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

Sathkumara, Harindra D., Muruganandah, Visai, Cooper, Martha M., Field, Matt A., Alim, Md Abdul, Brosch, Roland, Ketheesan, Natkunam, Govan, Brenda, Rush, Catherine M., Henning, Lars, and Kupz, Andreas (2020) Mucosal delivery of ESX-1–expressing BCG strains provides superior immunity against tuberculosis in murine type 2 diabetes. National Academy of Sciences. Proceedings, 117 (34). pp. 20848-20859.

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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 (Mtb) ESX-1 secretion system (BCG::RD1 and BCG::RD1 ESAT-6 ∆92–95) 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.

Item ID: 64078
Item Type: Article (Research - C1)
ISSN: 1091-6490
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Copyright Information: (C) PNAS
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A version of this publication was included as Chapter 4 of the following PhD thesis: Sathkumara, Harindra Darshana (2020) Mechanisms driving tuberculosis susceptibility and vaccine efficacy in HIV/AIDS and type 2 diabetes. PhD thesis, James Cook University, which is available Open Access in ResearchOnline@JCU. Please see the Related URLs for access.

Funders: National Health and Medical Research Council of Australia (NHMRC), Australian Institute of Tropical Health and Medicine (AITHM)
Projects and Grants: NHMRC APP1052764, NHMRC APP1140709, NHMRC PP1120808, AIHTM Capacity Building Grant 1503
Date Deposited: 02 Sep 2020 03:19
FoR Codes: 31 BIOLOGICAL SCIENCES > 3107 Microbiology > 310702 Infectious agents @ 40%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320211 Infectious diseases @ 40%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320407 Innate immunity @ 20%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 65%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 35%
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