ProfessorShiranee Sriskandan

STREPTOCOCCAL PATHOGENESIS

The classical phage-encoded scarlet fever toxins like SpeA play a role in perpetuating outbreaks of scarlet fever and pharyngitis in children in schools, with potential to trigger superantigen-mediated toxic shock during invasive infection. SpeA production is increased in the novel emergent lineage M1UK but it seems likely that additional factors confer advantage to this new lineage.
Evasion of the innate immune response is a trademark of S. pyogenes and research is ongoing related to the CXC-chemokine cleaving protease SpyCEP (cepA), and the homologue C5a peptidase (scpA) that cleaves C3a and C5a. Proteases like these, that are conserved, demonstrate that repulsion of the neutrophil response is central to S. pyogenes pathogenesis and highlight their potential as vaccine targets.
The group have also elucidated how virulent strains of S. pyogenes can spread from a non-invasive focus of infection to the bloodstream, demonstrating that extracellular bacteria can 'metastasise' in the lymphatic system to reach the blood circulation without necessarily invading endothelial cells or blood vessels to achieve this. This could explain the phenomenon whereby S. pyogenes necrotising fasciitis or myositis arises despite a lack of penetrating trauma; an innocuous throat infection might potentially lead to lymphatic and then blood-borne dissemination. Lymphatic tropism might also contribute to S. pyogenes-associated autoimmune phenomena.

Collaborations-
Molecular anatomy of S. pyogenes and scarlet fever in UK -MRC project in collaboration with UKHSA
Schools Transmission Studies -Action Medical Research and UKRI-funded, now LeDucq Foundation-funded in collaboration with UKHSA.
S. pyogenes transmission and aerosols -MRC-funded project with David Green (SPH)

STREPTOCOCCAL VACCINES

Collaborations-
Understanding and Exploiting Streptococcal Cell Envelope Proteases... - Wellcome Trust Collaborative grant with Steven Matthews (CBRB/Life Sciences) and James Pease (NHLI)
Systems approach to Streptococcal vaccines using saRNA- NIH/NIAID R01 with Robin Shattock (DOID)
The Immunity to Streptococcus pyogenes (iSpy) Network. iSpy-LIFE subnetwork collaboration https://www.imperial.ac.uk/news/251477/global-research-network-combat-deadly-strep/

AMR RESEARCH

As theme lead for ‘Priority Pathogens’ in the NIHR Health Protection Research Unit (HPRU) in Healthcare Associated Infection and Antimicrobial Resistance, the group has examined the molecular basis for bacterial infections relevant to healthcare settings, such as Escherichia coli bacteremia, antimicrobial resistance, and, of course, haemolytic streptococcal infections. All projects are in partnership with UKHSA (the UK Health Security Agency, formerly Public Health England).
Work has been influenced by the COVID-19 pandemic; where possible patient-focussed studies and even schools transmission studies have been adapted to identify biomarkers of infection and routes of SARS-CoV2 transmission. The BRC-supported Colebrook AMR laboratory supports clinical and microbial biobanking.

Collaborations-
BioAID Biobank for adult infectious diseases (cross-BRC Collaboration with UCLH and others) - ongoing biomarker projects using RNAseq, metabonomics, cytokines.
Molecular basis for upsurge in E. coli bacteremia, genomics, nitrofurantoin resistance (HPRU collaboration with UKHSA)
AMRWatch- NERC-funded project to understand the impact of antimicrobial manufacturing on AMR in India with partners in Centre for Environmental Policy (Nick Voulvoulis) and India (Professor Joseph Selvin and team)

HISTORY OF ANTIBACTERIAL RESEARCH & AMR: THE PLACE OF STREPTOCOCCUS PYOGENES IN SEPSIS HISTORY

Imperial's new NIHR BRC AMR Colebrook research laboratory at Charing Cross, which opened at the start of the COVID-19 pandemic, is named in honour of Dora and her brother Leonard. https://imperialbrc.nihr.ac.uk/facilities/colebrook-laboratory/

Dora Colebrook came to Queen Charlotte's Hospital in 1930 to study the source of group A streptococci that were causing so many deaths from puerperal sepsis, a leading cause of death in women who had just given birth. Using defined serological techniques, she undertook groundbreaking work to demonstrate that the streptococci that caused uterine infections and deaths were the very same streptococci present in the throats of those in the household or healthcare workers caring for the women. This confirmed that simple procedures -including what we now think of as PPE- could reduce the incidence and transmission of puerperal sepsis and Strep A in many settings. Her 1935 MRC report is available here. https://www.imperial.ac.uk/media/imperial-college/medicine/infectious-disease/mergedpdf.pdf

Leonard Colebrook undertook the very first trials of antibacterials in the Isolation Unit at Queen Charlotte's hospital in 1936, evaluating Prontosil Red to treat streptococcal puerperal sepsis. Within a year, use of sulphonamides was widespread, avoiding restrictive patents, and pre-dated general use of penicillin by a decade. Mortality from puerperal sepsis plummeted, and providing the world with an appetite for antibacterials. Somewhat inevitably, resistance to sulphonamides proved problematic, as predicted by Colebrook.