Susceptibility to mycobacteria: the role of influenza coinfection
File(s)
Author(s)
Friend, Claire
Type
Thesis
Abstract
Mycobacterium tuberculosis (Mtb) infection is now recognised as a dynamic continuum, ranging from quiescent, contained infection to destructive, life-threatening disease. Clinical outcomes reflect the ongoing balance between the host’s immunological defences and mycobacterial survival and virulence mechanisms, but the factors influencing these are incompletely understood. Co-infections, including influenza, have been proposed as a risk factor for progression to tuberculosis (TB) disease. We hypothesised that influenza infection increases susceptibility to mycobacteria via its disruptive effects on immunological pathways important for mycobacterial containment.
An adapted whole blood mycobacterial growth inhibition assay was employed, within the framework of a human influenza challenge study, to investigate the effects of systemic influenza infection on host mycobacterial restriction and anti-mycobacterial immune responses. Healthy adults were per-nasally inoculated with H3N2 influenza virus. Whole blood collected before (Day 0, “pre”) and after (Day 6, “post”) influenza inoculation was infected with Mycobacterium bovis Bacille Calmette Guerin (BCG) lux, incubated for 72 hours (h) and mycobacterial growth measured. In parallel, BCG-lux-infected and uninfected blood aliquots were incubated for up to 72 h and measurements of cytokines (Meso Scale Discovery) and gene expression (RNA-Sequencing) undertaken. Comparisons between pre- and post-influenza infection blood samples were made.
Influenza infection reduced mycobacterial growth restriction, with BCG lux growing more in pre- versus post-influenza blood samples. Influenza infection activated innate immune pathways important in TB control but inhibited their subsequent responsiveness to mycobacterial infection. Interferon signalling was a key pathway.
These novel findings suggest that influenza infection increases susceptibility to mycobacteria and may be a risk factor for TB disease. Influenza vaccine may have non-specific protective effects on TB immunity. The finding that influenza infection modulates anti-mycobacterial immune responses has implications for development of novel vaccines, TB diagnostics and immunotherapies.
An adapted whole blood mycobacterial growth inhibition assay was employed, within the framework of a human influenza challenge study, to investigate the effects of systemic influenza infection on host mycobacterial restriction and anti-mycobacterial immune responses. Healthy adults were per-nasally inoculated with H3N2 influenza virus. Whole blood collected before (Day 0, “pre”) and after (Day 6, “post”) influenza inoculation was infected with Mycobacterium bovis Bacille Calmette Guerin (BCG) lux, incubated for 72 hours (h) and mycobacterial growth measured. In parallel, BCG-lux-infected and uninfected blood aliquots were incubated for up to 72 h and measurements of cytokines (Meso Scale Discovery) and gene expression (RNA-Sequencing) undertaken. Comparisons between pre- and post-influenza infection blood samples were made.
Influenza infection reduced mycobacterial growth restriction, with BCG lux growing more in pre- versus post-influenza blood samples. Influenza infection activated innate immune pathways important in TB control but inhibited their subsequent responsiveness to mycobacterial infection. Interferon signalling was a key pathway.
These novel findings suggest that influenza infection increases susceptibility to mycobacteria and may be a risk factor for TB disease. Influenza vaccine may have non-specific protective effects on TB immunity. The finding that influenza infection modulates anti-mycobacterial immune responses has implications for development of novel vaccines, TB diagnostics and immunotherapies.
Version
Open Access
Date Issued
2023-05-25
Date Awarded
01/12/2023
License URL
Advisor
Levin, Michael
Newton, Sandra
Kaforou, Myrsini
Whittaker, Elizabeth
Sponsor
National Institute for Health Research (Great Britain)
Wellcome Trust (London, England)
Grant Number
RDA02
Publisher Department
Department of Infectious Disease
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)