedules and catch-up campaigns, is required.
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http://dx.doi.org/10.1038/s41467-020-15786-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203201PMC
May 2020

Inflammatory Phenotypes Predict Changes in Arterial Stiffness Following Antiretroviral Therapy Initiation.

Clin Infect Dis 2020 Dec;71(9):2389-2397

Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.

Background: Inflammation drives vascular dysfunction in HIV, but in low-income settings causes of inflammation are multiple, and include infectious and environmental factors. We hypothesized that patients with advanced immunosuppression could be stratified into inflammatory phenotypes that predicted changes in vascular dysfunction on ART.

Methods: We recruited Malawian adults with CD4 <100 cells/μL 2 weeks after starting ART in the REALITY trial (NCT01825031). Carotid femoral pulse-wave velocity (cfPWV) measured arterial stiffness 2, 12, 24, and 42 weeks post-ART initiation. Plasma inflammation markers were measured by electrochemiluminescence at weeks 2 and 42. Hierarchical clustering on principal components identified inflammatory clusters.

Results: 211 participants with HIV grouped into 3 inflammatory clusters representing 51 (24%; cluster-1), 153 (73%; cluster-2), and 7 (3%; cluster-3) individuals. Cluster-1 showed markedly higher CD4 and CD8 T-cell expression of HLADR and PD-1 versus cluster-2 and cluster-3 (all P < .0001). Although small, cluster-3 had significantly higher levels of cytokines reflecting inflammation (IL-6, IFN-γ, IP-10, IL-1RA, IL-10), chemotaxis (IL-8), systemic and vascular inflammation (CRP, ICAM-1, VCAM-1), and SAA (all P < .001). In mixed-effects models, cfPWV changes over time were similar for cluster-2 versus cluster-1 (relative fold-change, 0.99; 95% CI, .86-1.14; P = .91), but greater in cluster-3 versus cluster-1 (relative fold-change, 1.45; 95% CI, 1.01-2.09; P = .045).

Conclusions: Two inflammatory clusters were identified: one defined by high T-cell PD-1 expression and another by a hyperinflamed profile and increases in cfPWV on ART. Further clinical characterization of inflammatory phenotypes could help target vascular dysfunction interventions to those at highest risk.

Clinical Trials Network: NCT01825031.
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http://dx.doi.org/10.1093/cid/ciaa186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713681PMC
December 2020

The effect of HIV infection and exposure on cognitive development in the first two years of life in Malawi.

Eur J Paediatr Neurol 2020 Mar 21;25:157-164. Epub 2019 Nov 21.

Department of Epidemiology and Social Sciences, University of Antwerp, Antwerp, Belgium; Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.

Objectives: To assess longitudinal patterns and determinants of cognitive development in infants living with HIV, infants exposed to maternal HIV infection, and HIV-unexposed infants.

Methods: Prospective, community-based cohort study of 555 Malawian infants aged 8 weeks to 24 months, using multivariable linear mixed-effects regression models with random intercepts to analyze repeated measures of cognitive function.

Results: At 3 months of age, cognitive scores on the Bayley Scales of Infant Development (BSID 3rd edition) were lower in the 96 HIV-infected infants (mean = 14.1 (SD:4.8)) compared to the 289 HIV-exposed (mean = 16.5 (SD:3.7)) and the 170 unexposed infants (mean = 17.5 (SD:3.3)). Over the first two years of life, the small deficit in cognitive development of infants living with HIV who survived and remained in care did not increase (mean score 52.9 among HIV-infected vs 55.6 among HIV unexposed). In multivariable analysis, malnutrition and a more advanced clinical infant HIV stage had a negative impact on cognition at age 3, while financial security, care by the biological mother, and ART for mother and child were associated with better cognitive status at this young age. The positive influence of maternal ART reversed with age.

Conclusions: Malawian infants exposed to HIV had a cognitive development that was similar to their unexposed peers in the first two years of life, while that of HIV infected infants lagged behind from the start. Early initiation of effective ART in all HIV infected mothers and infants, and prevention of infant malnutrition are important to safeguard cognitive development of children affected by HIV.
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http://dx.doi.org/10.1016/j.ejpn.2019.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136137PMC
March 2020

Pneumococcal pneumonia and carriage in Africa before and after introduction of pneumococcal conjugate vaccines, 2000-2019: protocol for systematic review.

BMJ Open 2019 11 13;9(11):e030981. Epub 2019 Nov 13.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.

Introduction: Africa harbours a high burden of pneumococcal disease, with associated high mortality rates. Despite 34 countries introducing the pneumococcal conjugate vaccine, which reduces the risk of pneumococcal carriage (a prerequisite for disease) of some of the most pathogenic pneumococcal serotypes, it remains uncertain whether they will achieve the sustained direct or indirect protection necessary to reduce pneumococcal carriage to levels sufficient to interrupt transmission and disease. We will therefore summarise the available data on the impact of the pneumococcal conjugate vaccine in reducing vaccine serotype carriage and pneumococcal pneumonia in Africa between 2000 and 2019.

Methods And Analysis: Using a predetermined search strategy, we will conduct a comprehensive search of PubMed, MEDLINE database, the Excerpta Medica Database, the ISI Web of Science (Science Citation Index), Scopus and the African Index Medicus to identify published studies reporting the prevalence of carriage (vaccine type and non-vaccine type), incidence rates of pneumococcal pneumonia and mortality among children, adults and HIV-infected (all-ages) pre-pneumococcal conjugate vaccine (PCV) and post-PCV introduction (published between 1st January 2000 and 31st December 2019) in African countries that have introduced PCVs (PCV7/PCV10/PCV13) in their routine national immunisation programme. The studies retained and data extracted will be assessed for bias using prevalidated tools and checklists. Heterogeneity across studies will be assessed using the χ test on Cochrane Q statistic. A random effect meta-analysis will be used to estimate the overall prevalence of pneumococcal carriage and incidence of pneumococcal pneumonia across studies with similar characteristics. Results will be reported in compliance with the Meta-Analysis Of Observational Studies in Epidemiology guidelines. The protocol has been prepared in accordance to the 2015 guidelines on Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Ethics And Dissemination: This systematic review will not require ethical approval as we will be using already published data. The final manuscript will be submitted for publication in a peer-reviewed journal and presented at conferences.

Prospero Registration Number: CRD42019130976.
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http://dx.doi.org/10.1136/bmjopen-2019-030981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858229PMC
November 2019

Impact of Maternal HIV Infection and Placental Malaria on the Transplacental Transfer of Influenza Antibodies in Mother-Infant Pairs in Malawi, 2013-2014.

Open Forum Infect Dis 2019 Oct 28;6(10):ofz383. Epub 2019 Aug 28.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi.

Background: Maternal influenza vaccination protects infants against influenza virus infection. Impaired transplacental transfer of influenza antibodies may reduce this protection.

Methods: We conducted a cross-sectional study of influenza vaccine-naïve pregnant women recruited at delivery from Blantyre (urban, low malaria transmission) and Chikwawa (rural, high malaria transmission) in Southern Malawi. HIV-infected mothers were excluded in Chikwawa. Maternal and cord blood antibodies against circulating influenza strains A/California/7/2009, A/Victoria/361/2011, B/Brisbane/60/2008, and B/Wisconsin/1/2010 were measured by hemagglutination inhibition (HAI). We studied the impact of maternal HIV infection and placental malaria on influenza antibody levels in mother-infant pairs in Blantyre and Chikwawa, respectively.

Results: We included 454 mother-infant pairs (Blantyre, n = 253; Chikwawa, n = 201). HIV-infected mothers and their infants had lower seropositivity (HAI titer ≥1:40) against influenza A(H1N1)pdm09 (mothers, 24.3 vs 45.4%; = .02; infants, 24.3 vs 50.5%; = .003) and A(H3N2) (mothers, 37.8% vs 63.9%; = .003; infants, 43.2 vs 64.8%; = .01), whereas placental malaria had an inconsistent effect on maternal and infant seropositivity. In multivariable analyses, maternal HIV infection was associated with reduced infant seropositivity (A(H1N1)pdm09: adjusted odds ratio [aOR], 0.34; 95% confidence interval [CI], 0.15-0.79; A(H3N2): aOR, 0.43; 95% CI, 0.21-0.89). Transplacental transfer was not impaired by maternal HIV or placental malaria.

Conclusions: Maternal HIV infection influenced maternal antibody response to influenza A virus infection, and thereby antibody levels in newborns, but did not affect transplacental antibody transfer.
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http://dx.doi.org/10.1093/ofid/ofz383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785697PMC
October 2019

Community-acquired acute bacterial meningitis in adults: a clinical update.

Br Med Bull 2019 09;131(1):57-70

Hospital for Tropical Diseases, University College London Hospitals NHS Foundation Trust, 235 Euston Rd, Bloomsbury, London, UK.

Background: Acute bacterial meningitis (ABM) in adults is associated with a mortality that may exceed 30%. Immunization programs have reduced the global burden; in the UK, declining incidence but persistently high mortality and morbidity mean that clinicians must remain vigilant.

Sources Of Data: A systematic electronic literature search of PubMed was performed to identify all ABM literature published within the past 5 years.

Areas Of Agreement And Controversy: Clinical features cannot reliably distinguish between ABM and other important infectious and non-infectious aetiologies. Prompt investigation and empirical treatment are imperative. Lumbar puncture (LP) and cerebrospinal fluid microscopy, biochemistry and culture remain the mainstay of diagnosis, but molecular techniques are increasingly useful. The 2016 UK joint specialist societies' guideline provides expert recommendations for the management of ABM, yet published data suggest clinical care delivered in the UK is frequently not adherent. Anxiety regarding risk of cerebral herniation following LP, unnecessary neuroimaging, underutilization of molecular diagnostics and suboptimal uptake of adjunctive corticosteroids compromise management.

Growing Points: There is increasing recognition that current antibiotic regimens and adjunctive therapies alone are insufficient to reduce the mortality and morbidity associated with ABM.

Areas Timely For Developing Research: Research should be focused on optimization of vaccines (e.g. pneumococcal conjugate vaccines with extended serotype coverage), targeting groups at risk for disease and reservoirs for transmission; improving adherence to management guidelines; development of new faster, more accurate diagnostic platforms (e.g. novel point-of-care molecular diagnostics); and development of new adjunctive therapies (aimed at the host-inflammatory response and bacterial virulence factors).
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http://dx.doi.org/10.1093/bmb/ldz023DOI Listing
September 2019

Evaluating the reactivation of herpesviruses and inflammation as cardiovascular and cerebrovascular risk factors in antiretroviral therapy initiators in an African HIV-infected population (RHICCA): a protocol for a longitudinal cohort study.

BMJ Open 2019 09 12;9(9):e025576. Epub 2019 Sep 12.

Institute of Infection and Global Health, University of Liverpool, Liverpool, UK

Introduction: In Sub-Saharan Africa, the rising rates of cerebrovascular and cardiovascular diseases (CBD/CVD) are intersecting with an ageing HIV-infected population. The widespread use of antiretroviral therapy (ART) may confer an additive risk and may not completely suppress the risk associated with HIV infection. High-quality prospective studies are needed to determine if HIV-infected patients in Africa are at increased risk of CBD/CVD and to identify factors associated with this risk. This study will test the hypothesis that immune activation and dysfunction, driven by HIV and reactivation of latent herpesvirus infections, lead to increased CBD/CVD risk in Malawian adults aged ≥35 years.

Methods And Analysis: We will conduct a single-centre, 36-month, prospective cohort study in 800 HIV-infected patients initiating ART and 190 HIV-uninfected controls in Blantyre, Malawi. Patients and controls will be recruited from government ART clinics and the community, respectively, and will be frequency-matched by 5-year age band and sex. At baseline and follow-up visits, we will measure carotid intima-media thickness and pulse wave velocity as surrogate markers of vasculopathy, and will be used to estimate CBD/CVD risk. Our primary exposures of interest are cytomegalovirus and varicella zoster reactivation, changes in HIV plasma viral load, and markers of systemic inflammation and endothelial function. Multivariable regression models will be developed to assess the study's primary hypothesis. The occurrence of clinical CBD/CVD will be assessed as secondary study endpoints.

Ethics And Dissemination: The University of Malawi College of Medicine and Liverpool School of Tropical Medicine research ethics committees approved this work. Our goal is to understand the pathogenesis of CBD/CVD among HIV cohorts on ART, in Sub-Saharan Africa, and provide data to inform future interventional clinical trials. This study runs between May 2017 and August 2020. Results of the main trial will be submitted for publication in a peer-reviewed journal.

Trial Registration Number: ISRCTN42862937.
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http://dx.doi.org/10.1136/bmjopen-2018-025576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747662PMC
September 2019

Vaccine Effectiveness against DS-1-Like Rotavirus Strains in Infants with Acute Gastroenteritis, Malawi, 2013-2015.

Emerg Infect Dis 2019 09;25(9):1734-1737

Atypical DS-1-like G1P[8] rotaviruses emerged in 2013 in Malawi after rotavirus vaccine introduction. Vaccine effectiveness among infants hospitalized with acute DS-1-like G1P[8] rotavirus gastroenteritis was 85.6% (95% CI 34.4%-96.8%). These findings suggest that vaccine provides protection against these strains despite their emergence coinciding with vaccine introduction.
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http://dx.doi.org/10.3201/eid2509.190258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711242PMC
September 2019

Innate and adaptive nasal mucosal immune responses following experimental human pneumococcal colonization.

J Clin Invest 2019 07 30;129(10):4523-4538. Epub 2019 Jul 30.

Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

Streptococcus pneumoniae (Spn) is a common cause of respiratory infection, but also frequently colonizes the nasopharynx in the absence of disease. We used mass cytometry to study immune cells from nasal biopsy samples collected following experimental human pneumococcal challenge in order to identify immunological mechanisms of control of Spn colonization. Using 37 markers, we characterized 293 nasal immune cell clusters, of which 7 were associated with Spn colonization. B cell and CD8+CD161+ T cell clusters were significantly lower in colonized than in non-colonized subjects. By following a second cohort before and after pneumococcal challenge we observed that B cells were depleted from the nasal mucosa upon Spn colonization. This associated with an expansion of Spn polysaccharide-specific and total plasmablasts in blood. Moreover, increased responses of blood mucosal associated invariant T (MAIT) cells against in vitro stimulation with pneumococcus prior to challenge associated with protection against establishment of Spn colonization and with increased mucosal MAIT cell populations. These results implicate MAIT cells in the protection against pneumococcal colonization and demonstrate that colonization affects mucosal and circulating B cell populations.
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http://dx.doi.org/10.1172/JCI128865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763269PMC
July 2019

Early T Cell Differentiation with Well-Maintained Function across the Adult Life Course in Sub-Saharan Africa.

J Immunol 2019 09 29;203(5):1160-1171. Epub 2019 Jul 29.

Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, Birmingham Health Partners, University of Birmingham, Edgbaston, B15 2TT Birmingham, United Kingdom.

Immune senescence is a significant contributor to health problems in the developed world and may be accelerated by chronic viral infections. To date, there have been few studies of immune function in healthy older people in sub-Saharan Africa. We assessed T cell and B cell phenotypes and immune responses to CMV, EBV, and influenza virus in Malawians aged 20-69 y. Notably, the proportion of naive (CCR7CD45RA) CD4 and CD8 T cells was only 14% of the lymphoid repertoire even in donors aged under 30 y but did not decrease further with age. A small increase in the late differentiated (CD27CD28) CD8 T cell subpopulation was observed in older donors but the CD4/CD8 T cell ratio remained stable in all age groups. Interestingly, the regulatory (CD25FOXP3) T cell subpopulation was small in all age groups, and we observed no age-associated accumulation of cells expressing the senescence- and exhaustion-associated markers CD57 and PD-1. We assessed functional T cell responses to mitogenic and viral antigenic stimulation by the expression of CD154, IFN-γ, TNF-α, IL-2, and IL-17 and proliferation. All responses were robust across the life course, although we observed an age-associated shift from IFN-γ to TNF-α in the response to EBV. In summary, we found the naive T cell subpopulation of young adult Malawians was smaller than in their contemporaries in high-income settings but remains stable thereafter and that lymphocyte function is retained across the life course. These observations indicate that studies of the genetic and environmental factors influencing immune function in different environments may provide insights into minimizing immune ageing.
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http://dx.doi.org/10.4049/jimmunol.1800866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778523PMC
September 2019

Ascertaining the burden of invasive Salmonella disease in hospitalised febrile children aged under four years in Blantyre, Malawi.

PLoS Negl Trop Dis 2019 07 17;13(7):e0007539. Epub 2019 Jul 17.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi.

Typhoid fever is endemic across sub-Saharan Africa. However, estimates of the burden of typhoid are undermined by insufficient blood volumes and lack of sensitivity of blood culture. Here, we aimed to address this limitation by exploiting pre-enrichment culture followed by PCR, alongside routine blood culture to improve typhoid case detection. We carried out a prospective diagnostic cohort study and enrolled children (aged 0-4 years) with non-specific febrile disease admitted to a tertiary hospital in Blantyre, Malawi from August 2014 to July 2016. Blood was collected for culture (BC) and real-time PCR after a pre-enrichment culture in tryptone soy broth and ox-bile. DNA was subjected to PCR for invA (Pan-Salmonella), staG (S. Typhi), and fliC (S. Typhimurium) genes. A positive PCR was defined as invA plus either staG or fliC (CT<29). IgM and IgG ELISA against four S. Typhi antigens was also performed. In total, 643 children (median age 1.3 years) with nonspecific febrile disease were enrolled; 31 (4.8%) were BC positive for Salmonella (n = 13 S. Typhi, n = 16 S. Typhimurium, and n = 2 S. Enteritidis). Pre-enrichment culture of blood followed by PCR identified a further 8 S. Typhi and 15 S. Typhimurium positive children. IgM and IgG titres to the S. Typhi antigen STY1498 (haemolysin) were significantly higher in children that were PCR positive but blood culture negative compared to febrile children with all other non-typhoid illnesses. The addition of pre-enrichment culture and PCR increased the case ascertainment of invasive Salmonella disease in children by 62-94%. These data support recent burden estimates that highlight the insensitivity of blood cultures and support the targeting of pre-school children for typhoid vaccine prevention in Africa. Blood culture with real-time PCR following pre-enrichment should be used to further refine estimates of vaccine effectiveness in typhoid vaccine trials.
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http://dx.doi.org/10.1371/journal.pntd.0007539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663031PMC
July 2019

Microinvasion by Streptococcus pneumoniae induces epithelial innate immunity during colonisation at the human mucosal surface.

Nat Commun 2019 07 16;10(1):3060. Epub 2019 Jul 16.

Division of Infection and Immunity, University College London, London, UK.

Control of Streptococcus pneumoniae colonisation at human mucosal surfaces is critical to reducing the burden of pneumonia and invasive pneumococcal disease, interrupting transmission, and achieving herd protection. Here, we use an experimental human pneumococcal carriage model (EHPC) to show that S. pneumoniae colonisation is associated with epithelial surface adherence, micro-colony formation and invasion, without overt disease. Interactions between different strains and the epithelium shaped the host transcriptomic response in vitro. Using epithelial modules from a human epithelial cell model that recapitulates our in vivo findings, comprising of innate signalling and regulatory pathways, inflammatory mediators, cellular metabolism and stress response genes, we find that inflammation in the EHPC model is most prominent around the time of bacterial clearance. Our results indicate that, rather than being confined to the epithelial surface and the overlying mucus layer, the pneumococcus undergoes micro-invasion of the epithelium that enhances inflammatory and innate immune responses associated with clearance.
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http://dx.doi.org/10.1038/s41467-019-11005-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635362PMC
July 2019

One-year Mortality Outcomes From the Advancing Cryptococcal Meningitis Treatment for Africa Trial of Cryptococcal Meningitis Treatment in Malawi.

Clin Infect Dis 2020 01;70(3):521-524

Centre for Global Health, Institute for Infection and Immunity, St George's University of London, United Kingdom.

In Malawi, 236 participants from the Advancing Cryptococcal Meningitis Treatment for Africa trial were followed for 12 months. The trial outcomes reported at 10 weeks were sustained to 1 year. One-week amphotericin B plus flucytosine was associated with the lowest 1 year mortality (27.5% [95% confidence interval, 16.3 to 44.1]).
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http://dx.doi.org/10.1093/cid/ciz454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105249PMC
January 2020