Research interests
Professor Heckels’ research interests has have been in the structure and immunochemistry of bacterial surface antigens and the molecular basis of their interaction with the human host, with particular emphasis on mechanisms of pathogenesis and the development of protective immunity. The studies are aimed at informing the development of new therapies and vaccines. Since coming to Southampton his interests have focussed particular emphasis on pathogenic Neisseria; Neisseria gonorrhoeae (gonococci) the cause of gonorrhoea and Neisseria meningitidis (meningococci) the bacteria responsible for meningococcal meningitis and septicemia.
Gonococci
Antigenic variation
Professor Heckels’ group has a longstanding reputation for studies of antigenic structure and pathogenesis of gonococcal infections. Key findings include; the demonstration that a single strain of gonococcus is able to switch expression between several different forms of both the major outer membrane Opa protein and the pilus adhesion, that each form of the variant proteins is- antigenically distinct, that both Opa and pili undergo antigenic shift during the course of an episode of gonorrhoea, enabling the bacteria to evade the consequences of the host immune response.
Mechanisms of pathogenesis
With Dr. Myron Christodoulides studies into gonococcal infection have established an in vitro model of cultured primary human endometrial cells and reported the first use of gonococci expressing green fluorescent protein (GFP) for studying pathogen-host cell interactions.
Collaboration with colleagues in the University of Santiago has used a human Fallopian tube (FT) model to study the pathogenesis of gonococcal salpingitis. These studies have demonstrated that TNF-α-mediated apoptosis of FT epithelial cells is a primary host defence host defence mechanism to prevent colonization. However, epithelial cell-associated gonococci have evolved a mechanism to modulate the host innate response, inhibiting apoptosis so they can colonise the epithelial cells without alerting immune effector cells. This modulation of the host innate response appears to be a key event that facilitates the establishment of infection and subsequent spread to other tissues
Ongoing studies are focused on analysis of FT gene expression during infection with aim of to developing novel treatments for ascending gonococcal infection in order to prevent chronic sequelae including infertility, ectopic pregnancy and increased susceptibility to HIV infection.
Meningococci
Professor Heckels’ group has had longstanding interest in immunity to meningococcal infection, particularly serogroup B for which no proven vaccine exists. They were the first group to clone and sequence any gene encoding a meningococcal antigen (PorA protein), and this was subsequently shown to be the major protein responsible for immunity to infection. The PorA protein has also formed the basis of novel vaccines used in outbreaks of meningococcal infection in Norway and New Zealand. The cloned gene was used by collaborators in the Dutch National Institute of Health (RIVM) to produce a multivalent PorA based vaccine aimed at multiple serogroup B strains.
Following the identification of the importance of the protein for immunity the group were able to show that the “Stroud” outbreaks of meningococcal disease that had occurred in the UK during the 1980s had been caused by a strain with a point mutation in the porA gene which caused a major change in immune recognition of the protein. This also demonstrated the hyper variability of the protein and led to the adoption of porA sequencing, which now forms part of the internationally agreed standard for distinguishing meningococci in epidemiological studies.
Immunity to infection
In the late twentieth century outbreaks of serogroup C infection occurred at several UK Universities which led to considerable public alarm. During the outbreak, Professor Heckels and colleagues the PHLS were able to mobilise resources to study the incidence of meningococcal carriage in the student population and demonstrated to show that contemporary students had much lower levels of natural immunity than expected from earlier studies in the 1960s. This lack of natural immunity was associated with a high incidence of invasive disease in students who became colonised by the outbreak strain. The group also showed that any natural immunity to serogroup C meningococci in this population was directed against the capsular polysaccharide [7]. This was followed by the introduction of a new MenC capsule vaccine into the national vaccination schedule.
The group were able to take advantage of heightened awareness of meningococcal disease in the student population to carry out two longitudinal studies of the dynamics of meningococcal carriage in freshers during their first year in university. They demonstrated that acquired immunity to serogroup B meningococci was largely related to presence of antibodies to PorA protein and not to capsular polysaccharide. These antibodies were strain specific but individuals also developed broad spectrum immunity to other minor protein which could not then be identified.
Vaccine discovery
With improved methods of detection Professor Heckels’ group were subsequently able to identify minor proteins that were associated with the induction of broad spectrum immunity against serogroup B meningococci. This is a key step in the design of novel vaccines. Several such proteins have been identified, the genes cloned and used to express the individual proteins. One such protein, which is highly conserved, has been used for immunisation and shown to induce protective immune response against a wide range of meningococci of both serogroup B and several other serotypes. This work has led to the licensing of a patent to a major international pharmaceutical company. On-going work is aimed at determining the vaccine potential of the additional proteins with the aim of designing a multicomponent vaccine designed to prevent meningococcal infection.
Research group
Clinical and Experimental Sciences
Affiliate research group
Infection and Immunity Research group
Professor John HeckelsFaculty of Medicine, Room AB215, Mailpoint 801, South Academic Block, University Hospital Southampton, Tremona Road, Southampton, SO16 6YD
