Project: Neutrophils as effector cells in resistance to infection by Mycobacterium tuberculosis in HIV-infected persons

Acronym	Neutro-TB (Reference Number: TMA2018CDF-2353)
Duration	01/12/2019 - 30/11/2022
Project Topic	Mycobacterium tuberculosis (M. tuberculosis) is an airborne pathogen spread via the aerosol inhalation of transmitted droplets containing the bacteria from an infected individual. However, some individuals, despite persistent and heavy exposure to M. tuberculosis do not become infected as inferred by a lack of T-cell memory response to M. tuberculosis antigens (repeat negative IGRA and TST negative) and are so-called resisters. The existence of resistance to infection as a key step in tuberculosis (TB) pathogenesis is supported by multiple lines of evidence and is also observed in HIV-infected persons. HIV-infection predisposes to TB. However, despite having previously low CD4 counts and living in high TB incidence environments, some HIV-infected persons do not become infected with M. tuberculosis and have no history of previous or current TB. The contribution of the innate immune system and the exact cells involved in innate immune infection resistance remain incompletely elucidated. Neutrophils are some of the first phagocytes recruited from the pulmonary vasculature to the pulmonary interstitium to control infection and are prominent candidates for possible involvement as primers for microbial clearance. We hypothesize that resistance of HIV infected individuals to M. tuberculosis is due to neutrophils acting as effector cells. Significant transcriptional differences and effector functions will exist in the neutrophil response between hosts who do not develop evidence of immune sensitisation to M. tuberculosis using TST/IGRA, or innate resisters (IR), compared to those who develop evidence of immune sensitisation, or infection susceptible (IS) individuals. We will use samples previously collected from a total of 60 HIV infected persons screened and enrolled to the NIH-funded ResisTB study in Cape Town, South Africa. The samples are subdivided into 4 groups based on their IGRA/TST results (positive/negative) and age category (18- 25 years, 35-60 years). Age is used as a surrogate for exposure intensity in our area of high M. tuberculosis transmission. The objectives will be to: 1. Compare neutrophil numbers, phenotype and activation markers between the specified study groups. 2. Extract genomic total RNA from the M. tuberculosis infected and uninfected neutrophils at different time points and characterize for difference in transcriptional responses using RNA sequencing. 3. Investigate differences in effector mechanisms of neutrophils, such as NETosis, between the study groups using microscopy. By gaining a better understanding of the resister phenotype and the potential role of neutrophils in M. tuberculosis infection resistance, we may reveal clinically important activities for prevention and treatment development.
Network	EDCTP2
Call	Career Development Fellowships 2018

Project partner

Number	Name	Role	Country
1	Stellenbosch University	Coordinator	South Africa