Michael Lewis

Michael Lewis, Associate Professor

Tel : 024 765 74798 | Email Michael.D.Lewis@warwick.ac.uk

Plain English

Three of the most important neglected infectious diseases, African Trypanosomiasis (sleeping sickness), American trypanosomiasis (Chagas disease) and leishmaniasis are caused by members of a group of micro-organisms called kinetoplastid parasites. These parasites have evolved many strategies to evade the efforts of our immune systems to destroy them. This makes it very difficult for our bodies to get rid of these infections. Kinetoplastid infections cause a wide range of clinical outcomes, in terms of the organ systems that are involved, the speed with which symptoms develop, and the severity of disease that develops in different people. I aim to improve our understanding of how the host and parasite interact during infections and how variation in these interactions can lead to different disease presentations.

Currently, my main focus is the pathogenesis of Chagas disease and the biology of the causative parasite, Trypanosoma cruzi. There are approximately 6 million people affected by Chagas disease, the majority of whom live in Latin America. Migration patterns are leading to globalisation of this public health problem, with several thousand people infected with T. cruzi living in the UK. There is no vaccine, most infections remain undiagnosed and the only medicines that are available have severe side effects.

We are using experimental models of Trypanosoma cruzi infection in which the parasites have been engineered to emit light in a similar way to fireflies and to also fluoresce in a similar way to certain jellyfish. This enables us to track infections over time at both macro (whole organism) and micro (individual cell) levels. These data can then be integrated with information about the host’s immune responses and the development of disease, which typically involves scarring of muscle tissues and damage to the local nervous system in the heart and the gut. We are also studying the extent to which damaged tissues can be repaired after an infection has been treated using anti-parasitic drugs. This research will hopefully contribute to the development of more effective and safer medicines.

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Michael Lewis

Michael Lewis, Associate Professor

Tel : 024 765 74798 | Email Michael.D.Lewis@warwick.ac.uk

Google Scholar | ORCID

Plain English

Technical Summary

Kinetoplastid parasites comprise a diverse class of flagellated eukaryotic protozoa that diverged very early in the evolution of eukaryotes. This group includes three of the most important human protozoan pathogens: Trypanosoma cruzi, causative agent of American trypanosomiasis (Chagas disease); Trypanosoma brucei, which causes African trypanosomiasis (sleeping sickness); and species of the genus Leishmania which cause various clinical forms of leishmaniasis. As a result of sophisticated immune evasion strategies, kinetoplastids often cause long-term chronic infections. This can result in highly variable clinical outcomes between individual infected people, ranging from death and severe morbidity to milder forms and subclinical carrier states. The host, parasite and environmental factors that determine these heterogeneous outcomes are poorly understood. I aim to discover the mechanisms which determine host-parasite interaction dynamics during these infections and how these in turn shape tissue pathogenesis and organ dysfunction.

My main research focus is Trypanosoma cruzi biology and Chagas disease pathogenesis. There is a well-developed genetic engineering toolbox for T. cruzi, including bioluminescent:fluorescent fusion reporter genes and CRISPR-Cas9 systems for genome editing. This enables us to track the spatio-temporal dynamics of T. cruzi infections using in vitro, in vivo and ex vivo imaging models and to test hypotheses relating to parasite genetic factors by generating knockout, tagged and overexpression mutants. On the host side, we aim to use a variety of cutting-edge approaches to analyse immune responses, tissue damage and organ dysfunction, which can also be manipulated using genetic, chemical and immunomodulatory techniques. Integrating data on host, pathogen and pathology will help us to develop a more holistic understanding of the biological mechanisms involved in Chagas disease. We aim to use this knowledge to inform the development of more effective approaches to diagnosis and treatment.

Selected publications

Khan AA, Langston HC, Costa FC, Olmo F, Taylor MC, McCann CJ, Kelly JM, Lewis MD (2021). Local association of Trypanosoma cruzi chronic infection foci and enteric neuropathic lesions at the tissue micro-domain scale. PLoS Pathogens 17(8):e1009864. https://doi.org/10.1371/journal.ppat.1009864

Matos GM*, Lewis MD*, Talavera-López C, Yeo M, Grisard EC, Messenger LA, Miles MA, Andersson B (2022). Microevolution of Trypanosoma cruzi reveals hybridization and clonal mechanisms driving rapid genome diversification. eLife 11:e75237. https://doi.org/10.7554/eLife.75237

Pérez-Mazliah D, Ward AI, Lewis MD (2020). Host-parasite dynamics in Chagas disease from systemic to hyper-local scales. Parasite Immunology, 43 (2) e12786 https://doi.org/10.1111/pim.12786

Lewis MD, Paun A, Romano A, Langston H, Langner CA, Moore IN, Bock KW, Francisco AF, Brenchley JM, Sacks DL (2020). Fatal progression of experimental visceral leishmaniasis is associated with intestinal parasitism and secondary infection by commensal bacteria, and is delayed by antibiotic prophylaxis. PLoS Pathogens. 16(4):e1008456. https://doi.org/10.1371/journal.ppat.1008456

Lewis MD, Francisco AF, Taylor MC, Jayawardhana S, Kelly JM (2016). Host and parasite genetics shape a link between Trypanosoma cruzi infection dynamics and chronic cardiomyopathy. Cellular Microbiology 18(10):1429-43. https://doi.org/10.1111/cmi.12584