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Title: Investigating the pathogenesis of African trypanosome infection via the skin
Author: Alfituri, Omar Abdelsalam
ISNI:       0000 0004 7969 119X
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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African trypanosomes (Trypanosoma brucei sp.) are single-celled extracellular protozoan parasites that are transmitted via the tsetse fly vector across sub- Saharan Africa. T. brucei subspecies cause trypanosomiasis in both humans and animals, inflicting substantial disease and economic strains in affected regions. Mammalian infection begins when the tsetse fly takes a blood meal and injects trypanosomes into the dermal layer of skin. The parasites then invade the circulatory and lymphatic systems, reaching the draining lymph nodes and disseminate systemically. Little is understood about the host-pathogen interactions which influence the establishment of host infection at the initial bite site in the skin. Most experimental transmissions of African trypanosomiasis have studied the intraperitoneal or intravenous routes of exposure. However, these by-pass the natural route of infection via the skin. Therefore the aim of this thesis is to investigate the pathogenesis of African trypanosome infection via the skin. Chemokines play important roles in attracting leukocytes towards the lymphatics and lymph nodes. To investigate how trypanosomes migrate from the bite site to the draining lymph nodes, the hypothesis that chemokines may act as chemoattractants for trypanosomes was tested. Chemokines can also possess antimicrobial properties, including against the related protozoan parasite Leishmania mexicana, therefore their potential cytotoxic effects against T. brucei were tested. Data presented in this thesis shows that these chemokines do not induce the chemotaxis of T. brucei. The motility characteristics of the parasites were also not affected by chemokine exposure. Nor did these chemokines exert any trypanostatic effects on trypanosomes. These data suggest trypanosomes use alternative cues to reach the lymphatics post-infection. The skin is an overlooked area of research for African trypanosome infections. Therefore work in this thesis sought to investigate the hypothesis that the infection kinetics would be different in a host infected by the natural intradermal route when compared with the routinely-researched intraperitoneal route. Experiments in this thesis revealed clear differences in the infection kinetics and disease progression in mice infected intradermally when compared with those infected by the intraperitoneal route. These data imply that further infection models should utilise intradermal injections and investigate the overlooked skin stage of disease which occurs naturally in the wild. Upon deposition in the skin the trypanosomes home towards the lymphatic system before migrating systemically. Lymphotoxin-β-receptor signalling (LTβR) is essential for lymphoid organogenesis and the maintenance of secondary lymphoid tissue microarchitecture. For example, LTβ-/- mice lack most lymph nodes and have grossly disturbed splenic microarchitecture. As a consequence of these disturbances LTβ-/- mice have impaired antibody isotype class-switching. Experiments in this thesis were performed to test the hypothesis that deficiencies in lymph node development and antibody isotype class-switching would influence disease pathogenesis. These data show that disease susceptibility and pathogenesis were exacerbated in LTβ-/- mice, which lacked class-switched antibody isotypes in their sera. This disease profile was then reversed in LTβ-/- mice which received wild-type bone-marrow transfers after their haematopoietic system was ablated through lethal irradiation. These data could identify the importance of the class-switching capability of the adaptive immune system to combat trypanosome infection. Little is known of the early host-parasite interactions following injection of T. brucei into the dermis of the skin. Macrophages are key players in the innate immune response against African trypanosome infection, and manipulating these cells during infection may help our understanding of the disease pathogenesis. To address their potential role in disease susceptibility, experiments were designed to manipulate the density and inflammatory status of the macrophages in the skin prior to infection with T. brucei. These data show, that manipulation of the inflammatory status of the skin reduced susceptibility to infection with T. brucei via the skin. A greater understanding of the macrophage-parasite interactions which occur during the early stages of African trypanosome infection is important for understanding how the immune system responds to infection and how we can boost immunity to combat infection. A thorough identification of the mechanisms involved in establishing African trypanosome infections in the skin and their systemic dissemination will aid the development of novel approaches to block disease transmission.
Supervisor: Mabbott, Neil ; Morrison, Liam Sponsor: Biotechnology and Biological Sciences Research Council (BBSRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Trypanosoma brucei ; African trypanosomiasis ; parasite host interaction ; chemokines ; intradermal route ; lymphotoxin-beta ; LT-beta