A joint venture between the Department of Biology and The Hull York Medical School

Profile

Career

• Centre for Immunology and Infection
  Postdoctoral research associate

Research

Overview

• Human African Trypanosomiasis
• CNS invasion by African trypanosomes
• Focus-specific clinical phenotypes
• In vitro Blood Brain Barrier Model

My current research focuses on central nervous system (CNS) invasion by African trypanosomes. This work addresses one of the key deficiencies in development of new drugs for late stage African trypanosomiasis:  the lack of a robust model for parasite transmission across the blood brain barrier.

Human African trypanosomiasis (HAT) is caused by African trypanosomes, which are transmitted by the haematophagous tsetse fly. The disease is characterised by two stages, the early or haemo-lymphatic stage, and the late or meningo-encephalitic stage in which trypanosomes cross the blood brain barrier (BBB) invade the CNS leading to coma and death if untreated. HAT has a severe social and economic impact across sub-Saharan Africa with an estimated 60 million people at risk of African trypanosome infection. Despite the recent decline in cases reported to WHO, HAT is historically characterised by episodic epidemics, resurgences and outbreaks. In addition, disease staging requires lumbar puncture and analysis of patient CSF, late stage T.b. rhodesiense HAT is still treated by administering Melarsoprol, a highly toxic drug given intravenously over a 5 week period causing encephalitic syndrome in 5-8% cases, half of which will not survive. It is, therefore, critical that better diagnostics are made available so HAT cases are correctly staged for appropriate treatment, less toxic drug candidates are identified and that these can be rapidly screened for their ability to cross the BBB, the main obstacle in generating effective late stage treatments, before clinical trials are undertaken.

I have established foci-specific T.b.rhodesiense HAT clinical phenotypes showing dramatic variation in disease severity and rate of stage progression both between northern and southern East African foci and between geographically close Ugandan HAT foci (Study sites in Uganda and Malawi are shown in Figure 1, active screening for HAT cases in Uganda is shown in Figure 2). Such marked variation in disease severity suggests there are differences in host susceptibility to trypanosome infection and/or genetic variation in trypanosome virulence. Understanding the contribution of host and parasite factors in causing such clinical diversity in HAT is critical for improving management of this neglected disease as well as identifying late stage markers for diagnostics and new candidates for late stage treatment.

Little is known about the mechanism by which trypanosomes cross the BBB but it is thought that both parasite and host factors affect BBB integrity. The BBB is composed of brain microvascular endothelial cells (BMEC) surrounded by basal lamina and astrocytic perivascular endfeet. It has been proposed from studies using an in vitro BBB model that brucipain, a trypanosome cysteine protease, induces calcium activation signals in BMEC via protease-activated receptors (PARs), thereby causing brain endothelial barrier dysfunction allowing trypanosome BBB transmigration. There is also evidence in mouse models that the host neuroinflammatory response plays a role in determining trypanosome entry into the CNS.

I am currently developing a human BMEC in vitro system to mimic events at the human BBB using recently developed cell biological methods with fluorescent transgenic parasites (Figure 3) of different subspecies with known clinical profiles. Availability of a refined in vitro model will facilitate both identification of new diagnostic markers and development of new treatments for late stage HAT infection.

Research group(s)

• Smith research group (Experimental medicine, Immunology)
  Postdoctoral research associate

Publications

Selected publications

• MacLean. L., H. Reiber, P. G. E. Kennedy, J. M. Sternberg (2012). The pathophysiological role of CNS cellular and humoral responses in T. b. rhodesiense Sleeping Sickness (Submitted to PLoSNTD).
• MacLean. L., P. J. O’Toole, M. Stark, J. Marrison, C. Seelenmeyer, W. Nickel, D. F. Smith (2012). Trafficking and release of Leishmania metacyclic HASPB on macrophage invasion. Cellular Microbiology 14 (5): 740-761.
• Price. H. P., M. R. Hodgkinson, J. A. Brannigan, L. MacLean, M. Stark, D. F. Smith (2012). The orthologue of Sjögren's Syndrome nuclear autoantigen 1 (SSNA1) in Trypanosoma brucei is an immunogenic self-assembling molecule. PLoS ONE 7 (2): e31842.
• Depledge. D. P., L. MacLean, M. R. Hodgkinson, B. A. Smith, D. Harris, A. Jackson, S. Ma, S. R. B. Uliana, D. F. Smith. (2010). Leishmania-specific surface antigens show sub-genus sequence variation and differential immune recognition. PLoS Neglected Tropical Diseases 4 (9): e829.
• MacLean. L., M. Odiit, J. M. Sternberg (2010). Focus-specific clinical profiles in human African Trypanosomiasis caused by Trypanosoma brucei rhodesiense. PLoSNTD 4 (12): e906.
• Sternberg. J. & L. MacLean. (2010). A spectrum of disease in Human African Trypanosomiasis: host and parasite genetics of virulence. Parasitology 21:1-9.
• Price. H. P., L. MacLean, J. Marrison , P. J. O’Toole, D. F. Smith. (2010). Validation of a New Method for Immobilising Kinetoplastid Parasites for Live Cell Imaging. Molecular & Biolochemical Parasitology 169: 66-69.
• MacLean. L., M. Odiit, MacLeod A., Morrison L., Sweeney L., Cooper A., Kennedy P. G. E., & J. M. Sternberg (2007). Spatially and Genetically Distinct African Trypanosome Virulence Variants Defined by Host Interferon-g Response. Journal of Infectious Diseases 196: 1620- 1628.
• MacLean. L., M. Odiit & J. M. Sternberg (2006). Intrathecal Cytokine Responses in Trypanosoma brucei rhodesiense Sleeping Sickness patients. Transactions of the Royal Society of Tropical Medicine and Hygiene 100: 270-275.
• Sternberg. J. M., J. Rodgers, B. Bradley, L. MacLean, M. Murray, P. G. E. Kennedy (2005). Meningoencephalitic African Trypanosomiasis: Brain IL-10 & IL-6 are associated with protection from neuro-inflammatory pathology. Journal of Neuroimmunology 167: 81-89.
• MacLean. L., J. E. Chisi, M. Odiit, W. C. Gibson, V. Ferris, K. Picozzi & J. M. Sternberg (2004). Severity of Human African Trypanosomiasis in East Africa is associated with geographical location, parasite genotype and host inflammatory cytokine response profile. Infection and Immunity 72: 7040-7044.
• MacLean. L., A. T. Pardini, L. R. Noble, J. D. D. Bishop & C. S. Jones (2004). Polymorphic dinucleotide microsatellite loci in the clonal ascidian Diplosoma listerianum: predominance of compound and highly interrupted imperfect repeats. Molecular Ecology Notes 4: 283-285.
• MacLean, L. M., M. Odiit & J. M. Sternberg, (2001). Nitric oxide and cytokine synthesis in Human African Trypanosomiasis. The Journal of Infectious Diseases 184: 1086-1090.
• MacLean, L. M., M. Odiit, D. Okitoi & J. M. Sternberg, (1999). Plasma nitrate and interferon gamma in Trypanosoma brucei rhodesiense infections: evidence that nitric oxide production is induced during both early blood stage and late meningoencephalitic stage infections. Transactions of the Royal Society of Tropical Medicine and Hygiene 93: 169-170.