Imperial College London

ProfessorShiraneeSriskandan

Faculty of MedicineDepartment of Infectious Disease

Professor of Infectious Diseases
 
 
 
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Contact

 

+44 (0)20 3313 3135s.sriskandan

 
 
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Location

 

8N4CWBHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

160 results found

Lynskey NN, Jauneikaite E, Li H-K, Zhi X, Turner CE, Mosavie M, Pearson M, Asai M, Lobkowicz L, Chow JY, Parkhill J, Lamagni T, Chalker V, Sriskandan Set al., Emergence of dominant toxigenic M1T1 Streptococcus pyogenes clone during increased scarlet fever activity in England: a population-based molecular epidemiological study, Lancet Infectious Diseases, ISSN: 1473-3099

Journal article

Jauneikaite E, Ferguson T, Mosavie M, Fallowfield JL, Davey T, Thorpe N, Allsopp A, Shaw AM, Fudge D, O'Shea MK, Wilson D, Morgan M, Pichon B, Kearns AM, Sriskandan S, Lamb LEet al., Staphylococcus aureus colonisation and acquisition of skin and soft tissue infection amongst Royal Marines recruits: A prospective cohort study, Clinical Microbiology and Infection, ISSN: 1198-743X

Objectives: Skin and soft tissue infections (SSTIs) are a serious health issue for military personnel. Of particular importance are those caused by MRSA and PVL-positive S. aureus (PVL-SA), as they have been associated with outbreaks of SSTIs. A prospective observational study was conducted in Royal Marines recruits to investigate the prevalence of PVL-SA carriage and any association with SSTIs.Methods: 1,012 RM recruits were followed through a 32-week training programme, with nose and throat swabs obtained at weeks 1, 6, 15 and 32. S. aureus isolates were characterised by antibiotic susceptibility testing, spa typing, presence of mecA/C and PVL genes. Retrospective review of the clinical notes for SSTI acquisition was conducted.Results: S. aureus colonisation decreased from week-1 to week-32 (41% to 26%, p<0.0001). Of 1,168 S. aureus isolates, 3/1168 (0.3%) were MRSA and 10/1168 (0.9%) PVL-positive (all MSSA) and 169/1168 (14.5%) were resistant to clindamycin. Isolates showed genetic diversity with 238 different spa types associated with 25 MLST clonal complexes. SSTIs were seen in 35% (351/989) of recruits with 3 training days lost per recruit. SSTI acquisition rate was reduced amongst persistent carriers (p<0.0283). Conclusions: Nose and throat carriage of MRSA and PVL-SA was low amongst recruits, despite a high incidence of SSTIs being reported particularly cellulitis. Carriage strains were predominantly MSSA with a marked diversity of genotypes. Persistent nose and/or throat carriage was not associated with SSTI acquisition. Putative person-to-person transmission within troops was identified based on spa typing requiring further research to confirm and explore potential transmission routes.

Journal article

Herbert R, Hatcher J, Jauneikaite E, Gharbi M, d'Arc S, Obaray N, Rickards T, Rebec M, Blandy O, Hope R, Thomas A, Bamford K, Jepson A, Sriskandan Set al., 2019, Two year analysis of Clostridium difficile ribotypes associated with increased severity, Journal of Hospital Infection, ISSN: 0195-6701

BackgroundCertain Clostridium difficile ribotypes have been associated with complex disease phenotypes including recurrence and increased severity, especially the well-described hypervirulent ribotype RT027. In this study we set out to determine the pattern of ribotypes causing infection and association if any with severity.MethodsAll faecal samples submitted to a large diagnostic laboratory for C. difficile testing between 2011 and 2013 were subject to routine testing and cultured. All C. difficile isolates were ribotyped and associated clinical and demographic patient data were retrieved then linked to ribotyping data.ResultsA total of 86 distinct ribotypes were identified from 705 isolates of C. difficile. Ribotypes RT002 and RT015 were the most prevalent (22.5%, n=159). Only five isolates (0.7%) were the hypervirulent RT027. Ninety of 450 (20%) patients with clinical information available died within 30-days of C. difficile isolation. Ribotype RT220, one of the ten commonest ribotypes, was associated with elevated median C-reactive protein and significantly increased 30-day all-cause mortality when compared with ribotypes RT002 and RT015, and with all other ribotypes found in the study.ConclusionsA wide range of C. difficile ribotypes were responsible for C. difficile infection presentations. Although C. difficile-associated mortality has reduced in recent years, expansion of lineages associated with increased severity could herald increases in future mortality. Enhanced surveillance for emerging lineages such as RT220 that are associated with more severe disease is required, with genomic approaches to dissect pathogenicity.

Journal article

Mosavie M, Blandy O, Jauneikaite E, Caldas I, Ellington MJ, Woodford N, Sriskandan Set al., 2019, Sampling and diversity of Escherichia coli from the enteric microbiota in patients with Escherichia coli bacteraemia, BMC Research Notes, Vol: 12, ISSN: 1756-0500

ObjectiveThe increase in Escherichia coli bloodstream infections mandates better characterisation of the relationship between commensal and invasive isolates. This study adopted a simple approach to characterize E. coli in the gut reservoir from patients with either E. coli or other Gram-negative bacteraemia, or those without bacteraemia, establishing strain collections suitable for genomic investigation. Enteric samples from patients in the three groups were cultured on selective chromogenic agar. Genetic diversity of prevailing E. coli strains in gut microbiota was estimated by RAPD-PCR.ResultsEnteric samples from E. coli bacteraemia patients yielded a median of one E. coli RAPD pattern (range 1–4) compared with two (range 1–5) from groups without E. coli bacteraemia. Of relevance to large-scale clinical studies, observed diversity of E. coli among hospitalised patients was not altered by sample type (rectal swab or stool), nor by increasing the colonies tested from 10 to 20. Hospitalised patients demonstrated an apparently limited diversity of E. coli in the enteric microbiota and this was further reduced in those with E. coli bacteraemia. The reduced diversity of E. coli within the gut during E. coli bacteraemia raises the possibility that dominant strains may outcompete other lineages in patients with bloodstream infection.

Journal article

Parks T, Elliot K, Lamagni T, Auckland K, Mentzer AJ, Guy R, Cartledge D, Strakova L, O'Connor D, Pollard AJ, Neville MJ, Mahajan A, Ashrafian H, Chapman SJ, Hill AVS, Sriskandan S, Knight JCet al., Elevated risk of invasive group a streptococcal disease and host genetic variation in the human leukocyte antigen locus, Genes and Immunity, ISSN: 1466-4879

Invasive group A streptococcal (GAS) disease is uncommon but carries a high casefatality rate relative to other infectious diseases. Given the ubiquity of mild GASinfections, it remains unclear why healthy individuals will occasionally develop lifethreatening infections, raising the possibility of host genetic predisposition. Here, wepresent the results of a case-control study including 43 invasive GAS cases and1,540 controls. Using HLA imputation and linear mixed-models, we find each copy ofthe HLA-DQA1*01:03 allele associates with a two-fold increased risk of disease(odds ratio 2.3, 95% confidence interval 1.3-4.4, P=0.009), an association whichpersists with classical HLA typing of a subset of cases and analysis with analternative large control dataset with validated HLA data. Moreover, we propose theassociation is driven by the allele itself rather than the background haplotype. Overallthis finding provides impetus for further investigation of the immunogenetic basis ofthis devastating bacterial disease.

Journal article

Goldblatt J, Hoffland A, Lawrenson RA, Muir L, Dattani S, Tsuchiya T, Kanegasaki S, Sriskandan S, Pease Jet al., 2019, A requirement for neutrophil glycosaminoglycans in chemokine:receptor interactions is revealed by the streptococcal protease SpyCEP, Journal of Immunology, Vol: 202, Pages: 3246-3255, ISSN: 1550-6606

To evade the immune system, the lethal human pathogen Streptococcus pyogenes produces SpyCEP, an enzyme that cleaves the C-terminal α-helix of CXCL8, resulting in markedly impaired recruitment of neutrophils to sites of invasive infection. The basis for chemokine inactivation by SpyCEP is, however, poorly understood, as the core domain of CXCL8 known to interact with CXCL8 receptors is unaffected by enzymatic cleavage. We examined the in vitro migration of human neutrophils and observed that their ability to efficiently navigate a CXCL8 gradient was compromised following CXCL8 cleavage by SpyCEP. SpyCEP-mediated cleavage of CXCL8 also impaired CXCL8-induced migration of transfectants expressing the human chemokine receptors CXCR1 or CXCR2. Despite possessing an intact N terminus and preserved disulfide bonds, SpyCEP-cleaved CXCL8 had impaired binding to both CXCR1 and CXCR2, pointing to a requirement for the C-terminal α-helix. SpyCEP-cleaved CXCL8 had similarly impaired binding to the glycosaminoglycan heparin. Enzymatic removal of neutrophil glycosaminoglycans was observed to ablate neutrophil navigation of a CXCL8 gradient, whereas navigation of an fMLF gradient remained largely intact. We conclude, therefore, that SpyCEP cleavage of CXCL8 results in chemokine inactivation because of a requirement for glycosaminoglycan binding in productive chemokine:receptor interactions. This may inform strategies to inhibit the activity of SpyCEP, but may also influence future approaches to inhibit unwanted chemokine-induced inflammation.

Journal article

Reglinski M, Sriskandan S, 2019, Treatment potential of pathogen-reactive antibodies sequentially purified from pooled human immunoglobulin, BMC Research Notes, Vol: 12, ISSN: 1756-0500

ObjectiveIntravenous immune globulin (IVIG), pooled from human blood, is a polyspecific antibody preparation that inhibits the super-antigenic proteins associated with streptococcal and staphylococcal toxic shock, and the Shiga toxin. In addition to this toxin-neutralising activity, IVIG contains other pathogen-reactive antibodies that may confer additional therapeutic benefits. We sought to determine if pathogen-reactive antibodies that promote opsonophagocytosis of different organisms can be sequentially affinity-purified from one IVIG preparation.ResultsAntibodies that recognise cell wall antigens of Streptococcus pyogenes, Staphylococcus aureus, and vancomycin-resistant enterococcus (VRE) were sequentially affinity-purified from a single preparation of commercial IVIG and opsonophagocytic activity was assessed using a flow cytometry assay of neutrophil uptake. Non-specific IgG-binding proteins were removed from the S. aureus preparations using an immobilised Fc fragment column, produced using IVIG cleaved with the Immunoglobulin G-degrading enzyme of S. pyogenes (IdeS). Affinity-purified anti-S. aureus and anti-VRE immunoglobulin promoted significantly higher levels of opsonophagocytic uptake by human neutrophils than IVIG when identical total antibody concentrations were compared, confirming activity previously shown for affinity-purified anti-S. pyogenes immunoglobulin. The opsonophagocytic activities of anti-S. pyogenes, anti-S. aureus, and anti-VRE antibodies that were sequentially purified from a single IVIG preparation were undiminished compared to antibodies purified from previously unused IVIG.

Journal article

Rawson TM, Hernandez B, Moore L, Blandy O, Herrero P, Gilchrist M, Gordon A, Toumazou C, Sriskandan S, Georgiou P, Holmes Aet al., 2019, Supervised machine learning for the prediction of infection on admission to hospital: a prospective observational cohort study, Journal of Antimicrobial Chemotherapy, Vol: 74, Pages: 1108-1115, ISSN: 0305-7453

BackgroundInfection diagnosis can be challenging, relying on clinical judgement and non-specific markers of infection. We evaluated a supervised machine learning (SML) algorithm for diagnosing bacterial infection using routinely available blood parameters on presentation to hospital.MethodsAn SML algorithm was developed to classify cases into infection versus no infection using microbiology records and six available blood parameters (C-reactive protein, white cell count, bilirubin, creatinine, ALT and alkaline phosphatase) from 160 203 individuals. A cohort of patients admitted to hospital over a 6 month period had their admission blood parameters prospectively inputted into the SML algorithm. They were prospectively followed up from admission to classify those who fulfilled clinical case criteria for a community-acquired bacterial infection within 72 h of admission using a pre-determined definition. Predictive ability was assessed using receiver operating characteristics (ROC) with cut-off values for optimal sensitivity and specificity explored.ResultsOne hundred and four individuals were included prospectively. The median (range) cohort age was 65 (21–98)  years. The majority were female (56/104; 54%). Thirty-six (35%) were diagnosed with infection in the first 72 h of admission. Overall, 44/104 (42%) individuals had microbiological investigations performed. Treatment was prescribed for 33/36 (92%) of infected individuals and 4/68 (6%) of those with no identifiable bacterial infection. Mean (SD) likelihood estimates for those with and without infection were significantly different. The infection group had a likelihood of 0.80 (0.09) and the non-infection group 0.50 (0.29) (P < 0.01; 95% CI: 0.20–0.40). ROC AUC was 0.84 (95% CI: 0.76–0.91).ConclusionsAn SML algorithm was able to diagnose infection in individuals presenting to hospital using routinely available blood parameters.

Journal article

Hutchinson M, Sohal M, Layton M, Sriskandan S, Brett S, Hill P, Youngstein TABet al., 2019, STEROID-FREE MANAGEMENT OF LIFE-THREATENING HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN THE CONTEXT OF SUSPECTED LYMPHOPROLIFERATIVE DISEASE AND INFECTION, Annual Conference of the British-Soceity-for-Rheumatology, Publisher: OXFORD UNIV PRESS, ISSN: 1462-0324

Conference paper

Davies F, Olme C, Lynskey N, Turner CE, Sriskandan Set al., 2019, Streptococcal superantigen-induced expansion of human tonsil T cells leads to altered T follicular helper cell phenotype, B cell death, and reduced immunoglobulin release, Clinical and Experimental Immunology, ISSN: 1365-2249

Streptococcal pyrogenic exotoxin (Spe) A expression is epidemiologically linked to streptococcal tonsillo‐pharyngitis and outbreaks of scarlet fever, although the mechanisms by which superantigens confer advantage to Streptococcus pyogenes are unclear. S. pyogenes is an exclusively human pathogen. As the leucocyte profile of tonsil is unique, the impact of SpeA production on human tonsil cell function was investigated. Human tonsil cells from routine tonsillectomy were co‐incubated with purified streptococcal superantigens or culture supernatants from isogenic streptococcal isolates, differing only in superantigen production. Tonsil cell proliferation was quantified by tritiated thymidine incorporation, and cell surface characteristics assessed by flow cytometry. Soluble mediators including immunoglobulin were measured using enzyme‐linked immunosorbent assay. Tonsil T cells proliferated in response to SpeA and demonstrated typical release of proinflammatory cytokines. When cultured in the absence of superantigen, tonsil preparations released large quantities of immunoglobulin over 7 days. In contrast, marked B cell apoptosis and abrogation of total immunoglobulin (Ig)A, IgM, and IgG production occurred in the presence of SpeA and other superantigens. In SpeA‐stimulated cultures, T follicular helper (Tfh) cells showed a reduction in C‐X‐C chemokine receptor (CXCR)5 (CD185) expression, but up‐regulation of OX40 (CD134) and inducible T cell co‐stimulator (ICOS) (CD278) expression. The phenotypical change in the Tfh population was associated with impaired chemotactic response to CXCL13. SpeA and other superantigens cause dysregulated tonsil immune function, driving T cells from Tfh to a proliferating phenotype, with resultant loss of B cells and immunoglobulin production, providing superantigen‐producing bacteria with a probable survival advantage.

Journal article

Reglinski M, Sriskandan S, Turner CE, 2019, Identification of two new core chromosome-encoded superantigens in Streptococcus pyogenes; speQ and speR, Journal of Infection, ISSN: 0163-4453

Superantigens are ubiquitous within the Streptococcus pyogenes genome, which suggests that superantigen-mediated T-cell activation provides a significant selective advantage. S. pyogenes can carry a variable complement of the 11 known superantigens. We have identified two novel S. pyogenes superantigens, denoted speQ and speR, adjacent to each other in the core-chromosome of isolates belonging to eleven different emm-types. Although distinct from other superantigens, speQ and speR were most closely related to speK and speJ, respectively. Recombinant SPEQ and SPER were mitogenic towards human peripheral blood mononuclear cells at ng/ml concentrations, and SPER was found to be more mitogenic than SPEQ.

Journal article

Leonard A, Wright A, Saavedra-Campos M, Lamagni T, Cordery R, Nicholls M, Domoney C, Sriskandan S, Balasegaram Set al., 2019, Severe group A streptococcal infections in mothers and their newborns in London and the South East, 2010-2016: assessment of risk and audit of public health management, BJOG: An International Journal of Obstetrics and Gynaecology, Vol: 126, Pages: 44-53, ISSN: 1470-0328

ObjectiveWe describe cases of invasive group A Streptococcus (iGAS) in mothers or neonates and assess management according to national guidelines, which recommend administering antibiotics to both mother and neonate if either develops iGAS infection within 28 days of birth and investigation of clusters in maternity units.DesignCross‐sectional retrospective study.Setting and populationNotified confirmed iGAS cases in either mothers or neonates with onset within 28 days of birth in London and the South East of England between 2010 and 2016MethodReview of public health records of notified cases.Main outcome measuresIncidence and onset time of iGAS in postpartum mothers and babies, proportion given prophylaxis, maternity unit clusters within 6 months.ResultsWe identified 134 maternal and 21 neonatal confirmed iGAS infections. The incidence (in 100 000 person years) of iGAS in women within 28 days postpartum was 109 (95% CI 90–127) compared with 1.3 in other females aged 15–44. For neonates the incidence was 1.5 (95% CI 9–23). The median onset time was 2 days postpartum [interquartile range (IQR) 0–5 days] for mothers and 12 days (IQR 7–15 days) for neonates. All eligible mothers and most (109, 89%) eligible neonates received chemoprophylaxis. Of 20 clusters (59 cases of GAS and iGAS) in maternity units, two clusters involved possible transmission. However, in 6 of 15 clusters, GAS isolates were not saved for comparison even after relevant guidance was issued.ConclusionsiGAS infection remains a potential postpartum risk. Prophylaxis among neonates and storage of isolates from maternity cases can be improved.

Journal article

Blandy O, Honeyford K, Gharbi M, Thomas A, Ramzan F, Ellington MJ, Hope R, Holmes A, Johnson AP, Aylin P, Woodford N, Sriskandan Set al., 2018, Factors that impact on the burden of Escherichia coli bacteraemia: Multivariable regression analysis of 2011-2015 data from West London, Journal of Hospital Infection, ISSN: 0195-6701

BackgroundThe incidence of Escherichia coli bacteraemia in England is increasing amid concern regarding the roles of antimicrobial resistance and nosocomial acquisition on burden of disease.AimTo determine the relative contributions of hospital-onset E. coli blood stream infection and specific E. coli antimicrobial resistance patterns to the burden and severity of E. coli bacteremia in West London.MethodsPatient and antimicrobial susceptibility data were collected for all cases of E. coli bacteraemia between 2011 and 2015. Multivariable logistic regression was used to determine the association between the category of infection (hospital or community-onset) and length of stay, intensive care unit admission, and 30-day all-cause mortality.FindingsE. coli bacteraemia incidence increased by 76% during the study period, predominantly due to community-onset cases. Resistance to quinolones, third-generation cephalosporins, and aminoglycosides also increased over the study period, occurring in both community- and hospital-onset cases. Hospital-onset and non-susceptibility to either quinolones or third-generation cephalosporins were significant risk factors for prolonged length of stay, as was older age. Rates of mortality were 7% and 12% at 7 and 30 days, respectively. Older age, a higher comorbidity score, and bacteraemia caused by strains resistant to three antibiotic classes were all significant risk factors for mortality at 30 days.ConclusionMultidrug resistance, increased age, and comorbidities were the main drivers of adverse outcome. The rise in E. coli bacteraemia was predominantly driven by community-onset infections, and initiatives to prevent community-onset cases should be a major focus to reduce the quantitative burden of E. coli infection.

Journal article

Mearkle R, Balasegaram S, Sriskandan S, Chalker V, Lamagni Tet al., 2018, Familial transmission of emm12 group A streptococcus, Emerging Infectious Diseases, Vol: 24, Pages: 2133-2134, ISSN: 1080-6040

Journal article

Parks T, Wilson C, Curtis N, Norrby-Teglund A, Sriskandan Set al., 2018, Polyspecific intravenous immunoglobulin in clindamycin-treated patients with streptococcal toxic shock syndrome: a systematic review and meta-analysis., Clinical Infectious Diseases, Vol: 67, Pages: 1434-1436, ISSN: 1058-4838

We evaluated the effect of adjunctive intravenous immunoglobulin (IVIG) on mortality in clindamycin-treated streptococcal toxic shock syndrome patients using a meta-analysis. In association with IVIG, mortality fell from 33.7% to 15.7% (risk ratio 0.46, 95% confidence intervals 0.26-0.83, p=0.010) with remarkable consistency across the single randomised and four non-randomised studies.

Journal article

Jauneikaite E, Kapatai G, Davies F, Gozar I, Coelho J, Bamford K, Simone B, Begum L, Katiyo S, Patel B, Hoffman P, Lamagni T, Brannigan ET, Holmes A, Kadhani T, Galletly T, Martin K, Lyall H, Chow Y, Godambe S, Chalker V, Sriskandan Set al., 2018, Serial clustering of late onset group B streptococcal infections in the neonatal unit - a genomic re-evaluation of causality, Clinical Infectious Diseases, Vol: 67, Pages: 854-860, ISSN: 1058-4838

Background. Invasive Group B streptococcus (GBS) is a major cause of serious neonatal infection. Current strategies to reduce early onset GBS disease have no impact on late onset disease (LOD). Although GBS is a normal part of the enteric microbiota in healthy term infants, LOD cases arising in the neonatal intensive care unit setting raise questions about mode of acquisition.Methods. Enhanced surveillance for any case of late onset GBS sepsis admitted to a level 3, 24-bed neonatal intensive care unit over a 2 year period was instituted following a cluster of four cases. All late onset GBS isolates were serotyped and genomes sequenced. Rectal screening of neonates for GBS was undertaken weekly. Healthcare workers and parents were not screened.Results. Over 24 months, a total of 12 late onset invasive GBS episodes were identified (incidence 0.6/1000 live births). Genomic analysis revealed that 11/12 GBS isolates (92%) were linked to at least one other LOD isolate. Four isolates from the first cluster were serotype V, resistant to macrolides and lincosamides, providing early evidence of a common source. Sequencing confirmed isolates were indistinguishable, or distinguishable by 1 SNP, from each other, and distinct from contemporary serotype V GBS. Although a common environmental source was not identified, prompt infection prevention interventions were instituted and no further serotype V GBS infections arose. Prospective surveillance identified three further clusters of LOD due to serotypes Ia, Ib, and III, leading to re-evaluation of interventions required for preventing GBS LOD. Conclusion. Acquisition routes for LOD GBS in the neonatal unit are poorly understood; such cases may not necessarily be sporadic. Within this neonatal unit, our data suggest that a single case of LOD GBS sepsis should be considered a potential nosocomial transmission event warranting prompt investigation, heightened infection prevention vigilance and action where required.

Journal article

Shallcross L, Mentzer A, Rahman S, Cooke G, Sriskandan S, Noursadeghi Met al., 2018, Cohort study protocol: Bioresource in Adult Infectious Diseases (BioAID), Wellcome Open Research, Vol: 3, ISSN: 2398-502X

Introduction: Infectious diseases have a major impact on morbidity and mortality in hospital. Microbial diagnosis remains elusive for most cases of suspected infection which impacts on the use of antibiotics. Rapid advances in genomic technologies combined with high-quality phenotypic data have great potential to improve the diagnosis, management and clinical outcomes of infectious diseases. The aim of the Bioresource in Adult Infectious Diseases (BioAID) is to provide a platform for biomarker discovery, trials and clinical service developments in the field of infectious diseases, by establishing a registry linking clinical phenotype to microbial and biological samples in adult patients who attend hospital with suspected infection.Methods and analysis: BioAID is a cohort study which employs deferred consent to obtain an additional 2.5mL RNA blood sample from patients who attend the Emergency Department (ED) with suspected infection when they undergo peripheral blood culture sampling. Clinical data and additional biological samples including DNA, serum and microbial isolates are obtained from BioAID participants during hospital admission. Participants are also asked to consent to be recalled for future studies. BioAID aims to recruit 10,000 patients from 5-8 sites across England. Since February 2014 >4000 individuals have been recruited to the study. The final cohort will be characterised using descriptive statistics including information on the number of cases that can be linked to biological and microbial samples to support future research studies. Ethical approval and section 251 exemption have been obtained for BioAID researchers to seek deferred consent from patients from whom a RNA specimen has been collected. Samples and meta-data obtained through BioAID will be made available to researchers worldwide following submission of an application form and research protocol. Conclusions: BioAID will support a range of study designs spanning discovery science

Journal article

Taylor E, Sriskandan S, Woodford N, Hopkins Ket al., 2018, High prevalence of 16S rRNA methyltransferases among carbapenemase-producing Enterobacteriaceae in the UK & Ireland, International Journal of Antimicrobial Agents, Vol: 52, Pages: 278-282, ISSN: 0924-8579

The emergence of 16S rRNA methyltransferases (16S RMTases) worldwide is a growing concern due to their ability to confer high-level resistance (MICs >256 mg/L) to all clinically-relevant aminoglycosides. As the occurrence of 16S RMTases in the United Kingdom has not been investigated to date, we screened 806 Enterobacteriaceae isolates displaying high-level aminoglycoside resistance (amikacin, gentamicin and tobramycin MICs ≥64, ≥32 and ≥32 mg/L, respectively) for 16S RMTases either by analysing whole-genome sequence (WGS) data (which were available for 449 isolates) or by PCR. A total of 94.5% (762/806) pan-aminoglycoside resistant Enterobacteriaceae were positive for one or more 16S RMTase genes; armA was the most common (340, 44.6%) followed by rmtC (146, 19.2%), rmtF (137, 18.0%), rmtB (87, 11.4%) and various two gene combinations (52, 6.8%). Most (93.4%; 712/762) 16S RMTase producers also carried acquired carbapenemase genes, with blaNDM the most common (592/712; 83.1%). Additionally, high-risk bacterial clones associated with blaNDM were identified in the subset of isolates with WGS data. These included E. coli sequence types (STs) 405 [21.8%, 19/87], 167 [20.7%, 18/87] 410 [12.6%, 11/87] and K. pneumoniae STs 14 [35.6%, 112/315], 231 [15.6%, 49/315] and 147 [10.5%, 33/315]. These accounted for 4.2% [15/358], 5.0% [18/358], 3.1% [11/358], 28.2% [101/358], 3.1% [11/358] and 7.0% [25/358] blaNDM-producing isolates, respectively. This study shows that 16S RMTases occur in the UK & Ireland and carbapenemases are particularly prevalent in 16S RMTase-producing Enterobacteriaceae. This association poses a risk to the treatment of multidrug-resistant Gram-negative infections in the clinical setting.

Journal article

Lamb LE, Siggins MK, Scudamore C, Macdonald W, Turner CE, Lynskey NN, Tan LKK, Sriskandan Set al., 2018, Impact of contusion injury on intramuscular emm1 group A-Streptococcus infection and Lymphatic spread, Virulence, Vol: 9, Pages: 1074-1084, ISSN: 2150-5594

Invasive group A Streptococcus (iGAS) is frequently associated with emm1 isolates, with an attendant mortality of around 20%. Cases occasionally arise in previously healthy individuals with a history of upper respiratory tract infection, soft tissue contusion, and no obvious portal of entry. Using a new murine model of contusion, we determined the impact of contusion on iGAS bacterial burden and phenotype. Calibrated mild blunt contusion did not provide a focus for initiation or seeding of GAS that was detectable following systemic GAS bacteremia, but instead enhanced GAS migration to the local draining lymph node following GAS inoculation at the same time and site of contusion. Increased migration to lymph node was associated with emergence of mucoid bacteria, although was not specific to mucoid bacteria. In one study, mucoid colonies demonstrated a significant increase in capsular hyaluronan that was not linked to a covRS or rocA mutation, but to a deletion in the promoter of the capsule synthesis locus, hasABC, resulting in a strain with increased fitness for lymph node migration. In summary, in the mild contusion model used, we could not detect seeding of muscle by GAS. Contusion promoted bacterial transit to the local lymph node. The consequences of contusion-associated bacterial lymphatic migration may vary depending on the pathogen and virulence traits selected.

Journal article

Lamb L, Zhi X, Alam F, Pyzio M, Scudamore CL, Wiles S, Sriskandan Set al., 2018, Modelling invasive group A streptococcal disease using bioluminescence, BMC Microbiology, Vol: 18, ISSN: 1471-2180

Background:The development of vaccines and evaluation of novel treatment strategies for invasive group A streptococcal (iGAS) disease requires suitable models of human infection that can be monitored longitudinally and are preferably non-invasive. Bio-photonic imaging provides an opportunity to reduce use of animals in infection modelling and refine the information that can be obtained, however the range of bioluminescent GAS strains available is limited. In this study we set out to develop bioluminescent iGAS strains for use in in vivo pneumonia and soft tissue disease models.Results:Using clinical emm1, emm3, and emm89 GAS strains that were transformed with constructs carrying the luxABCDE operon, growth and bioluminescence of transformed strains were characterised in vitro and in vivo.Emm3 and emm89 strains expressed detectable bioluminescence when transformed with a replicating plasmid and light production correlated with viable bacterial counts in vitro, however plasmid instability precluded use in the absence of antimicrobial pressure. Emm89 GAS transformed with an integrating construct demonstrated stable bioluminescence that was maintained in the absence of antibiotics. Bioluminescence of the emm89 strain correlated with viable bacterial counts both in vitro and immediately following infection in vivo. Although bioluminescence conferred a detectable fitness burden to the emm89 strain during soft tissue infection in vivo, it did not prevent dissemination to distant tissues.Conclusion:Development of stably bioluminescent GAS for use in vitro and in vivo models of infection should facilitate development of novel therapeutics and vaccines while also increasing our understanding of infection progression and transmission routes.

Journal article

Jones S, Moreland NJ, Zancolli M, Raynes J, Loh JMS, Smeesters PR, Sriskandan S, Carapetis JR, Fraser JD, Goldblatt Det al., 2018, Development of an opsonophagocytic killing assay for group a streptococcus, Vaccine, Vol: 36, Pages: 3756-3763, ISSN: 0264-410X

Group A Streptococcus (GAS) or Streptococcus pyogenes is responsible for an estimated 500,000 deaths worldwide each year. Protection against GAS infection is thought to be mediated by phagocytosis, enhanced by bacteria-specific antibody. There are no licenced GAS vaccines, despite many promising candidates in preclinical and early stage clinical development, the most advanced of which are based on the GAS M-protein. Vaccine progress has been hindered, in part, by the lack of a standardised functional assay suitable for vaccine evaluation. Current assays, developed over 50 years ago, rely on non-immune human whole blood as a source of neutrophils and complement. Variations in complement and neutrophil activity between donors result in variable data that is difficult to interpret. We have developed an opsonophagocytic killing assay (OPKA) for GAS that utilises dimethylformamide (DMF)-differentiated human promyelocytic leukemia cells (HL-60) as a source of neutrophils and baby rabbit complement, thus removing the major sources of variation in current assays. We have standardised the OPKA for several clinically relevant GAS strain types (emm1, emm6 and emm12) and have shown antibody-specific killing for each emm-type using M-protein specific rabbit antisera. Specificity was demonstrated by pre-incubation of the antisera with homologous M-protein antigens that blocked antibody-specific killing. Additional qualifications of the GAS OPKA, including the assessment of the accuracy, precision, linearity and the lower limit of quantification, were also performed. This GAS OPKA assay has the potential to provide a robust and reproducible platform to accelerate GAS vaccine development.

Journal article

Edwards RJ, Pyzio M, Gierula M, Turner CE, Abdul-Salam VB, Sriskandan Set al., 2018, Proteomic analysis at the sites of clinical infection with invasive Streptococcus pyogenes, Scientific Reports, Vol: 8, ISSN: 2045-2322

Invasive Streptococcus pyogenes infections are rare, with often-unexplained severity. Prompt diagnosis is desirable, as deaths can occur rapidly following onset and there is an increased, but preventable, risk to contacts. Here, proteomic analyses of clinical samples from invasive human S. pyogenes infections were undertaken to determine if novel diagnostic targets could be detected, and to augment our understanding of disease pathogenesis. Fluid samples from 17 patients with confirmed invasive S. pyogenes infection (empyema, septic arthritis, necrotising fasciitis) were analysed by proteomics for streptococcal and human proteins; 16/17 samples had detectable S. pyogenes DNA. Nineteen unique S. pyogenes proteins were identified in just 6/17 samples, and 15 of these were found in a single pleural fluid sample including streptococcal inhibitor of complement, trigger factor, and phosphoglycerate kinase. In contrast, 469 human proteins were detected in patient fluids, 177 (38%) of which could be identified as neutrophil proteins, including alpha enolase and lactotransferrin which, together, were found in all 17 samples. Our data suggest that streptococcal proteins are difficult to detect in infected fluid samples. A vast array of human proteins associated with leukocyte activity are, however, present in samples that deserve further evaluation as potential biomarkers of infection.

Journal article

Sharma H, Smith D, Turner CE, Game L, Pichon B, Hope R, Hill R, Kearns A, Sriskandan Set al., 2018, Clinical and Molecular Epidemiology of Staphylococcal Toxic Shock Syndrome in the United Kingdom, Emerging Infectious Diseases, Vol: 24, Pages: 258-266, ISSN: 1080-6040

Journal article

Sharma H, Smith D, Turner CE, Game L, Pichon B, Hope R, Hill R, Kearns A, Sriskandan Set al., Staphylococcal Toxic Shock Syndrome in the UK: Clinical and Molecular Epidemiology, Emerging Infectious Diseases, ISSN: 1080-6040

Journal article

Lynskey NN, Reglinski M, Calay D, Siggins MK, mason JC, Botto M, Sriskandan Set al., 2017, Multi-functional mechanisms of immune evasion by the streptococcal complement inhibitor C5a peptidase, PLOS Pathogens, Vol: 13, ISSN: 1553-7366

The complement cascade is crucial for clearance and control of invading pathogens, and as such is a key target for pathogen mediated host modulation. C3 is the central molecule of the complement cascade, and plays a vital role in opsonization of bacteria and recruitment of neutrophils to the site of infection. Streptococcal species have evolved multiple mechanisms to disrupt complement-mediated innate immunity, among which ScpA (C5a peptidase), a C5a inactivating enzyme, is widely conserved. Here we demonstrate for the first time that pyogenic streptococcal species are capable of cleaving C3, and identify C3 and C3a as novel substrates for the streptococcal ScpA, which are functionally inactivated as a result of cleavage 7 amino acids upstream of the natural C3 convertase. Cleavage of C3a by ScpA resulted in disruption of human neutrophil activation, phagocytosis and chemotaxis, while cleavage of C3 generated abnormally-sized C3a and C3b moieties with impaired function, in particular reducing C3 deposition on the bacterial surface. Despite clear effects on human complement, expression of ScpA reduced clearance of group A streptococci in vivo in wildtype and C5 deficient mice, and promoted systemic bacterial dissemination in mice that lacked both C3 and C5, suggesting an additional complement-independent role for ScpA in streptococcal pathogenesis. ScpA was shown to mediate streptococcal adhesion to both human epithelial and endothelial cells, consistent with a role in promoting bacterial invasion within the host. Taken together, these data show that ScpA is a multi-functional virulence factor with both complement-dependent and independent roles in streptococcal pathogenesis.

Journal article

Mearkle R, Saavedra-Campos M, Lamagni T, Usdin M, Coelho J, Chalker V, Sriskandan S, Cordery R, Rawlings C, Balasegaram Set al., 2017, Household transmission of invasive group A Streptococcus infections in England: a population-based study, 2009, 2011 to 13, Eurosurveillance, Vol: 22, ISSN: 1560-7917

Invasive group A streptococcal infection has a 15% case fatality rateand a risk of secondary transmission.This retrospective studyusedtwo national data sourcesfrom England; enhanced surveillance (2009) and a case management system(2011-13) to identify clustersof severegroup A streptococcaldisease.24household pairswere identified.The median onset interval between cases was 2 days (range 0-28)with simultaneous onset in 8pairs.The attack rate during the 30 days after first exposure to aprimarycase was 4520per 100000 person-years at risk (95% CI2900-6730)a 1940(1240-2880) fold elevation over the background incidence.The theoretical number needed to treat (NNT)to prevent one secondary case using antibiotic prophylaxis was 271(194-454)overall,50formother-neonate pairs (27-393) and 82for couples aged75 yearsand over(46-417). Whilst a dramatic increased risk of infection was noted in all household contacts, increased risk was greatest for mother-neonatepairs and couplesaged 75 and over, suggesting targeted prophylaxis could be considered.Offering prophylaxis is challenging due to the shorttime interval between casesemphasising the importance of immediate notificationand assessment of contacts.

Journal article

Afshar B, Turner CE, Lamagni TL, Smith K, Al-Shahib A, Underwood A, Holden MTG, Efstratiou A, Sriskandan Set al., 2017, Enhanced nasopharyngeal infection and shedding associated with an epidemic lineage of emm3 group A Streptococcus, Virulence, Vol: 8, Pages: 1390-1400, ISSN: 2150-5608

Background: A group A Streptococcus (GAS) lineage of genotype emm3, sequence type 15 (ST15) was associated with a 6 month upsurge in invasive GAS disease in the UK. The epidemic lineage (Lineage C) had lost 2 typical emm3 prophages, Φ315.1 and Φ315.2 associated with the superantigen ssa, but gained a different prophage (ΦUK-M3.1) associated with a different superantigen, speC and a DNAse spd1. Methods and Results: The presence of speC and spd1 in Lineage C ST15 strains enhanced both in vitro mitogenic and DNase activities over non-Lineage C ST15 strains. Invasive disease models in Galleria mellonella and SPEC-sensitive transgenic mice, revealed no difference in overall invasiveness of Lineage C ST15 strains compared with non-Lineage C ST15 strains, consistent with clinical and epidemiological analysis. Lineage C strains did however markedly prolong murine nasal infection with enhanced nasal and airborne shedding compared with non-Lineage C strains. Deletion of speC or spd1 in 2 Lineage C strains identified a possible role for spd1 in airborne shedding from the murine nasopharynx. Conclusions: Nasopharyngeal infection and shedding of Lineage C strains was enhanced compared with non-Lineage C strains and this was, in part, mediated by the gain of the DNase spd1 through prophage acquisition.

Journal article

Pearson M, Fallowfield JL, Davey T, Thorpe N, Allsopp A, Shaw A, Wilson D, Sriskandan S, Lamb Let al., 2017, Asymptomatic group A Streptococcal throat carriage in Royal Marines recruits and young officers, Journal of Infection, Vol: 74, Pages: 585-589, ISSN: 1532-2742

Aims A prospective observational study was conducted in Royal Marines (RM) recruits to investigate throat carriage of group A Streptococcus (GAS) and incidence of soft tissue infections. Methods 1012 RM recruits were followed through a 32-week training programme, with throat swabs being obtained in weeks 1, 6, 15, and 32. Alongside a separate cohort of 46 RM Young Officers (YO) undergoing training were sampled in parallel. Results Carriage of group A Streptococcus was detected in only 5/1012 (0.49%) recruits at the beginning of training and remained low throughout training. There was no association between GAS carriage and development of soft tissue infection. There was no carriage of GAS in the smaller YO cohort at the start of training, (0/46). At week 6, a surge in GAS carriage was detected in 8/46 (17%) YO, that could be ascribed to a cluster of GAS genotype emm83. Conclusions Asymptomatic GAS carriage is very infrequent among young adults in England and this should be borne in mind when considering the relevance of a positive throat swab result in symptomatic patients or outbreaks. Despite low prevalence, there is however potential for GAS to rapidly and transiently disseminate among adults during outbreaks.

Journal article

Parks T, Auckland K, Rautanen A, Watson C, Mirabel MM, Kado J, Kauwe JK, Lamagni TL, Mentzer AJ, Sriskandan S, Thomas M, Chapman S, Brodlie M, Pollard AJ, Colot J, Scott JAG, Williams TN, Steer AC, Hill AVSet al., 2017, Common genetic variants in the immunoglobulin heavy chain locus and their differential impact on group A streptococcal disease susceptibility: a comparative meta-analysis of genetic susceptibility studies, Spring Meeting on Clinician Scientists in Training, Publisher: ELSEVIER SCIENCE INC, Pages: 76-76, ISSN: 0140-6736

Conference paper

Jauneikaite E, Khan-Orakzai Z, Kapatai G, Bloch S, Singleton J, Atkin S, Sriskandan S, Shah V, Hatcher J, Sheppard C, Fry NK, Sata G, Samaragsinghe Det al., 2016, Nosocomial outbreak of drug resistant Streptococcus pneumoniae serotype 9V in an adult respiratory medicine ward, Journal of Clinical Microbiology, Vol: 55, Pages: 776-782, ISSN: 1098-660X

Streptococcus pneumoniae infections arising in hospitalized patients are often assumed to be sporadic, and linked to community carriage. Here, whole genome sequencing was used to demonstrate nosocomial acquisition of antimicrobially-resistant ST156-9V S. pneumoniae in 3 respiratory patients resulting in two bacteremias and one lower respiratory tract infection. Two of the cases arose in patients who had recently been discharged from hospital and were re-admitted from the community. Nosocomial spread was suspected solely because of a highly unusual resistance pattern and case presentations within 24h of one another. The outbreak highlights a potential for rapid transmission and short incubation period in the respiratory ward setting.

Journal article

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