Doctoral Degrees (Molecular Biology and Human Genetics)
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Browsing Doctoral Degrees (Molecular Biology and Human Genetics) by browse.metadata.advisor "Coussens, Anna"
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- ItemNeutrophils as effector cells in resistance to infection by mycobacterium tuberculosis in HIV-infected individuals(Stellenbosch : Stellenbosch University, 2022-03) Kroon, Elouise Elizabeth; Hoal, Eileen ; Moller, Marlo; Tromp, Gerard; Schurr, Erwin; Wilkinson, Robert J.; Coussens, Anna; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics.ENGLISH ABSTRACT: Epidemiological studies have highlighted persons who, despite exposure to Mycobacterium tuberculosis (Mtb), the causative organism of tuberculosis (TB), do not show immune conversion to tests used to infer Mtb infection. Current immunological tests used to infer latent Mtb infection, the tuberculin skin test (TST) and interferon gamma release assay (IGRA) do not capture the full spectrum of T-cell responses to Mtb. Persons defined as Mtb infection resisters show Mtb specific antibodies and interferon gamma (IFN-γ)-independent T-cell responses. This has highlighted a range of responses to Mtb, with an interplay between innate and adaptive immune cells in host resistance to TB. The study of host resistance to TB within the context of persons living with HIV (HIV+), was until recently still limited. HIV+ persons have an increased risk for TB. Identifying persons who despite previously low CD4+ counts and prolonged and persistent TB exposure, do not develop TB, pointed to remarkable underlying host protection mechanisms. In this thesis we classified and identified 48/286 (17%) HIV+ persons, aged 35-60 years old, who prior to ART initiation had low CD4+ counts, are now immune reconstituted on ART, and despite prolonged and persistent exposure to TB, remained consistently TST and IGRA negative over an average period of 206±154 days. Age was used as a proxy for prolonged exposure and exposure intensity was reflected by the persons living in Cape Town, South Africa, a high TB prevalence environment. None of these persons have a history of current or previous TB. This phenotype has been defined as HIV-1-positive persistently TB, tuberculin and IGRA negative (HITTIN). In addition, we identified a group of persons, following similar criteria, but with repeated TST and IGRA positive results. This group was defined as HIV-1-positive IGRA positive tuberculin positive (HIT). Next, we investigated the role of the innate immune system in host resistance to Mtb by examining the role of neutrophils. Neutrophils are among the first innate cells to make contact with Mtb after infection. The dichotomous role of neutrophils in TB is well researched, with disease severity in some linked to neutrophil driven type 1 IFN responses. Neutrophils in mice exert their beneficial role early in the infection process though controlled apoptosis. Here the role of human neutrophils in host resistance to Mtb was explored by comparing neutrophil gene responses to Mtb infection between HITTIN and HIT. Neutrophils from HITTIN (PMNHITTIN) had 1068 more upregulated and 1217 more downregulated genes compared to neutrophils from HIT (PMNHIT), after 6 hours of infection with Mtb. Key pathways and genes controlling cell death and inflammation were highlighted. This research highlights a unique phenotype of neutrophils showing an altered gene expression profile, with key mechanisms of innate host resistance to TB which require further investigation. This can contribute to identifying novel TB prevention and treatment strategies.