199 results found
Camille H, Tomas U, Romain B, et al., 2022, Necrotising Soft Tissue Infections, The Lancet Infectious Diseases, ISSN: 1473-3099
The incidence of necrotising soft tissue infections (NSTI) has increased during recent decades such that most physicians might see at least one case of these potentially life-threatening infections in their career. Despite advances in care, NSTI are still associated with high morbidity and mortality, underlining a need for continued education of the medical community. In particular, failure to suspect NSTI fueled by poor awareness of the disease promotes delays to first surgical debridement, amplifying disease severity and adverse outcomes. This review will focus on practical approaches to management of NSTI including prompt recognition, initiation of specific management, exploratory surgery, and aftercare. Increased alertness and awareness for NSTI should improve time to diagnosis and early referral to specialised centers, with consequent improvement in NSTI prognosis.
Broderick C, Calle IR, Gómez Carballa A, et al., 2022, Pseudotemporal whole blood transcriptional profiling of COVID-19 patients stratified by clinical severity reveals differences in immune responses and possible role of monoamine oxidase B
<jats:title>Abstract</jats:title><jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with highly variable clinical outcomes. Studying the temporal dynamics of host whole blood gene expression during SARS-CoV-2 infection can elucidate the biological processes that underlie these diverse clinical phenotypes. We employed a novel pseudotemporal approach using MaSigPro to model and compare the trajectories of whole blood transcriptomic responses in patients with mild, moderate and severe COVID-19 disease. We identified 5,267 genes significantly differentially expressed (SDE) over pseudotime and between severity groups and clustered these genes together based on pseudotemporal trends. Pathway analysis of these gene clusters revealed upregulation of multiple immune, coagulation, platelet and senescence pathways with increasing disease severity and downregulation of T cell, transcriptional and cellular metabolic pathways. The gene clusters exhibited differing pseudotemporal trends. Monoamine oxidase B was the top SDE gene, upregulated in severe>moderate>mild COVID-19 disease. This work provides new insights into the diversity of the host response to SARS-CoV-2 and disease severity and highlights the utility of pseudotemporal approaches in studying evolving immune responses to infectious diseases.</jats:p>
Cordery R, Purba A, Begum L, et al., 2022, Frequency of transmission, asymptomatic shedding, and airborne spread of Streptococcus pyogenes in schoolchildren exposed to scarlet fever: a prospective, longitudinal, multicohort, molecular epidemiological, contact-tracing study in England, UK, The Lancet Microbe, Vol: 3, Pages: e366-e375, ISSN: 2666-5247
BackgroundDespite recommendations regarding prompt treatment of cases and enhanced hygiene measures, scarlet fever outbreaks increased in England between 2014 and 2018. We aimed to assess the effects of standard interventions on transmission of Streptococcus pyogenes to classroom contacts, households, and classroom environments to inform future guidance.MethodsWe did a prospective, longitudinal, multicohort, molecular epidemiological, contact-tracing study in six settings across five schools in Greater London, UK. Schools and nurseries were eligible to participate if they had reported two cases of scarlet fever within 10 days of each other among children aged 2–8 years from the same class, with the most recent case arising in the preceding 48 h. We cultured throat swabs from children with scarlet fever, classroom contacts, and household contacts at four timepoints. We also cultured hand swabs and cough plates from all cases in years 1 and 2 of the study, and from classroom contacts in year 2. Surface swabs from toys and other fomites in classrooms were cultured in year 1, and settle plates from classrooms were collected in year 2. Any sample with S pyogenes detected was recorded as positive and underwent emm genotyping and genome sequencing to compare with the outbreak strain.FindingsSix classes, comprising 12 cases of scarlet fever, 17 household contacts, and 278 classroom contacts were recruited between March 1 and May 31, 2018 (year 1), and between March 1 and May 31, 2019 (year 2). Asymptomatic throat carriage of the outbreak strains increased from 11 (10%) of 115 swabbed children in week 1, to 34 (27%) of 126 in week 2, to 26 (24%) of 108 in week 3, and then five (14%) of 35 in week 4. Compared with carriage of outbreak S pyogenes strains, colonisation with non-outbreak and non-genotyped S pyogenes strains occurred in two (2%) of 115 swabbed children in week 1, five (4%) of 126 in week 2, six (6%) of 108 in week 3, and in none of the 35 children in week 4
Taylor E, Jauneikaite E, Sriskandan S, et al., 2022, Novel 16S rRNA methyltransferase RmtE3 in acinetobacter baumannii ST79., Journal of Medical Microbiology, Vol: 71, ISSN: 0022-2615
Introduction. The 16S rRNA methyltransferase (16S RMTase) gene armA is the most common mechanism conferring high-level aminoglycoside resistance in Acinetobacter baumannii, although rmtA, rmtB, rmtC, rmtD and rmtE have also been reported.Hypothesis/Gap statement. The occurrence of 16S RMTase genes in A. baumannii in the UK and Republic of Ireland is currently unknown.Aim. To identify the occurrence of 16S RMTase genes in A. baumannii isolates from the UK and the Republic of Ireland between 2004 and 2015.Methodology. Five hundred and fifty pan-aminoglycoside-resistant A. baumannii isolates isolated from the UK and the Republic of Ireland between 2004 and 2015 were screened by PCR to detect known 16S RMTase genes, and then whole-genome sequencing was conducted to screen for novel 16S RMTase genes.Results. A total of 96.5 % (531/550) of isolates were positive for 16S RMTase genes, with all but 1 harbouring armA (99.8 %, 530/531). The remaining isolates harboured rmtE3, a new rmtE variant. Most (89.2 %, 473/530) armA-positive isolates belonged to international clone II (ST2), and the rmtE3-positive isolate belonged to ST79. rmtE3 shared a similar genetic environment to rmtE2 but lacked an ISCR20 element found upstream of rmtE2.Conclusion. This is the first report of rmtE in A. baumannii in Europe; the potential for transmission of rmtE3 to other bacterial species requires further research.
Cordery R, Reeves L, Zhou J, et al., 2022, Transmission of SARS-CoV-2 by children to contacts in schools and households: a prospective cohort and environmental sampling study in London, The Lancet Microbe, ISSN: 2666-5247
Background: Assessing transmission of SARS-CoV-2 by children in schools is of critical importance to inform public health action. We assessed frequency of acquisition of SARS-CoV-2 by contacts of pupils with COVID-19 in schools and households, and quantified SARS-CoV-2 shed into air and onto fomites in both settings.Methods: Incidents involving exposure to at least one index pupil with COVID-19 in 8 schools were identified between October 2020-July 2021 (prevailing variants, original, alpha and delta). Weekly PCR testing for SARS-CoV-2 was undertaken on immediate classroom contacts (the “bubble”), non-bubble school contacts, and household contacts of index pupils, supported by genome sequencing, and on surface and air samples from school and home environments.Findings: Secondary transmission of SARS-CoV-2 was not detected in 28 bubble contacts, representing 10 bubble classes (participation rate 8.8%, IQR 4.6-15.3%). Across 8 non-bubble classes, 3/62 pupils tested positive but these were unrelated to the original index case (participation rate 22.5%, IQR 9.7-32.3%). All three were asymptomatic and tested positive in one setting on the same day. In contrast, secondary transmission to previously-negative household contacts from infected index pupils was 17.1% (6/35) rising to 27.7% (13/47) when considering all potentialinfections in household contacts. Environmental contamination with SARS-CoV-2 was rare in schools; fomite SARS-CoV-2 was identified in 4/189 (2.1%) samples in bubble classrooms, 2/127 (1.6%) samples in non-bubble classrooms, and 5/130 (3.8%) samples in washrooms. This contrasted with fomites in households, where SARS-CoV-2 was identified in 60/248 (24.2%) bedroom samples, 66/241 (27.4%) communal room samples, and 21/188 (11.2%) bathroom samples. Air sampling identified SARS-CoV-2 RNA in just 1/68 (1.5%) of school air samples, compared with 21/85 (24.7%) of air samples taken in homes.Interpretation: There was no evidence of large scale SARS-Co
Seethalakshmi PS, Charity OJ, Giakoumis T, et al., 2022, Delineating the impact of COVID-19 on antimicrobial resistance: An Indian perspective, Science of the Total Environment, Vol: 818, ISSN: 0048-9697
The COVID-19 pandemic has shattered millions of lives globally and continues to be a challenge to public health due to the emergence of variants of concern. Fear of secondary infections following COVID-19 has led to an escalation in antimicrobial use during the pandemic, while some antimicrobials have been repurposed as treatments for SARS-CoV-2, further driving antimicrobial resistance. India is one of the largest producers and consumers of antimicrobials globally, hence the task of curbing antimicrobial resistance is a huge challenge. Practices like empirical antimicrobial prescription and repurposing of drugs in clinical settings, self-medication and excessive use of antimicrobial hygiene products may have negatively impacted the prevalence of antimicrobial resistance in India. However, the expanded production of antimicrobials and disinfectants during the pandemic in response to increased demand may have had an even greater impact on the threat of antimicrobial resistance through major impacts on the environment. The review provides an outline of the impact COVID-19 can have on antimicrobial resistance in clinical settings and the possible outcomes on the environment. This review calls for the upgrading of existing antimicrobial policies and emphasizes the need for research studies to understand the impact of the pandemic on antimicrobial resistance in India.
McKenna S, Huse KK, Giblin S, et al., 2022, The role of streptococcal cell-envelope proteases in bacterial evasion of the innate immune system, Journal of Innate Immunity, Vol: 14, Pages: 69-88, ISSN: 1662-811X
Bacteria possess the ability to evolve varied and ingenious strategies to outwit the host immune system, instigating an evolutionary arms race. Proteases are amongst the many weapons employed by bacteria, which specifically cleave and neutralize key signalling molecules required for a coordinated immune response. In this article, we focus on a family of S8 subtilisin-like serine proteases expressed as cell-envelope proteases (CEPs) by group A and group B streptococci. Two of these proteases known as Streptococcus pyogenes CEP (SpyCEP) and C5a peptidase cleave the chemokine CXCL8 and the complement fragment C5a, respectively. Both CXCL8 and C5a are potent neutrophil-recruiting chemokines, and by neutralizing their activity, streptococci evade a key defence mechanism of innate immunity. We review the mechanisms by which CXCL8 and C5a recruit neutrophils and the characterization of SpyCEP and C5a peptidase, including both in vitro and in vivo studies. Recently described structural insights into the function of this CEP family are also discussed. We conclude by examining the progress of prototypic vaccines incorporating SpyCEP and C5a peptidase in their preparation. Since streptococci-producing SpyCEP and C5a peptidase are responsible for a considerable global disease burden, targeting these proteases by vaccination strategies or by small-molecule antagonists should provide protection from and promote the resolution of streptococcal infections.
Mehta R, Chekmeneva E, Jackson H, et al., 2022, Antiviral metabolite 3’-Deoxy-3’,4’-didehydro-cytidine is detectable in serum and identifies acute viral infections including COVID-19, Med, Vol: 3, Pages: 204-215.e6, ISSN: 2666-6340
Background:There is a critical need for rapid viral infection diagnostics to enable prompt case identification in pandemic settings and support targeted antimicrobial prescribing.Methods:Using untargeted high-resolution liquid chromatography coupled with mass spectrometry, we compared the admission serum metabolome of emergency department patients with viral infections including COVID-19, bacterial infections, inflammatory conditions, and healthy controls. Sera from an independent cohort of emergency department patients admitted with viral or bacterial infections underwent profiling to validate findings. Associations between whole-blood gene expression and the identified metabolite of interest were examined.Findings:3'-Deoxy-3',4'-didehydro-cytidine (ddhC), a free base of the only known human antiviral small molecule ddhC-triphosphate (ddhCTP), was detected for the first time in serum. When comparing 60 viral to 101 non-viral cases in the discovery cohort, ddhC was the most differentially abundant metabolite, generating an area under the receiver operating characteristic curve (AUC) of 0.954 (95% CI: 0.923-0.986). In the validation cohort, ddhC was again the most significantly differentially abundant metabolite when comparing 40 viral to 40 bacterial cases, generating an AUC of 0.81 (95% CI 0.708-0.915). Transcripts of viperin and CMPK2, enzymes responsible for ddhCTP synthesis, were amongst the five genes most highly correlated to ddhC abundance.Conclusions:The antiviral precursor molecule ddhC is detectable in serum and an accurate marker for acute viral infection. Interferon-inducible genes viperin and CMPK2 are implicated in ddhC production in vivo. These findings highlight a future diagnostic role for ddhC in viral diagnosis, pandemic preparedness, and acute infection management.
Taylor E, Jauneikaite E, Sriskandan S, et al., 2022, Detection and characterisation of 16S rRNA methyltransferase-producing Pseudomonas aeruginosa from the UK and Republic of Ireland from 2003-2015, International Journal of Antimicrobial Agents, Vol: 59, ISSN: 0924-8579
16S rRNA methyltransferase (16S RMTase) genes confer high-level aminoglycoside resistance, reducing treatment options for multidrug-resistant Gram-negative bacteria. Pseudomonas aeruginosa isolates (n = 221) exhibiting high-level pan-aminoglycoside resistance (amikacin, gentamicin and tobramycin MICs ≥64, ≥32 and ≥32 mg/L, respectively) were screened for 16S RMTase genes to determine their occurrence among isolates submitted to a national reference laboratory from December 2003 to December 2015. 16S RMTase genes were identified using two multiplex PCRs, and whole-genome sequencing (WGS) was used to identify other antibiotic resistance genes, sequence types (STs) and the genetic environment of 16S RMTase genes. 16S RMTase genes were found in 8.6% (19/221) of isolates, with rmtB4 (47.4%; 9/19) being most common, followed by rmtD3 (21.1%; 4/19), rmtF2 (15.8%; 3/19) and single isolates harbouring rmtB1, rmtC and rmtD1. Carbapenemase genes were found in 89.5% (17/19) of 16S RMTase-positive isolates, with blaVIM (52.9%; 9/17) being most common. 16S RMTase genes were found in ‘high-risk’ clones known to harbour carbapenemase genes (ST233, ST277, ST357, ST654 and ST773). Analysis of the genetic environment of 16S RMTase genes identified that IS6100 was genetically linked to rmtB1; IS91 to rmtB4, rmtC or rmtD3; ISCR14 to rmtD1; and rmtF2 was linked to Tn3, IS91 or Tn1721. Although 16S RMTase genes explained only 8.6% of pan-aminoglycoside resistance in the P. aeruginosa isolates studied, the association of 16S RMTase genes with carbapenemase-producers and ‘high-risk’ clones highlights that continued surveillance is required to monitor spread as well as the importance of suppressing the emergence of dually-resistant clones in hospital settings.
Baruch J, Rojek A, Kartsonaki C, et al., 2022, Symptom-based case definitions for COVID-19: Time and geographical variations for detection at hospital admission among 260,000 patients, Influenza and other Respiratory Viruses, ISSN: 1750-2640
Introduction: Case definitions are used to guide clinical practice, surveillance and research protocols. However, how they identify COVID-19-hospitalised patients is not fully understood. We analysed the proportion of hospitalised patients with laboratory-confirmed COVID-19, in the ISARIC prospective cohort study database, meeting widely used case definitions. Methods: Patients were assessed using the Centers for Disease Control (CDC), European Centre for Disease Prevention and Control (ECDC), World Health Organization (WHO) and UK Health Security Agency (UKHSA) case definitions by age, region and time. Case fatality ratios (CFRs) and symptoms of those who did and who did not meet the case definitions were evaluated. Patients with incomplete data and non-laboratory-confirmed test result were excluded. Results: A total of 263,218 of the patients (42%) in the ISARIC database were included. Most patients (90.4%) were from Europe and Central Asia. The proportions of patients meeting the case definitions were 56.8% (WHO), 74.4% (UKHSA), 81.6% (ECDC) and 82.3% (CDC). For each case definition, patients at the extremes of age distribution met the criteria less frequently than those aged 30 to 70 years; geographical and time variations were also observed. Estimated CFRs were similar for the patients who met the case definitions. However, when more patients did not meet the case definition, the CFR increased. Conclusions: The performance of case definitions might be different in different regions and may change over time. Similarly concerning is the fact that older patients often did not meet case definitions, risking delayed medical care. While epidemiologists must balance their analytics with field applicability, ongoing revision of case definitions is necessary to improve patient care through early diagnosis and limit potential nosocomial spread.
Herdman MT, Cordery R, Karo B, et al., 2021, Clinical management and impact of scarlet fever in the modern era: findings from a cross-sectional study of cases in London, 2018-2019, BMJ Open, Vol: 12, Pages: 1-9, ISSN: 2044-6055
Objectives In response to increasing incidence of scarlet fever and wider outbreaks of group A streptococcal infections in London, we aimed to characterise the epidemiology, symptoms, management and consequences of scarlet fever, and to identify factors associated with delayed diagnosis.Design and setting Cross-sectional community-based study of children with scarlet fever notified to London’s three Health Protection Teams, 2018–2019.Participants From 2575 directly invited notified cases plus invitations via parental networks at 410 schools/nurseries with notified outbreaks of confirmed/probable scarlet fever, we received 477 responses (19% of those directly invited), of which 412 met the case definition. Median age was 4 years (range <1 to 16), 48% were female, and 70% were of white ethnicity.Outcome measures Preplanned measures included quantitative description of case demographics, symptoms, care-seeking, and clinical, social, and economic impact on cases and households. After survey completion, secondary analyses of factors associated with delayed diagnosis (by logistic regression) and consequences of delayed diagnosis (by Cox’s regression), and qualitative analysis of free text comments were added.Results Rash was reported for 89% of cases, but followed onset of other symptoms for 71%, with a median 1-day delay. Pattern of onset varied with age: sore throat was more common at onset among children 5 years and older (OR3.1, 95% CI 1.9 to 5.0). At first consultation, for 28%, scarlet fever was not considered: in these cases, symptoms were frequently attributed to viral infection (60%, 64/106). Delay in diagnosis beyond first consultation occurred more frequently among children aged 5+ who presented with sore throat (OR 2.8 vs 5+without sore throat; 95% CI 1.3 to 5.8). Cases with delayed diagnosis took, on average, 1 day longer to return to baseline activities.Conclusions Scarlet fever may be initially overlooked, es
Siggins MK, Sriskandan S, 2021, Bacterial lymphatic metastasis in infection and immunity, Cells, Vol: 11, ISSN: 2073-4409
Lymphatic vessels permeate tissues around the body, returning fluid from interstitial spaces back to the blood after passage through the lymph nodes, which are important sites for adaptive responses to all types of pathogens. Involvement of the lymphatics in the pathogenesis of bacterial infections is not well studied. Despite offering an obvious conduit for pathogen spread, the lymphatic system has long been regarded to bar the onward progression of most bacteria. There is little direct data on live virulent bacteria, instead understanding is largely inferred from studies investigating immune responses to viruses or antigens in lymph nodes. Recently, we have demonstrated that extracellular bacterial lymphatic metastasis of virulent strains of Streptococcus pyogenes drives systemic infection. Accordingly, it is timely to reconsider the role of lymph nodes as absolute barriers to bacterial dissemination in the lymphatics. Here, we summarise the routes and mechanisms by which an increasing variety of bacteria are acknowledged to transit through the lymphatic system, including those that do not necessarily require internalisation by host cells. We discuss the anatomy of the lymphatics and other factors that influence bacterial dissemination, as well as the consequences of underappreciated bacterial lymphatic metastasis on disease and immunity.
Wan Y, Mills E, Leung RCY, et al., 2021, Alterations in chromosomal genes nfsA, nfsB, and ribE are associated with nitrofurantoin resistance in escherichia coli from the UK, Microbial Genomics, Vol: 7, Pages: 1-19, ISSN: 2057-5858
Antimicrobial resistance in enteric or urinary Escherichia coli is a risk factor for invasive E. coli infections. Due to widespread trimethoprim resistance amongst urinary E. coli and increased bacteraemia incidence, a national recommendation to prescribe nitrofurantoin for uncomplicated urinary tract infection was made in 2014. Nitrofurantoin resistance is reported in <6% urinary E. coli isolates in the UK, however, mechanisms underpinning nitrofurantoin resistance in these isolates remain unknown. This study aimed to identify the genetic basis of nitrofurantoin resistance in urinary E. coli isolates collected from north west London and then elucidate resistance-associated genetic alterations in available UK E. coli genomes. As a result, an algorithm was developed to predict nitrofurantoin susceptibility.Deleterious mutations and gene-inactivating insertion sequences in chromosomal nitroreductase genes nfsA and/or nfsB were identified in genomes of nine nitrofurantoin-resistant urinary E. coli isolates, as well as all further 11 E. coli isolates that were experimentally validated to be nitrofurantoin resistant. Eight categories of allelic changes in nfsA, nfsB, and the associated gene ribE were detected in 12,412 E. coli genomes from the UK. Evolutionary analysis of these three genes revealed homoplasic mutations and explained the previously reported order of stepwise mutations. The mobile gene complex oqxAB, which is associated with reduced nitrofurantoin susceptibility, was identified in only one of the 12,412 genomes.In conclusion, mutations and insertion sequences in nfsA and nfsB were leading causes of nitrofurantoin resistance in UK E. coli. As nitrofurantoin exposure increases in human populations, the prevalence of nitrofurantoin resistance in carriage E. coli isolates and those from urinary and bloodstream infections should be monitored.
Pearson M, Haslam C, Fosberry A, et al., 2021, Non-conventional serine protease activity of the CXC chemokine-cleaving streptococcal enzyme, SpyCEP
<jats:title>Abstract</jats:title><jats:p>The <jats:italic>Streptococcus pyogenes</jats:italic> cell envelope protease (SpyCEP) is a vital virulence factor in streptococcal pathogenesis. Despite its key role in disease progression and strong association with invasive disease, little is known about the enzymatic function beyond the ELR<jats:sup>+</jats:sup> CXC chemokine substrate range. We utilised multiple SpyCEP constructs to interrogate the protein domains and catalytic residues necessary for enzyme function. We leveraged high-throughput mass spectrometry to describe the Michaelis-Menton parameters of active SpyCEP, revealing a Michaelis-Menton constant (K<jats:sub>M</jats:sub>) of 53.49 nM and a turnover of 1.34 molecules per second, for the natural chemokine substrate CXCL8.</jats:p><jats:p>Unexpectedly, we found that an N-terminally-truncated SpyCEP C-terminal construct consisting of only the H279 and S617 catalytic dyad had specific CXCL8 cleaving activity, albeit with a reduced substrate turnover of 2.45 molecules per hour, representing a <jats:sup>~</jats:sup>2000-fold reduction in activity. In contrast, the K<jats:sub>M</jats:sub> of the C-terminal SpyCEP construct and full-length enzyme did not differ. We conclude that the SpyCEP C-terminus plays a key role in substrate binding and recognition with key implications for both current and future streptococcal vaccine designs.</jats:p>
Li HK, Kaforou M, Rodriguez-Manzano J, et al., 2021, Discovery and validation of a 3-gene signature to distinguish COVID-19 and other viral infections in emergency infectious disease presentations; a case-control then observational cohort study, The Lancet Microbe, Vol: 2, Pages: 594-603, ISSN: 2666-5247
Background: Emergency admissions for infection often lack initial diagnostic certainty. COVID-19 has highlighted a need for novel diagnostic approaches to indicate likelihood of viral infection in a pandemic setting. We sought to derive and validate a blood transcriptional signature to detect viral infections including COVID-19 among adults with suspected infection presenting to the Emergency Department (ED).Methods: Blood RNA sequencing was performed on a discovery cohort of adults attending the ED with suspected infection who had subsequently-confirmed viral, bacterial, or no infection diagnoses. Differentially expressed host genes were subjected to feature selection to derive the most parsimonious discriminating signature. RT-qPCR validation of the signature was then performed in a prospective cohort of ED patients presenting with undifferentiated fever, and a second case-control cohort of ED patients with COVID-19 or bacterial infection. Signature performance was assessed by calculating area under receiver-operating characteristic curves (AUC-ROCs), sensitivities, and specificities.Findings: A 3-gene transcript signature was derived from the discovery cohort of 56 bacterial and 27 viral infection cases. In the validation cohort of 200 cases, the signature differentiated bacterial from viral infections with an AUC-ROC of 0.976 (95% CI: 0.919-1.000), sensitivity 97.3% and specificity of 100%. The AUC-ROC for C-reactive protein (CRP) and leucocyte count (WCC) was 0.833 (95% CI: 0.694-0.944) and 0.938 (95% CI: 0.840-0.986) respectively. The signature achieved higher net benefit in decision curve analysis than either CRP or WCC for discriminating viral infections from all other cases. In the second validation analysis the signature discriminated 35 bacterial infections from 34 SARS-CoV-2 positive COVID-19 infections with AUC-ROC of 0.953 (95% CI: 0.893-0.992), sensitivity 88.6% and specificity of 94.1%.Interpretation: This novel 3-gene signature discriminates viral i
Gibson JF, Pidwill GR, Carnell OT, et al., 2021, Commensal bacteria augment Staphylococcus aureus infection by inactivation of phagocyte-derived reactive oxygen species, PLoS Pathogens, Vol: 17, ISSN: 1553-7366
Staphylococcus aureus is a human commensal organism and opportunist pathogen, causing potentially fatal disease. The presence of non-pathogenic microflora or their components, at the point of infection, dramatically increases S. aureus pathogenicity, a process termed augmentation. Augmentation is associated with macrophage interaction but by a hitherto unknown mechanism. Here, we demonstrate a breadth of cross-kingdom microorganisms can augment S. aureus disease and that pathogenesis of Enterococcus faecalis can also be augmented. Co-administration of augmenting material also forms an efficacious vaccine model for S. aureus. In vitro, augmenting material protects S. aureus directly from reactive oxygen species (ROS), which correlates with in vivo studies where augmentation restores full virulence to the ROS-susceptible, attenuated mutant katA ahpC. At the cellular level, augmentation increases bacterial survival within macrophages via amelioration of ROS, leading to proliferation and escape. We have defined the molecular basis for augmentation that represents an important aspect of the initiation of infection.
Taylor E, Bal AM, Balakrishnan I, et al., 2021, A prospective surveillance study to determine the prevalence of 16S rRNA methyltransferase-producing Gram-negative bacteria in the UK, Journal of Antimicrobial Chemotherapy, Vol: 76, Pages: 2428-2436, ISSN: 0305-7453
OBJECTIVES: To determine the prevalence of 16S rRNA methyltransferase- (16S RMTase-) producing Gram-negative bacteria in patients in the UK and to identify potential risk factors for their acquisition. METHODS: A 6 month prospective surveillance study was conducted from 1 May to 31 October 2016, wherein 14 hospital laboratories submitted Acinetobacter baumannii, Enterobacterales and Pseudomonas aeruginosa isolates that displayed high-level amikacin resistance according to their testing methods, e.g. no zone of inhibition with amikacin discs. Isolates were linked to patient travel history, medical care abroad, and previous antibiotic exposure using a surveillance questionnaire. In the reference laboratory, isolates confirmed to grow on Mueller-Hinton agar supplemented with 256 mg/L amikacin were screened by PCR for 16S RMTase genes armA, rmtA-rmtH and npmA, and carbapenemase genes (blaKPC, blaNDM, blaOXA-48-like and blaVIM). STs and total antibiotic resistance gene complement were determined via WGS. Prevalence was determined using denominators for each bacterial species provided by participating hospital laboratories. RESULTS: Eighty-four isolates (44.7%), among 188 submitted isolates, exhibited high-level amikacin resistance (MIC >256 mg/L), and 79 (94.0%) of these harboured 16S RMTase genes. armA (54.4%, 43/79) was the most common, followed by rmtB (17.7%, 14/79), rmtF (13.9%, 11/79), rmtC (12.7%, 10/79) and armA + rmtF (1.3%, 1/79). The overall period prevalence of 16S RMTase-producing Gram-negative bacteria was 0.1% (79/71 063). Potential risk factors identified through multivariate statistical analysis included being male and polymyxin use. CONCLUSIONS: The UK prevalence of 16S RMTase-producing Gram-negative bacteria is low, but continued surveillance is needed to monitor their spread and inform intervention strategies.
Jauneikaite E, Pichon B, Mosavie M, et al., 2021, Staphylococcus argenteus transmission among healthy Royal Marines: a molecular epidemiology case-study, Journal of Infection, Vol: 83, ISSN: 0163-4453
Objectives: During a prospective study of S. aureus carriage in Royal Marines recruits, six S. argenteus strains were identified in four recruits. As S. argenteus sepsis leads to mortality similar to S. aureus, we determined the potential for within same troop transmission, to evaluate future outbreak risk.Methods: We used whole-genome sequencing to characterise S. argenteus and investigate phylogenetic relationships between isolates.Results: S. argenteus strains (t5078, ST2250) were detected in 4/40 recruits in the same troop (training cohort) in weeks 1, 6 or 15 of training. No mec, tsst or LukPV genes were detected. We identified differences of 1-17 core SNPs between S. argenteus from different recruits. In two recruits, two S. argenteus strains were isolated; these could be distinguished by 2 and 15 core SNPs.Conclusions: The identification of S. argenteus within a single troop from the total recruit population suggests a common source for transmission, though high number of SNPs were identified, both within-host and within-cluster. The high number of SNPs between some isolates may indicate a common source of diverse isolates or a high level of S. argenteus mutation in carriage. S. argenteus is newly recognised species; and understanding of the frequency of genetic changes during transmission and transition from asymptomatic carriage to disease is required.
Herdman T, Cordery R, Karo B, et al., 2021, Clinical management and impact of scarlet fever in the modern era: findings from a cross-sectional study of cases in London, 2018-2019
<h4>Background</h4> Scarlet fever incidence has risen steeply in recent years, and is associated with wider outbreaks of severe Group A Streptococcal infections. Yet, few studies of its epidemiology, clinical features, and management have been undertaken in the antibiotic era. <h4>Aim</h4> To characterize symptomatology, management, and consequences of scarlet fever and identify associations with delayed diagnosis. <h4>Design/Setting</h4> Cross-sectional study of children with scarlet fever in London, 2018-2019. <h4>Methods</h4> online survey of parents/guardians of children with scarlet fever identified by Health Protection Teams, recording demographics, symptoms, care-seeking, and management; logistic regression for factors associated with delayed diagnosis; Cox’s regression for consequences of delayed diagnosis. <h4>Results</h4> Responses represented 412 cases in a period with 6828 notifications for children 0-14 years old, and 410 school/nursery outbreaks. 70% first sought care from general practice, and 31% had multiple consultations. For 28%, scarlet fever was not considered at first consultation: in these cases, symptoms were frequently attributed to viral infection (60%, 64/106). Delay in diagnosis beyond first consultation occurred more frequently among children aged 5+ who presented with sore throat (odds ratio 2.8 vs . 5+ without sore throat; 95%CI 1.3-5.8; P=0.006). On average, cases with delayed diagnosis took one day longer to return to baseline activities, and required one additional day off school versus those diagnosed at first consultation. <h4>Conclusions</h4> In assessing children with fever, rash, and sore throat, practitioners should be alert to the possibility of scarlet fever: it is frequently missed at first consultation, and prompt recognition speeds clinical recovery and public health management. <h4>How this fits in [4 sentences summarising key messages of
Jauneikaite E, Honeyford K, Blandy O, et al., 2021, Bacterial genotypic and patient risk factors for adverse outcomes in Escherichia coli bloodstream infections: a prospective molecular-epidemiological study, Journal of Antimicrobial Chemotherapy, Vol: 77, Pages: 1753-1761, ISSN: 0305-7453
<h4>Background</h4> Escherichia coli bloodstream infections have increased rapidly in the UK, for reasons that are unclear. The relevance of highly fit, or multi-drug resistant lineages such as ST131 to overall E. coli disease burden remains to be fully determined. We set out to characterise the prevalence of E. coli multi-locus sequence types (MLST) and determine if these were associated with adverse outcomes in an urban population of E. coli bacteraemia patients. <h4>Methods</h4> We undertook whole genome sequencing of E. coli blood isolates from all patients with diagnosed E. coli bacteraemia in north-west London from July 2015 to August 2016 and assigned multi-locus sequence types to all isolates. Isolate sequence types were linked to routinely collected antimicrobial susceptibility, patient demographic, and clinical outcome data to explore relationships between the E. coli sequence types, patient factors, and outcomes. <h4>Findings</h4> A total of 551 E. coli genomes were available for analysis. More than half of these cases were caused by four E. coli sequence types: ST131 (21%), ST73 (15%), ST69 (9%) and ST95 (8%). E. coli genotype ST131-C2 was associated with non-susceptibility to quinolones and third-generation cephalosporins, and also to amoxicillin, augmentin, gentamicin and trimethoprim. An association between the ST131-C2 lineage and longer length-of-stay was detected, although multivariable regression modelling did not demonstrate an association between E. coli sequence type and mortality. However, a number of unexpected associations were identified, including gentamicin non-susceptibility, ethnicity, and sex that might influence mortality and length-of-stay, requiring further research. <h4>Interpretation</h4> Although E. coli sequence type was associated with antimicrobial non-susceptibility patterns and length-of-stay, we did not find that E. coli sequence type was associated with increased mortality. W
Rawson TM, Hernandez B, Moore L, et al., 2021, A real-world evaluation of a case-based reasoning algorithm to support antimicrobial prescribing decisions in acute care, Clinical Infectious Diseases, Vol: 72, Pages: 2103-2111, ISSN: 1058-4838
BackgroundA locally developed Case-Based Reasoning (CBR) algorithm, designed to augment antimicrobial prescribing in secondary care was evaluated.MethodsPrescribing recommendations made by a CBR algorithm were compared to decisions made by physicians in clinical practice. Comparisons were examined in two patient populations. Firstly, in patients with confirmed Escherichia coli blood stream infections (‘E.coli patients’), and secondly in ward-based patients presenting with a range of potential infections (‘ward patients’). Prescribing recommendations were compared against the Antimicrobial Spectrum Index (ASI) and the WHO Essential Medicine List Access, Watch, Reserve (AWaRe) classification system. Appropriateness of a prescription was defined as the spectrum of the prescription covering the known, or most-likely organism antimicrobial sensitivity profile.ResultsIn total, 224 patients (145 E.coli patients and 79 ward patients) were included. Mean (SD) age was 66 (18) years with 108/224 (48%) female gender. The CBR recommendations were appropriate in 202/224 (90%) compared to 186/224 (83%) in practice (OR: 1.24 95%CI:0.392-3.936;p=0.71). CBR recommendations had a smaller ASI compared to practice with a median (range) of 6 (0-13) compared to 8 (0-12) (p<0.01). CBR recommendations were more likely to be classified as Access class antimicrobials compared to physicians’ prescriptions at 110/224 (49%) vs. 79/224 (35%) (OR: 1.77 95%CI:1.212-2.588 p<0.01). Results were similar for E.coli and ward patients on subgroup analysis.ConclusionsA CBR-driven decision support system provided appropriate recommendations within a narrower spectrum compared to current clinical practice. Future work must investigate the impact of this intervention on prescribing behaviours more broadly and patient outcomes.
Jauneikaite E, Pichon B, Mosavie M, et al., 2021, Characterisation of <i>Staphylococcus argenteus</i> carried by healthy Royal Marines: a molecular epidemiology case-study
<jats:title>Abstract</jats:title><jats:sec><jats:title>Objectives</jats:title><jats:p>During a prospective study of <jats:italic>S. aureus</jats:italic> carriage in Royal Marines (RM) recruits, six <jats:italic>S. argenteus</jats:italic> strains were identified in four recruits undertaking military training together. As <jats:italic>S. argenteus</jats:italic> sepsis leads to mortality similar to <jats:italic>S. aureus</jats:italic>, we determined the potential for person-to-person transmission, to evaluate future outbreak risk.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We used whole-genome sequencing to characterise <jats:italic>S. argenteus</jats:italic> and investigate phylogenetic relationships between isolates. Participant colonisation with <jats:italic>S. aureus</jats:italic> and skin and soft tissue infection acquisition were recorded.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>All six <jats:italic>S. argenteus</jats:italic> strains were <jats:italic>spa</jats:italic>-type t5078, ST2250. Strains were detected in 4/40 recruits in the same troop (training cohort) in weeks 1, 6 or 15 of training. No <jats:italic>mec, tsst</jats:italic> or <jats:italic>LukPV</jats:italic> genes were detected. We identified differences of 10-35 core SNPs between <jats:italic>S. argenteus</jats:italic> from different recruits. In two recruits, two <jats:italic>S. argenteus</jats:italic> strains were isolated; these could be distinguished by 3 and 15 core SNPs in each case. <jats:italic>S. argenteus</jats:italic> was not identified in any one of the other 21 participating troops (1,012 recruits).</jats:p></jats:sec><jats:sec><jats:title>Conclusions&
Collin SM, Groves N, O' Sullivan C, et al., 2021, Uncovering infant group B streptococcal (GBS) disease clusters in the UK and Ireland through genomic analysis: a population-based epidemiological study, Clinical Infectious Diseases, Vol: 72, Pages: e296-e302, ISSN: 1058-4838
BackgroundThe true frequency of hospital outbreaks of invasive group B streptococcal (iGBS; Streptococcus agalactiae) disease in infants is unknown. We used whole genome sequencing (WGS) of iGBS isolates collected during a period of enhanced surveillance of infant iGBS disease in the UK and Ireland to determine the number of clustered cases.MethodsPotentially linked iGBS cases from infants with early (<7 days of life) or late-onset (7–89 days) disease were identified from WGS data (HiSeq 2500 platform, Illumina) from clinical sterile site isolates collected between 04/2014 and 04/2015. We assessed time and place of cases to determine a single-nucleotide polymorphism (SNP) difference threshold for clustered cases. Case details were augmented through linkage to national hospital admission data and hospital record review by local microbiologists.ResultsAnalysis of sequences indicated a cutoff of ≤5 SNP differences to define iGBS clusters. Among 410 infant iGBS isolates, we identified 7 clusters (4 genetically identical pairs with 0 SNP differences, 1 pair with 3 SNP differences, 1 cluster of 4 cases with ≤1 SNP differences) of which 4 clusters were uncovered for the first time. The clusters comprised 16 cases, of which 15 were late-onset (of 192 late-onset cases with sequenced isolates) and 1 an early-onset index case. Serial intervals between cases ranged from 0 to 59 (median 12) days.ConclusionsApproximately 1 in 12 late-onset infant iGBS cases were part of a hospital cluster. Over half of the clusters were previously undetected, emphasizing the importance of routine submission of iGBS isolates to reference laboratories for cluster identification and genomic confirmation.
Tan LKK, Reglinski M, Teo D, et al., 2021, Vaccine-induced, but not natural immunity, against the Streptococcal Inhibitor of complement protects against invasive disease, npj Vaccines, Vol: 6, Pages: 1-9, ISSN: 2059-0105
Highly pathogenic emm1 Streptococcus pyogenes strains secrete the multidomain Streptococcal inhibitor of complement (SIC) that binds and inactivates components of the innate immune response. We aimed to determine if naturally occurring or vaccine-induced antibodies to SIC are protective against invasive S. pyogenes infection. Immunisation with full-length SIC protected mice against systemic bacterial dissemination following intranasal or intramuscular infection with emm1 S. pyogenes. Vaccine-induced rabbit anti-SIC antibodies, but not naturally occurring human anti-SIC antibodies, enhanced bacterial clearance in an ex vivo whole-blood assay. SIC vaccination of both mice and rabbits resulted in antibody recognition of all domains of SIC, whereas naturally occurring human anti-SIC antibodies recognised the proline-rich region of SIC only. We, therefore, propose a model whereby natural infection with S. pyogenes generates non-protective antibodies against the proline-rich region of SIC, while vaccination with full-length SIC permits the development of protective antibodies against all SIC domains.
Cordery R, Reeves L, Zhou J, et al., 2021, Transmission of SARS-CoV-2 by children to contacts in schools and households: a prospective cohort and environmental sampling study in London
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Assessing transmission of SARS-CoV-2 by children in schools is of critical importance to inform public health action. We assessed frequency of acquisition of SARS-CoV-2 by contacts of children with COVID-19 in schools and households, as well as the amount of virus shed into the air and onto fomites in both settings.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Cases of COVID-19 in children in London schools were identified via notification. Weekly sampling for 3-4 weeks and PCR testing for SARS-CoV-2 of immediate classroom contacts (the “bubble”), non-bubble school contacts, and household contacts was undertaken supported by genome sequencing, along with surface and air sampling in the school and home environment.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Within schools, secondary transmission was not detected in 28 individual bubble contacts, representing 10 distinct bubble classes. Across 8 non-bubble classes, 3/62 pupils tested positive– all three were asymptomatic and tested positive in one setting on the same day, unrelated to the original index case. In contrast, the secondary attack rate in naïve household contacts was 14.3% (5/35) rising to 19.1% (9/47) when considering all household contacts. Environmental contamination with SARS-CoV-2 was rare in schools, regardless of school type; fomite SARS-CoV-2 RNA was identified in 4/189 (2.1%) samples in bubble classrooms, 2/127 (1.6%) samples in non-bubble classrooms, and 5/130 (3.8%) samples in washrooms. This contrasted with fomites in households, where SARS-CoV-2 RNA was identified in 60/248 (24.2%) bedroom samples, 66/241 (27.4%) communal room samples, and 21/188 (11.2%) bathroom samples. Air sampling identified SARS-CoV-2 RNA in just 1/68 (1.5%) o
Ellington MJ, Davies F, Jauneikaite E, et al., 2020, A multi-species cluster of GES-5 carbapenemase producing Enterobacterales linked by a geographically disseminated plasmid, Clinical Infectious Diseases, Vol: 71, Pages: 2553-2560, ISSN: 1058-4838
BACKGROUND: Early and accurate treatment of infections due to carbapenem-resistant organisms is facilitated by rapid diagnostics but rare resistance mechanisms can compromise detection. One year after a GES-5 carbapenemase-positive Klebsiella oxytoca infection was identified by whole genome sequencing (WGS) (later found to be part of a cluster of three cases), a cluster of 11 patients with GES-5-positive K. oxytoca was identified over 18 weeks in the same hospital.METHODS: Bacteria were identified by MALDI-TOF, antimicrobial susceptibility testing followed EUCAST guidelines. Ertapenem-resistant isolates were referred to Public Health England for characterization using PCR detection of GES, pulse-field gel electrophoresis (PFGE) and WGS for the second cluster.RESULTS: The identification of the first GES-5 K. oxytoca isolate was delayed, being identified on WGS. A GES-gene PCR informed the occurrence of the second cluster in real-time. In contrast to PFGE, WGS phylogenetic analysis refuted an epidemiological link between the two clusters; it also suggested a cascade of patient-to-patient transmission in the later cluster. A novel GES-5-encoding plasmid was present in K. oxytoca,E. coli and E. cloacae isolates from unlinked patients within the same hospital group and in human and wastewater isolates from three hospitals elsewhere in the UK.CONCLUSIONS: Genomic sequencing revolutionized the epidemiological understanding of the clusters, it also underlined the risk of covert plasmid propagation in healthcare settings and revealed the national distribution of the resistance-encoding plasmid. Sequencing results also informed and led to the ongoing use of enhanced diagnostic tests for detecting carbapenemases locally and nationally.
Thompson CP, Grayson NE, Paton RS, et al., 2020, Detection of neutralising antibodies to SARS-CoV-2 to determine population exposure in Scottish blood donors between March and May 2020., Euro Surveillance, Vol: 25, Pages: 1-9
BackgroundThe progression and geographical distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United Kingdom (UK) and elsewhere is unknown because typically only symptomatic individuals are diagnosed. We performed a serological study of blood donors in Scotland in the spring of 2020 to detect neutralising antibodies to SARS-CoV-2 as a marker of past infection and epidemic progression.AimOur objective was to determine if sera from blood bank donors can be used to track the emergence and progression of the SARS-CoV-2 epidemic.MethodsA pseudotyped SARS-CoV-2 virus microneutralisation assay was used to detect neutralising antibodies to SARS-CoV-2. The study comprised samples from 3,500 blood donors collected in Scotland between 17 March and 18 May 2020. Controls were collected from 100 donors in Scotland during 2019.ResultsAll samples collected on 17 March 2020 (n = 500) were negative in the pseudotyped SARS-CoV-2 virus microneutralisation assay. Neutralising antibodies were detected in six of 500 donors from 23 to 26 March. The number of samples containing neutralising antibodies did not significantly rise after 5-6 April until the end of the study on 18 May. We found that infections were concentrated in certain postcodes, indicating that outbreaks of infection were extremely localised. In contrast, other areas remained comparatively untouched by the epidemic.ConclusionAlthough blood donors are not representative of the overall population, we demonstrated that serosurveys of blood banks can serve as a useful tool for tracking the emergence and progression of an epidemic such as the SARS-CoV-2 outbreak.
Drake TM, Docherty AB, Harrison EM, et al., 2020, Outcome of hospitalization for COVID-19 in patients with interstitial lung disease: an international multicenter study., American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 1656-1665, ISSN: 1073-449X
RATIONALE: The impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established. OBJECTIVES: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age, sex and comorbidity matched population. METHODS: An international multicenter audit of patients with a prior diagnosis of ILD admitted to hospital with COVID-19 between 1 March and 1 May 2020 was undertaken and compared with patients, without ILD obtained from the ISARIC 4C cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished IPF from non-IPF ILD and used lung function to determine the greatest risks of death. MEASUREMENTS AND MAIN RESULTS: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity-score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching ILD patients with COVID-19 had higher mortality (HR 1.60, Confidence Intervals 1.17-2.18 p=0.003) compared with age, sex and co-morbidity matched controls without ILD. Patients with a Forced Vital Capacity (FVC) of <80% had an increased risk of death versus patients with FVC ≥80% (HR 1.72, 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR 2.27, 1.39-3.71). CONCLUSIONS: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Siggins MK, Lynskey NN, Lamb L, et al., 2020, Extracellular bacterial lymphatic metastasis drives Streptococcus pyogenes systemic infection, Nature Communications, Vol: 11, ISSN: 2041-1723
Unassisted metastasis through the lymphatic system is a mechanism of dissemination thus far ascribed only to cancer cells. Here, we report that Streptococcus pyogenes also hijack lymphatic vessels to escape a local infection site, transiting through sequential lymph nodes and efferent lymphatic vessels to enter the bloodstream. Contrasting with previously reported mechanisms of intracellular pathogen carriage by phagocytes, we show S. pyogenes remain extracellular during transit, first in afferent and then efferent lymphatics that carry the bacteria through successive draining lymph nodes. We identify streptococcal virulence mechanisms important for bacterial lymphatic dissemination and show that metastatic streptococci within infected lymph nodes resist and subvert clearance by phagocytes, enabling replication that can seed intense bloodstream infection. The findings establish the lymphatic system as both a survival niche and conduit to the bloodstream for S. pyogenes, explaining the phenomenon of occult bacteraemia. This work provides new perspectives in streptococcal pathogenesis with implications for immunity.
Matthews S, McKenna S, Malito E, et al., 2020, Structure, dynamics and immunogenicity of a catalytically inactive CXC Chemokine-degrading Protease SpyCEP from Streptococcus pyogenes, Computational and Structural Biotechnology Journal, Vol: 18, Pages: 650-660, ISSN: 2001-0370
Over 18 million disease cases and half a million deaths worldwide are estimated to be caused annually by Group A Streptococcus. A vaccine to prevent GAS disease is urgently needed. SpyCEP (Streptococcus pyogenes Cell-Envelope Proteinase) is a surface-exposed serine protease that inactivates chemokines, impairing neutrophil recruitment and bacterial clearance, and has shown promising immunogenicity in preclinical models. Although SpyCEP structure has been partially characterized, a more complete and higher resolution understanding of its antigenic features would be desirable prior to large scale manufacturing. To address these gaps and facilitate development of this globally important vaccine, we performed immunogenicity studies with a safety-engineered SpyCEP mutant, and comprehensively characterized its structure by combining X-ray crystallography, NMR spectroscopy and molecular dynamics simulations. We found that the catalytically-inactive SpyCEP antigen conferred protection similar to wild-type SpyCEP in a mouse infection model. Further, a new higher-resolution crystal structure of the inactive SpyCEP mutant provided new insights into this large chemokine protease comprising nine domains derived from two non-covalently linked fragments. NMR spectroscopy and molecular simulation analyses revealed conformational flexibility that is likely important for optimal substrate recognition and overall function. These combined immunogenicity and structural data demonstrate that the full-length SpyCEP inactive mutant is a strong candidate human vaccine antigen. These findings show how a multi-disciplinary study was used to overcome obstacles in the development of a GAS vaccine, an approach applicable to other future vaccine programs. Moreover, the information provided may also facilitate the structure-based discovery of small-molecule therapeutics targeting SpyCEP protease inhibition.
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