Sivro, Aida.Naidoo, Kogieleum.Rambaran, Santhuri.2024-05-282024-05-2820232023https://hdl.handle.net/10413/23009Doctoral Degree. University of KwaZulu-Natal, Durban.Background: Tuberculosis is one of the major causes of morbidity and mortality worldwide. The COVID -19 pandemic has had a devastating impact on TB, contributing to increased incidence of both TB and drug-resistant TB. Identification of host immune biomarkers of TB risk, treatment outcome and disease severity are key to the development of more efficient diagnostics and treatment modalities. There is an urgent need for accurate and easily detectable non-sputum-based biomarkers that can correlate with the activity or burden of Mycobacterium tuberculosis. Here, we characterised soluble and cellular phenotypes during active TB and TB/HIV co-infection and assessed their associations with time to negative culture conversion and disease severity. Methods: The study was performed utilizing stored plasma and peripheral blood mononuclear cells from the Improving Retreatment Success (IMPRESS) trial. Multiplex immunoassays and ELISAs were used to evaluate 24 cytokine and chemokine expression during active TB (n=132). Flow cytometry was used to evaluate phenotypic profiles of monocytes, dendritic cells (n=90) and CD4+ T cells (n=75). A Cox proportional hazards and logistic regression models were used to assess the associations between the measured cytokines and chemokines, phenotypic profiles of monocytes, dendritic cells and CD4+ T cells and time to negative culture conversion and lung cavitation in individuals with TB and TB/HIV co-infection. Results: We identified soluble inflammatory signatures of treatment response and disease severity. IP-10 expression during active TB was associated with increased odds of sputum culture conversion by 8-weeks in the total cohort and among the HIV-infected individuals. Increased MCP-3 expression was associated with a shorter time to culture conversion in the total cohort. While among the HIV-infected individuals, higher expression of IL-1RA, IP-10 and IL-1α associated with a shorter time to culture conversion. Higher expression of IL-6 was significantly associated with shorter time to culture conversion and increased risk of lung cavitation in the overall cohort and among TB/HIV co-infected individuals. Additionally, higher IL-1RA expression was associated with the presence of lung cavitation in the total cohort and in HIV-infected individuals. We observed distinct monocyte and dendritic cell profiles in TB/HIV co-infection. Individuals with TB/HIV co-infection had a significantly higher percentage of total monocytes and dendritic cells compared to healthy controls. Increase in CCR2, CD11b and CD40 was associated with active TB while decrease in CX3CR1 and increase in CD163 was associated with HIV infection. Expression of CX3CR1 on non-classical monocytes was associated with longer time to culture conversion while expression of CD86 on intermediate monocytes was associated with presence of lung cavitation. With respect to CD4+ T cells HIV positive individuals with active TB had significantly lower percentage of CD4+ T cells and significantly higher proportion of activated CD4+ T cells compared to TB and healthy control groups. Percentage of CD4+ T cells was significantly associated with increased risk, while the percentage of activated CD4+ T cells was associated with decreased risk of lung cavitation. Integrin α4β7 expressing CD4+ T cells were increased in TB/HIV compared to TB group and was associated with longer time to TB culture conversion in co-infected individuals. Conclusion: The data from this study provides valuable insight into the role that plasma immune biomarkers, monocytes, dendritic and CD4+ T cells play in TB treatment response and disease severity in active TB and TB/HIV co-infection.enTB/HIV coinfection.Inflammation.Thesishttps://doi.org/10.29086/10413/23009