Targeting immunometabolism to protect children from Tuberculosis infection

Introduction

Tuberculosis is the top global infectious killer in the last decade. The neonatal period is the most susceptible time to TB infection, with increased risk of active and disseminated disease. TB treatments require months of multiple drugs and resistance to first line agents is increasing annually. My research has previously demonstrated an immunometabolic defect in neonatal macrophages which is correctable with the administration of IFN-γ and has determined the potential for lactate as a host directed therapy.

Aim

The overall aim of this research project is to manipulate the immunometabolic and functional deficits in neonatal macrophages and to determine how immunometabolism changes over the course of childhood and throughout TB infection in order to develop host directed therapies and inform policy and practice.

Objectives

Defining the immunometabolic response of neonatal cord blood cells to Mtb infection.
Manipulating the immunometabolic response of neonatal cord blood cells to improve clearance of tuberculosis infection.  
Defining the immunometabolic response of children infected with Mtb from infancy to adolescence throughout the course of their illness.

Methods

Macrophages will be derived from neonatal cord blood taken immediately following delivery and adult blood donated to the Irish Blood Transfusion Service. Macrophages will then be infected with live, virulent mycobacteria to determine defects in immunometabolic responses. IFN-γ and lactate will be administered prior to infection to examine if the correction seen in stimulated neonatal macrophages is replicated during live infection. The immunometabolic response to TB in paediatric patients will be determined over the course of their illness from samples biobanked in the All Ireland Infectious Disease cohort study.

Outcomes

Neonatal susceptibility to live TB infection will be defined and the range of immunometabolic responses from infancy to adolescence determined. Novel methods of manipulating the immunometabolic response will be defined, paving the way for new host directed therapies.

Award Date: 22 September 2023
Award Value: €728,352.00
Principal Investigator: Dr Cilian Ó Maoldomhnaigh
Host Institution: Trinity College Dublin
Scheme: HRB Postdoctoral Fellowships: CSF 2023