Understanding the mechanism of action of E coli O157:H7 virulence inhibitors at unprecedented resolution

 

Supervisor: Professor Jim Brewer, School of Infection & Immunity

Children in malaria endemic regions have weakened immune responses against immune challenges, such as infection or childhood vaccines (1). This poses a particularly significant problem for malaria vaccines, which have been much less successful in malaria exposed, compared with non-exposed (western) populations. Research by our team, and others, has led to the hypothesis that malaria blocks the physical interaction of two key immune cells, T cells and Dendritic Cells (DC) (2, 3). The interaction of T cells with DC is essential to form a protective immune response to infections or vaccines. To understand why this happens, we found that when malaria parasites are eaten by DC they damage the key generators of cellular energy, called mitochondria. While this should cause DC to die, we have shown that DC adapt by using other energy generating approaches to stay alive. We believe that this loss of power, or the adaptation process resulting from this, produces the failure in DC function during malaria infection.

This project will investigate the immunology and metabolism of DC exposed to malaria parasites using a variety of metabolomic, transcriptomic and imaging techniques, together with training in data analysis. Immunometabolism is a rapidly developing and increasingly important area in biomedical science. We propose that drugs that can block alterations in these metabolic processes or their downstream effectors could restore immune function and therefore overcome malaria induced immune suppression.

References

  1. R. S. Osii, T. D. Otto, P. Garside, F. M. Ndungu, J. M. Brewer, Front. Immunol. 11, 1–16 (2020).
  2. O. R. Millington, C. Di Lorenzo, R. S. Phillips, P. Garside, J. M. Brewer, J. Biol. 5, 5 (2006).
  1. O. R. Millington et al., PLoS Pathog. 3, 1380–7 (2007).