Petter Holmberg - Institutionen för translationell medicin

Title: Strategies for assessment of the persistence of viable bacilli in tuberculosis infection

Main supervisor: 

Per Björkman MD, Professor 

Reviewers: 

Pernille Ravn MD, PhD, Associate professor

Adam Linder MD, PhD, Associate professor

Abstract

Background

All currently available methods for detecting tuberculosis infection (TBI) relies on assessment of host immune responses to Mycobacterium tuberculosis (Mtb) unable to distinguish between ongoing and resolved infection. 

The hypothesis underlying this PhD project is that persons with TBI either do, or do not, harbor live bacilli and that longitudinal change in host mediator levels, degradation of tryptophan and RNA expression during tuberculosis preventive treatment (TPT) can reflect the presence of viable bacilli in people with immunological signs of TBI.

Research questions

1. Can longitudinal changes of levels of host mediators in Mtb antigen-stimulated blood from persons with TBI receiving TPT be used to distinguish individuals that harbour live bacteria from those with spontaneously cleared infection?
2. Can longitudinal changes in the degradation of tryptophan to kynurenine in plasma, kynurenine/tryptophan ratio, in Mtb antigen-stimulated blood from persons with TBI receiving TPT be used to distinguish individuals that harbour live bacteria from those with spontaneously cleared infection?
3. Can longitudinal changes in RNA expression in Mtb antigen-stimulated blood cells from persons with TBI receiving TPT be used to distinguish individuals that harbour live bacteria from those with spontaneously cleared infection? 

Preliminary results

Research question 1

1. We identified 9 host mediators (GM-CSF, IL-2, I-TAC, IL-12p70, IP10, VEGF, I-309, MCP-2, MIG) in plasma stimulated with Mtb antigens with the ability to differentiate interferon-γ release assay (IGRA) positive individuals before start of TPT from IGRA- persons, furthermore most of these mediators were not correlated to interferon-γ, suggesting that they might be used as alternative readout mediators in immune-based assays
2. We observed a concordant trend in changes of levels between the three categories of participants: IGRA + pre- treatment, IGRA + post-treatment and IGRA- of the 9 host mediators able to differentiate IGRA+ pre-treatment from IGRA-. We speculate that this phenomenon could reflect presence of viable Mtb.

Significance

To develop a complementary test for IGRA+ persons to assess the probability of bacterial clearance would be of great clinical value by directing treatment to those who harbor viable bacilli, and prevent unnecessary treatment for people with spontaneously resolved infection. 

Published studies

Holmberg, P., Janoušková, M., Schmidt, T., Neumann, A., Olsson, O., Isberg, P. E., Reimann, M., Riesbeck, K., Skogmar, S., & Björkman, P. (2025). Blood levels of Mycobacterium tuberculosis (Mtb)antigen-triggered immune mediators in people exposed to tuberculosis with regard to Mtb infection status and receipt of tuberculosis preventive treatment. Tuberculosis (Edinburgh, Scotland), 151, 102595. https://doi.org/10.1016/j.tube.2024.102595