Mucosal delivery of ESX-1–expressing BCG strains provides superior immunity against tuberculosis in murine type 2 diabetes

Harindra D. Sathkumara1, Visai Muruganandah1,2, Martha M. Cooper1,3, Matt A. Field1,3, Md Abdul Alim1,4, Roland Brosch5, Natkunam Ketheesan6, Brenda Govan1,7, Catherine M. Rush1,7, Lars Henning7, and Andreas Kupz1

1Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns & Townsville, QLD 4878, Australia
2College of Medicine and Dentistry, James Cook University, Cairns & Townsville, QLD 4878, Australia
3Centre for Tropical Bioinformatics and Molecular Biology, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4878, Australia
4Faculty of Veterinary Medicine, Chattogram Veterinary and Animal Sciences University, Chattogram 4225, Bangladesh
5Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, 75015 Paris, France
6Science and Technology, University of New England, Armidale, NSW 2351, Australia
7College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD 4811, Australia

Abstract
Tuberculosis (TB) claims 1.5 million lives per year. This situation is largely due to the low efficacy of the only licensed TB vaccine, Bacillus Calmette–Guérin (BCG) against pulmonary TB. The metabolic disease type 2 diabetes (T2D) is a risk factor for TB and the mechanisms underlying increased TB susceptibility in T2D are not well understood. Furthermore, it is unknown if new TB vaccines will provide protection in the context of T2D. Here we used a diet-induced murine model of T2D to investigate the underlying mechanisms of TB/T2D comorbidity and to evaluate the protective capacity of two experimental TB vaccines in comparison to conventional BCG. Our data reveal a distinct immune dysfunction that is associated with diminished recognition of mycobacterial antigens in T2D. More importantly, we provide compelling evidence that mucosal delivery of recombinant BCG strains expressing the Mycobacterium tuberculosis (HMtb) ESX-1 secretion system (BCG::RD1 and BCG::RD1 ESAT-6 Δ92–95) are safe and confer superior immunity against aerosol Mtb infection in the context of T2D. Our findings suggest that the remarkable anti-TB immunity by these recombinant BCG strains is achieved via augmenting the numbers and functional capacity of antigen presenting cells in the lungs of diabetic mice.

Harindra D. Sathkumara PhD

Australian Institute of Tropical Health and Medicine, James Cook University

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