Dr Simon Johnston PhD
MRC Career Development Fellow
Department of Infection, Immunity & Cardiovascular Disease
I studied Biochemistry at the University of Birmingham graduating in 2003. I went on to do a PhD in cell biology with Professor Laura Machesky (Beatson Institute) studying the actin cytoskeleton and cell motility. In 2007 I was awarded a Birmingham University Prize for Research. During my post-doctoral work with Dr. Robin May (Institute of Microbiology and Infection, University of Birmingham) I investigated the host pathogen interactions, particularly the interaction with macrophages, of the human fungal pathogen Cryptococcus. While in Dr. May’s laboratory I developed a model of cryptococcosis in the zebrafish. In 2012 I was awarded a MRC Career Development Award Fellowship to develop this model for the study of the cell biology of host pathogen interactions in vivo and I moved to the University of Sheffield to take up this fellowship and establish my research group.
When the immune system does not function properly, for example, in HIV infection (the virus that causes AIDS), cancer and old age, we are vulnerable to microbes that normally do not cause disease. One such microbe is the fungus Cryptococcus that causes an estimated 600,000 deaths each year. I want to understand why we become vulnerable to infections such as Cryptococcus.
We already know that Cryptococcus can avoid parts of our immune system, for example it escapes immune cells whose job it is to eat and digest microbes, but we do not know how single aspects like this come together to cause life-threatening disease. The zebrafish represents a unique opportunity to study these interactions as they are transparent in their early life and have an immune system that is similar to our own. I have developed ways to look at zebrafish in three-dimensions over time that mean I can study the individual behaviour of many immune cells and microbes at the same time during infection. I believe that this will dramatically further our understanding of how microbes cause disease, how the immune system is able to respond and how to develop new treatments and therapies.
Understanding of the macrophage interaction with pathogens is crucial for the study of infectious disease, with many important pathogens known to manipulate phagocyte function (e.g. HIV, Tuberculosis, Salmonella). However, there are very few examples of where this interaction can be studied at a cellular level, in vivo during infection, especially with high-resolution light microscopy, a technique that has proved fundamental for insights in vitro.
Cryptococcus is a fatal fungal infection of humans causing death through meningitis. C. neoformans is a significant pathogen of the immunocompromised, especially AIDS patients, and causes an estimated 600,000 deaths per year. In contrast, C. gattii is predominantly a pathogen of immunocompetent individuals and although predominantly localised to the tropics and sub-tropics, there are increasing numbers of cases outside of this region, in particular the Vancouver Island Outbreak (VIO), which highlights how particular groups of C. gattii are becoming hypervirulent.
By evading or manipulating phagocytes, particularly macrophages, Cryptococcus is able to cross the immune barriers that normally prevent fatal disseminated disease. Current studies focus on in vitro analysis in isolated (mammalian) cells, such as macrophages or in vivo studies in rodent hosts. However, such approaches are unable to capture the complex cellular events that define how this fatal disease progresses or is stopped. Therefore, I have developed a new integrated model of cryptococcosis in zebrafish to simultaneously study host and pathogen factors that determine disease progression and outcome in vivo. Zebrafish (Danio rerio) are proven models of human disease as well as immune cell and infection biology and are unparalleled for this work due to the ability to perform in vivo sub-cellular resolution imaging in the entire body of a living vertebrate.
MRC Career Development Award Fellow
Member of Society for General Microbiology
Member of British Society of Cell Biology
Editorial Reviewer Frontiers in Microbiology
- Defining the role of host and pathogen factors that determine disease outcome in cryptococcosis.
- Screening for novel therapeutics for improving cryptococcosis outcome.
- Developing quantitative in vivo imaging and analysis for infection and immunity research.
For Key Publications see below. For a full list of publications click here.
- Johnston SA & May RC (2013) Cryptococcus interactions with macrophages: evasion and manipulation of the phagosome by a fungal pathogen.. Cell Microbiol, 15(3), 403-411.
- Chayakulkeeree M, Johnston SA, Oei JB, Lev S, Williamson PR, Wilson CF, Zuo X, Leal AL, Vainstein MH, Meyer W, Sorrell TC, May RC & Djordjevic JT (2011) SEC14 is a specific requirement for secretion of phospholipase B1 and pathogenicity of Cryptococcus neoformans. Molecular Microbiology, 80(4), 1088-1101.
- Carnell M, Zech T, Calaminus SD, Ura S, Hagedorn M, Johnston SA, May RC, Soldati T, Machesky LM & Insall RH (2011) Actin polymerization driven by WASH causes V-ATPase retrieval and vesicle neutralization before exocytosis. Journal of Cell Biology, 193(5), 831-839.
- Johnston SA & May RC (2010) The human fungal pathogen Cryptococcus neoformans escapes macrophages by a phagosome emptying mechanism that is inhibited by arp2/3 complex- mediated actin polymerisation. PLoS Pathogens, 6(8), 27-28.
- Voelz K, Johnston SA, Rutherford JC & May RC (2010) Automated analysis of cryptococcal macrophage parasitism using GFP-tagged cryptococci.. PLoS One, 5(12), e15968.
- Ma H, Hagen F, Stekel DJ, Johnston SA, Sionov E, Falk R, Polacheck I, Boekhout T & May RC (2009) The fatal fungal outbreak on Vancouver Island is characterized by enhanced intracellular parasitism driven by mitochondrial regulation.. Proc Natl Acad Sci U S A, 106(31), 12980-12985.
- Johnston SA, Bramble JP, Yeung CL, Mendes PM & Machesky LM (2008) Arp2/3 complex activity in filopodia of spreading cells.. BMC Cell Biol, 9, 65.
- Machesky LM & Johnston SA (2007) MIM: a multifunctional scaffold protein.. J Mol Med (Berl), 85(6), 569-576.
- Legg JA, Bompard G, Dawson J, Morris HL, Andrew N, Cooper L, Johnston SA, Tramountanis G & Machesky LM (2007) N-WASP involvement in dorsal ruffle formation in mouse embryonic fibroblasts.. Mol Biol Cell, 18(2), 678-687.