Alasdair Leslie, Ph.D.
When Alasdair Leslie left Africa in 2002 to return to his native England, it wasn’t to do science—that’s just how things turned out. But ten years later, he is returning to the sub-equatorial continent with a clear scientific purpose: he wants to understand exactly how human cells respond to infection with HIV and tuberculosis.
Leslie arrived in Malawi in 1997 as a volunteer with the United Kingdom’s Voluntary Service Overseas program. After teaching for two years at Kasungu Secondary School, he remained in the country to work with local farmers. That work followed naturally on the agricultural master’s degree Leslie had earned at the University of Bath, and when he returned to England a few years later, accompanying the woman who would soon become his wife, he expected to continue along a similar path.
But Leslie’s prospects in agriculture in the UK didn’t pan out, and he needed a job. Broadening his search, he came across an ad from a lab devoted to studying the immune response to HIV infection. He recognized an opportunity to work on a problem whose devastating effects had been painfully apparent in Malawi, where high rates of HIV infection are compounded by extreme poverty and a lack of health care infrastructure. Leslie recalls losing several friends to the disease during his time there. “At least, we assumed that’s what it was. It wasn’t really talked about,” he says.
Leslie took the job as a research assistant at Oxford University, and within six months, the head of the lab had offered him a position as a Ph.D. student. Since then, he has devoted his studies to understanding the relationship between HIV and its host, focusing on immune cells’ earliest response to the pathogen. Recently, he’s expanded those studies to include the tuberculosis-causing bacteria Mycobacterium tuberculosis (mTB).
Now he is returning to Africa with deliberate plans to advance that work. As he sets up his lab at K-RITH, he will pursue two main strategies for understanding HIV and TB.
Leslie uses a technique called mass spectrometry to identify host cell proteins that undergo chemical changes immediately following infection. He focuses on proteins that undergo changes in phosphorylation, which can signal that a protein’s function has been switched on or off, in the first half hour following infection. “We want to know how cells respond immediately, when they first encounter a pathogen,” he says. “It’s pretty clear that pathogens like HIV and mTB have evolved ways of interfering with this initial signaling, and that allows them to survive.” By surveying a cell’s full complement of proteins – rather than focusing only on molecules predicted to respond to a pathogen – scientists can uncover unexpected relationships and events, Leslie says. That approach could reveal new targets for potential drugs or biological markers of disease that might be useful for diagnostics.
In conjunction with that work, Leslie will explore the effects of HIV and mTB infection in three-dimensional human tissue models. Under the right conditions it is possible to culture various types of human lung or gut cells in a Petri dish and coax them to organize themselves into structures that are virtually indistinguishable from the natural tissues. The system bridges the gap between studies of isolated human cells and animal studies. “It’s a tractable technology that will allow us to look at how cells and pathogens are interacting in a more realistic setting,” Leslie explains. The models will be invaluable in studying how HIV severely damages the gut mucosa, a process that has been difficult to study in humans. Leslie also plans to investigate the formation and maintenance of TB granulomas; the clusters of infected and uninfected cells that form in the lungs of patients as their immune systems attempt to wall off the pathogen. Granulomas are a hallmark of TB infection, yet whether their formation favors the host or the pathogen remains uncertain. By introducing cells from infected patients into the tissue models, Leslie hopes to learn even more about how host cells and pathogens affect one another.
Leslie is excited to bring these technologies to K-RITH. “These techniques don’t require extremely high-tech equipment,” he says. “You need the expertise – we’ve got that – and you need access to patient samples – which we will have in South Africa. But the end result is really cutting-edge technology.” And that’s exactly the kind of research that should be happening in the part of the world where the effects of TB and HIV are most keenly felt, he says.
I began my HIV research looking at the role of CD8 T-cells in the control of HIV infection and the virus’s adaptation to these responses. I still do some work in this area but now focus mainly on studying the innate immune response to HIV and, with the move to K-RITH, to TB and HIV/TB co-infection. My current research uses sensitive phospho-proteomic techniques to study Pattern Recognition Receptor (PRR) signalling in human dendritic cells in response to HIV. Dendritic cells are among the first immune cells to encounter the virus, and are essential in driving an effective immune response. However, it is becoming increasingly apparent that HIV is able to interfere with this interaction in ways that impair the initial immune response. This is at least in part responsible for the rapid early viral spread and damage to the immune system that is the hallmark of this deadly disease. By looking at the early signalling events occurring when DCs encounter HIV and other pathogens, we can start to build up a clearer picture of the key proteins involved in their recognition and pin down some of the ways in which they are able to modify this interaction to their benefit. These techniques are extremely powerful and have uncovered many interesting and novel aspects of DC/HIV interaction. I will be continuing this research at K-RITH and aim to use the same techniques to study TB and HIV/TB co-infection. This will answer interesting academic questions, but the ultimate aim is to provide data that will aid vaccine adjuvant design and biomarker discovery.
In addition to this work, I am interested in using newly developed 3D-organotypic models of lung and gut mucosa to study innate immune cell interaction with TB and HIV in the more physiologically relevant setting that these models provide. Traditional in vitro techniques typically involve the study of single populations of immune cells grown in suspension or adhered to a plastic surface. It is clear, however, that cells can behave very differently in tissue, as a consequence of interaction with other immune and non-immune cells, such as stroma, and the microenvironment generated. One can try to address this using an animal model, but again there are many draw backs, not least of which being you are no longer dealing with human cells. 3D-organotypic models allow one to keep using human cells, but come closer to the in-vivo setting of an animal model. This approach has a great potential to address many key questions about the pathogenesis of both HIV and TB–both diseases for which the mucosa is probably the key battle ground. Specifically I am interested in using the lung model to study TB granuloma formation and maintenance and the gut model to look at how HIV leads to degradation of this mucosal barrier. This work will be done in collaboration with Dr. Mattias Svensson from the Karolinska Institute and Dr. Ben Owens in Oxford, who have developed the lung and gut mucosal models respectively.
If you are interested in working with Dr. Leslie, e-mail Alleslie8@googlemail.com.
- D.Phil Clinical Medicine, University of Oxford, U.K
- MSc, University of Bath, U.K.
- BSc Honours in Biology, University of Nottingham, U.K
- Young and Early Career Investigators (YECI) committee of the Global HIV Vaccine Enterprise
- The hypervariable HIV-1 capsid protein residues comprise HLA-driven CD8+ T-cell escape mutations and covarying HLA-independent polymorphisms. J Virol. 2010 Nov 24. [Epub ahead of print]
- HLA-Cw*03 -restricted CD8+ T-cell responses targeting the HIV-1 Gag Major Homology Region drive virus immune escape and fitness constraints compensated by intra-codon variation. J Virol. 2010 Nov;84(21):11279-88.
- Additive Contribution of HLA Class I Alleles in the Immune Control of HIV-1 Infection. J Virol. 2010 Oct;84(19):9879-88
- E.Evolution of HLA-B*5703 HIV-1 escape mutations in HLA- B*5703-positive individuals and their transmission recipients. J Exp Med. 2009 Apr 13;206(4):909-21.
- HLA footprints on human immunodeficiency virus type 1 are associated with interclade polymorphisms and intraclade phylogenetic clustering. J Virol. 2009 May;83(9):4605-15.
- Adaptation of HIV-1 to human leukocyte antigen class I. Nature. 2009 Apr 2;458(7238):641-5. Epub 2009 Feb 25.
- Compensatory mutation partially restores fitness and delays reversion of escape mutation within the immunodominant HLA-B*5703-restricted Gag epitope in chronic human immunodeficiency virus type 1 infection. J Virol. 2007 Aug;81(15):8346-51.
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