Publications
216 results found
Lamb L, MacDonald W, Scudamore C, et al., 2015, THE EFFECT OF TRAUMA ON INVASIVE GROUP A STREPTOCOCCAL (IGAS) DISEASE, JOURNAL OF INFECTION, Vol: 71, Pages: 686-686, ISSN: 0163-4453
Reglinski M, Gierula M, Lynskey NN, et al., 2015, Identification of the Streptococcus pyogenes surface antigens recognised by pooled human immunoglobulin, Scientific Reports, Vol: 5, ISSN: 2045-2322
Immunity to common bacteria requires the generation of antibodies that promote opsonophagocytosis and neutralise toxins. Pooled human immunoglobulin is widely advocated as an adjunctive treatment for clinical Streptococcus pyogenes infection however, the protein targets of the reagent remain ill defined. Affinity purification of the anti-streptococcal antibodies present within pooled immunoglobulin resulted in the generation of an IgG preparation that promoted opsonophagocytic killing of S. pyogenes in vitro and provided passive immunity in vivo. Isolation of the streptococcal surface proteins recognised by pooled human immunoglobulin permitted identification and ranking of 94 protein antigens, ten of which were reproducibly identified across four contemporary invasive S. pyogenes serotypes (M1, M3, M12 and M89). The data provide novel insight into the action of pooled human immunoglobulin during invasive S. pyogenes infection, and demonstrate a potential route to enhance the efficacy of antibody based therapies.
Hughes GJ, Van Hoek AJ, Sriskandan S, et al., 2015, The cost of hospital care for management of invasive group A streptococcal infections in England, EPIDEMIOLOGY AND INFECTION, Vol: 143, Pages: 1719-1730, ISSN: 0950-2688
The objective of this study was to estimate the direct financial costs of hospital care for management of invasive group A streptococcal (GAS) infections using hospital records for cases diagnosed in England. We linked laboratory-confirmed cases (n = 3696) identified through national surveillance to hospital episode statistics and reimbursement codes. From these codes we estimated the direct hospital costs of admissions. Almost all notified invasive GAS cases (92% of 3696) were successfully matched to a primary hospital admission. Of these, secondary admissions (within 30 days of primary admission) were further identified for 593 (17%). After exclusion of nosocomial cases (12%), the median costs of primary and secondary hospital admissions were estimated by subgroup analysis as £1984–£2212 per case, totalling £4·43–£6·34 million per year in England. With adjustment for unmatched cases this equated to £4·84–£6·93 million per year. Adults aged 16–64 years accounted for 48% of costs but only 40% of cases, largely due to an increased number of surgical procedures. The direct costs of hospital admissions for invasive GAS infection are substantial. These estimated costs will contribute to a full assessment of the total economic burden of invasive GAS infection as a means to assess potential savings through prevention measures.
Lynskey NN, Banerji S, johnson L, et al., 2015, Rapid lymphatic dissemination of encapsulated group A streptococci via lymphatic vessel endothelial receptor-1 interaction, PLOS Pathogens, Vol: 11, ISSN: 1553-7366
The host lymphatic network represents an important conduit for pathogen dissemination. Indeed, the lethal human pathogen group A streptococcus has a predilection to induce pathology in the lymphatic system and draining lymph nodes, however the underlying basis and subsequent consequences for disease outcome are currently unknown. Here we report that the hyaluronan capsule of group A streptococci is a crucial virulence determinant for lymphatic tropism in vivo, and further, we identify the lymphatic vessel endothelial receptor-1 as the critical host receptor for capsular hyaluronan in the lymphatic system. Interference with this interaction in vivo impeded bacterial dissemination to local draining lymph nodes and, in the case of a hyper-encapsulated M18 strain, redirected streptococcal entry into the blood circulation, suggesting a pivotal role in the manifestation of streptococcal infections. Our results reveal a novel function for bacterial capsular polysaccharide in directing lymphatic tropism, with potential implications for disease pathology.
Moore LS, Leslie A, Meltzer M, et al., 2015, Corynebacterium ulcerans cutaneous diphtheria., The Lancet Infectious Diseases, Vol: 15, Pages: 1100-1107, ISSN: 1474-4457
We describe the case of a patient with cutaneous diphtheria caused by toxigenic Corynebacterium ulcerans who developed a right hand flexor sheath infection and symptoms of sepsis such as fever, tachycardia, and elevated C-reactive protein, after contact with domestic cats and dogs, and a fox. We summarise the epidemiology, clinical presentation, microbiology, diagnosis, therapy, and public health aspects of this disease, with emphasis on improving recognition. In many European countries, C ulcerans has become the organism commonly associated with cutaneous diphtheria, usually seen as an imported tropical disease or resulting from contact with domestic and agricultural animals. Diagnosis relies on bacterial culture and confirmation of toxin production, with management requiring appropriate antimicrobial therapy and prompt administration of antitoxin, if necessary. Early diagnosis is essential for implementation of control measures and clear guidelines are needed to assist clinicians in managing clinical diphtheria. This case was a catalyst to the redrafting of the 2014 national UK interim guidelines for the public health management of diphtheria, released as final guidelines in March, 2015.
Turner CE, Abbott J, Lamagni T, et al., 2015, Emergence of a new highly successful acapsular group A Streptococcus clade of the genotype emm89 in the United Kingdom, mBio, Vol: 6, ISSN: 2161-2129
Group A Streptococcus (GAS) genotype emm89 is increasingly recognized as a leading cause of disease worldwide, yet factors that underlie the success of this emm type are unknown. Surveillance identified a sustained nationwide increase in emm89 invasive GAS disease in the United Kingdom, prompting longitudinal investigation of this genotype. Whole-genome sequencing revealed a recent dramatic shift in the emm89 population with the emergence of a new clade that increased to dominance over previous emm89 variants. Temporal analysis indicated that the clade arose in the early 1990s but abruptly increased in prevalence in 2008, coinciding with an increased incidence of emm89 infections. Although standard variable typing regions (emm subtype, tee type, sof type, and multilocus sequence typing [MLST]) remained unchanged, uniquely the emergent clade had undergone six distinct regions of homologous recombination across the genome compared to the rest of the sequenced emm89 population. Two of these regions affected known virulence factors, the hyaluronic acid capsule and the toxins NADase and streptolysin O. Unexpectedly, and in contrast to the rest of the sequenced emm89 population, the emergent clade-associated strains were genetically acapsular, rendering them unable to produce the hyaluronic acid capsule. The emergent clade-associated strains had also acquired an NADase/streptolysin O locus nearly identical to that found in emm12 and modern emm1 strains but different from the rest of the sequenced emm89 population. The emergent clade-associated strains had enhanced expression of NADase and streptolysin O. The genome remodeling in the new clade variant and the resultant altered phenotype appear to have conferred a selective advantage over other emm89 variants and may explain the changes observed in emm89 GAS epidemiology.
Turner CE, Sriskandan S, 2015, Panton-Valentine leucocidin expression by Staphylococcus aureus exposed to common antibiotics, Journal of Infection, Vol: 71, Pages: 338-346, ISSN: 1532-2742
Lynskey NN, Turner CE, Heng LS, et al., 2015, A Truncation in the Regulator RocA Underlies Heightened Capsule Expression in Serotype M3 Group A Streptococci, Infection and Immunity, Vol: 83, Pages: 1732-1733, ISSN: 1098-5522
Lamb L, McDonald W, Scudamore C, et al., 2015, The effect of trauma on invasive group A streptococcal disease, Spring Meeting on Clinician Scientists in Training, Publisher: ELSEVIER SCIENCE INC, Pages: 60-60, ISSN: 0140-6736
Lamb LEM, Sriskandan S, Tan LKK, 2014, Bromine, bear-claw scratch fasciotomies, and the Eagle effect: management of group A streptococcal necrotising fasciitis and its association with trauma, The Lancet Infectious Diseases, Vol: 15, Pages: 109-121, ISSN: 1474-4457
Necrotising fasciitis is a rare, but potentially fatal, soft-tissue infection. Historical depictions of the disease have been described since classical times and were mainly recorded in wartime reports of battle injuries. Although several different species of bacteria can cause necrotising fasciitis, perhaps the most widely known is group A streptococcus (GAS). Infection control, early surgical debridement, and antibiotic therapy are now the central tenets of the clinical management of necrotising fasciitis; these treatment approaches all originate from those used in wars in the past 150 years. We review reports from the 19th century, early 20th century, and mid-20th century onwards to show how the management of necrotising fasciitis has progressed in parallel with prevailing scientific thought and medical practice. Historically, necrotising fasciitis has often, but not exclusively, been associated with penetrating trauma. However, along with a worldwide increase in invasive GAS disease, recent reports have cited cases of necrotising fasciitis following non-combat-related injuries or in the absence of antecedent events. We also investigate the specific association between GAS necrotising fasciitis and trauma. In the 21st century, molecular biology has improved our understanding of GAS pathogenesis, but has not yet affected attributable mortality.
Moore LSP, Moore M, Sriskandan S, 2014, Ebola and other viral haemorrhagic fevers: a local operational approach, British Journal of Hospital Medicine, Vol: 75, Pages: 515-522, ISSN: 1750-8460
With the current Ebola outbreak in west Africa and continued intermittent outbreaks of other viral haemorrhagic fevers, there are concerns about identifying and managing cases imported to the UK. This article summarizes new guidance for acute care units, and describes a local approach to patients with suspected viral haemorrhagic fever.
Moreland NJ, Waddington CS, Williamson DA, et al., 2014, Working towards a Group A Streptococcal vaccine: Report of a collaborative Trans-Tasman workshop, VACCINE, Vol: 32, Pages: 3713-3720, ISSN: 0264-410X
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- Citations: 37
Ascough S, Ingram RJ, Chu KK, et al., 2014, Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4<SUP>+</SUP> T Cell Immunity, PLOS PATHOGENS, Vol: 10, ISSN: 1553-7366
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- Citations: 15
Tan LKK, Sriskandan S, 2014, Step on the GAS: Are We Almost There for Clindamycin and Intravenous Immunoglobulin?, Clinical Infectious Diseases, Vol: 59, Pages: 366-368, ISSN: 1537-6591
Tan LKK, Eccersley LRJ, Sriskandan S, 2014, Current views of haemolytic streptococcal pathogenesis, CURRENT OPINION IN INFECTIOUS DISEASES, Vol: 27, Pages: 155-164, ISSN: 0951-7375
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- Citations: 29
Reglinski M, Sriskandan S, 2014, The contribution of group A streptococcal virulence determinants to the pathogenesis of sepsis, Virulence, Vol: 5, Pages: 127-136, ISSN: 2150-5594
Streptococcus pyogenes (group A streptococcus, GAS) is responsible for a wide range of pathologies ranging from mild pharyngitis and impetigo to severe invasive soft tissue infections. Despite the continuing susceptibility of the bacterium to β-lactam antibiotics there has been an unexplained resurgence in the prevalence of invasive GAS infection over the past 30 years. Of particular importance was the emergence of a GAS-associated sepsis syndrome that is analogous to the systemic toxicosis associated with TSST-1 producing strains of Staphylococcus aureus. Despite being recognized for over 20 years, the etiology of GAS associated sepsis and the streptococcal toxic shock syndrome remains poorly understood. Here we review the virulence factors that contribute to the etiology of GAS associated sepsis with a particular focus on coagulation system interactions and the role of the superantigens in the development of streptococcal toxic shock syndrome.
Reglinski M, Sriskandan S, 2014, Streptococcus pyogenes, Molecular Medical Microbiology, Pages: 675-716, ISBN: 9780123977632
Streptococcus pyogenes, also known as group A streptococcus (GAS), is most commonly associated with mild, self-resolving infections of the skin and oropharynx. However, dissemination of the bacteria to normally sterile sites within the body can lead to a variety of invasive conditions that are associated with high morbidity and mortality. In addition, the generation of human cross-reactive antibodies in response to lingering GAS infection can result in the development of post-streptococcal autoimmune sequelae that afflict the organs, joints and CNS. GAS pathogenesis is mediated by an extensive repertoire of extracellular virulence factors. Initial colonization of the skin and oropharynx is facilitated by cell-associated adhesins that bind to multiple components of the host extracellular matrix. While a battery of antiphagocytic molecules allow the organism to persist at the initial site of infection, the production of multiple toxigenic and tissue-destructive virulence factors facilitates the transition from a superficial to an invasive disease phenotype. Despite the continuing susceptibility of GAS to β-lactam antibiotics a resurgence of serious streptococcal disease has been observed over the past 30 years. While the cause of this resurgence is incompletely understood it has been tentatively attributed to the reappearance and/or increased circulation of a highly invasive clone of serotype M1T1 GAS. This shift in the epidemiology of GAS infection highlights the need for increased surveillance of GAS in the community, faster, more reliable diagnostic tests for GAS infection in a clinical setting, and more targeted treatments of invasive GAS disease. Above all, the development of a safe, effective GAS vaccine would prove invaluable.
Lynskey NN, Goulding DA, Gierula M, et al., 2013, RocA truncation underpins hyper-encapsulation, carriage longevity and transmissibility of serotype M18 group A streptococci, Plos Pathogens, Vol: 9, ISSN: 1553-7374
Alam FM, Bateman C, Turner CE, et al., 2013, Non-invasive monitoring of streptococcus pyogenes vaccine efficacy using biophotonic imaging, PLOS One, Vol: 8, ISSN: 1932-6203
Streptococcus pyogenes infection of the nasopharynx represents a key step in the pathogenic cycle of this organism and a major focus for vaccine development, requiring robust models to facilitate the screening of potentially protective antigens. One antigen that may be an important target for vaccination is the chemokine protease, SpyCEP, which is cell surface-associated and plays a role in pathogenesis. Biophotonic imaging (BPI) can non-invasively characterize the spatial location and abundance of bioluminescent bacteria in vivo. We have developed a bioluminescent derivative of a pharyngeal S. pyogenes strain by transformation of an emm75 clinical isolate with the luxABCDE operon. Evaluation of isogenic recombinant strains in vitro and in vivo confirmed that bioluminescence conferred a growth deficit that manifests as a fitness cost during infection. Notwithstanding this, bioluminescence expression permitted non-invasive longitudinal quantitation of S. pyogenes within the murine nasopharynx albeit with a detection limit corresponding to approximately 105 bacterial colony forming units (CFU) in this region. Vaccination of mice with heat killed streptococci, or with SpyCEP led to a specific IgG response in the serum. BPI demonstrated that both vaccine candidates reduced S. pyogenes bioluminescence emission over the course of nasopharyngeal infection. The work suggests the potential for BPI to be used in the non-invasive longitudinal evaluation of potential S. pyogenes vaccines.
Sharma H, Smith D, Kearns A, et al., 2013, THE EXPRESSION OF TSST-1 BY EMRSA-16, Publisher: W B SAUNDERS CO LTD, Pages: 346-346, ISSN: 0163-4453
Ingram RJ, Harris A, Ascough S, et al., 2013, Exposure to anthrax toxin alters human leucocyte expression of anthrax toxin receptor 1, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 173, Pages: 84-91, ISSN: 0009-9104
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- Citations: 8
Al-Shahib A, Afshar B, Underwood A, et al., 2013, Molecular anatomy of invasive group A streptococcal (iGAS) isolates in England, 28th International Congress of Chemotherapy and Infection Incorporating / 14th Asia-Pacific Congress of Clinical Microbiology and Infection, Publisher: ELSEVIER SCIENCE BV, Pages: S103-S104, ISSN: 0924-8579
Alam FM, Turner CE, Smith K, et al., 2013, Inactivation of the CovR/S Virulence Regulator Impairs Infection in an Improved Murine Model of Streptococcus pyogenes Naso-Pharyngeal Infection, PLOS One, Vol: 8, ISSN: 1932-6203
Turner CE, Dryden M, Holden MTG, et al., 2013, Molecular Analysis of an Outbreak of Lethal Postpartum Sepsis Caused by Streptococcus pyogenes, Journal of Clinical Microbiology, Vol: 51, Pages: 2089-2095, ISSN: 1098-660X
Sharma H, Smith D, Kearns A, et al., 2013, Expression of toxic shock syndrome toxin-1 by epidemic meticillin-resistant <i>Staphylococcus aureus</i> 16, Spring Meeting for Clinician Scientists in Training, Publisher: ELSEVIER SCIENCE INC, Pages: 98-98, ISSN: 0140-6736
Alam FM, Turner CE, Smith K, et al., 2013, Correction: Inactivation of the CovR/S Virulence Regulator Impairs Infection in an Improved Murine Model of Streptococcus pyogenes Naso-Pharyngeal Infection., PLoS One, Vol: 8
[This corrects the article on p. e61655 in vol. 8.].
Lawrenson RA, Sriskandan S, 2013, Cell Envelope Proteinase A (<i>Streptococcus</i>), HANDBOOK OF PROTEOLYTIC ENZYMES, VOLS 1 AND 2, 3RD EDITION, Editors: Rawlings, Salvesen, Publisher: ELSEVIER SCIENCE BV, Pages: 3195-3202, ISBN: 978-0-12-382219-2
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- Citations: 2
Turner CE, Sommerlad M, McGregor K, et al., 2012, Superantigenic activity of emm3 Streptococcus pyogenes is abrogated by a conserved naturally occurring smeZ mutation, PLOS One, Vol: 7, ISSN: 1932-6203
Streptococcus pyogenes M/emm3 strains have been epidemiologically linked with enhanced infection severity and risk of streptococcal toxic shock syndrome (STSS), a syndrome triggered by superantigenic stimulation of T cells. Comparison of S. pyogenes strains causing STSS demonstrated that emm3 strains were surprisingly less mitogenic than other emm-types (emm1, emm12, emm18, emm28, emm87, emm89) both in vitro and in vivo, indicating poor superantigenic activity. We identified a 13bp deletion in the superantigen smeZ gene of all emm3 strains tested. The deletion led to a premature stop codon in smeZ, and was not present in other major emm-types tested. Expression of a functional non-M3-smeZ gene successfully enhanced mitogenic activity in emm3 S. pyogenes and also restored mitogenic activity to emm1 and emm89 S. pyogenes strains where the smeZ gene had been disrupted. In contrast, the M3-smeZ gene with the 13bp deletion could not enhance or restore mitogenicity in any of these S. pyogenes strains, confirming that M3-smeZ is non-functional regardless of strain background. The mutation in M3-smeZ reduced the potential for M3 S. pyogenes to induce cytokines in human tonsil, but not during invasive infection of superantigen-sensitive mice. Notwithstanding epidemiological associations with STSS and disease severity, emm3 strains have inherently poor superantigenicity that is explained by a conserved mutation in smeZ.
Ascough S, Ingram RJ, Musson JA, et al., 2012, Identification of immunodominant T cell epitopes from anthrax protective antigen for inclusion in a rationally designed sub-unit based vaccine, European Congress of Immunology, Publisher: WILEY-BLACKWELL, Pages: 761-761, ISSN: 0019-2805
Chong DLW, Ingram RJ, Lowther DE, et al., 2012, The nature of innate and adaptive interleukin-17A responses in sham or bacterial inoculation, IMMUNOLOGY, Vol: 136, Pages: 325-333, ISSN: 0019-2805
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- Citations: 10
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