ESX-5-targeted export of ESAT-6 in BCG combines enhanced immunogenicity & efficacy against murine tuberculosis with low virulence and reduced persistence

Heijmenberg, Isis, Husain, Aliabbas, Sathkumara Mudiyanse, Harindra D., Muruganandah, Visai, Seifert, Julia, Miranda-Hernandez, Socorro, Kashyap, Rajpal Singh, Field, Matt A., Krishnamoorthy, Gopinath, and Kupz, Andreas (2021) ESX-5-targeted export of ESAT-6 in BCG combines enhanced immunogenicity & efficacy against murine tuberculosis with low virulence and reduced persistence. Vaccine, 39 (50). pp. 7265-7276.

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Abstract

Tuberculosis (TB) is the leading infectious cause of death globally. The only licensed TB vaccine, Bacille Calmette–Guérin (BCG), has low efficacy against TB in adults and is not recommended in people with impaired immunity. The incorporation of the Mycobacterium tuberculosis (Mtb) secretion system ESX-1 into BCG improves immunogenicity and protection against TB in animal models, which is associated with the secretion of the ESX-1-dependent protein ESAT-6. However, the resulting strain, BCG::ESX1Mtb, has been deemed unsafe as a human vaccine, due to prolonged persistence and increased virulence in immunocompromised mice. In this study, we describe a new recombinant BCG strain that uncouples the beneficial aspects of ESAT-6 secretion from the detrimental ESX-1effects on virulence and persistence. The strain was constructed by fusing the ESAT-6-encoding gene esxA to the general secretion signal for the mycobacterial type VII secretion pathway protein PE25. This new strain, BCG::ESAT6-PE25SS, secretes full-length ESAT-6 via the ESX-5 secretion system, which in contrast to ESX-1 is also present in BCG. In vivo testing revealed that ESX-5-targeted ESAT-6 export, induces cytosolic contact, generates ESAT-6-specific T cells and enhances the protective efficacy against TB disease, but is associated with low virulence and reduced persistence in immunocompetent and immunocompromised mice. Additionally, compared to BCG::ESX1Mtb and parental BCG, mucosal administration of BCG::ESAT6-PE25SS is associated with more rapid clearance from the lung. These results warrant further studies to evaluate BCG::ESAT6-PE25SS as a potential live attenuated vaccine candidate for TB.

Item ID: 69828
Item Type: Article (Research - C1)
ISSN: 1873-2518
Keywords: BCG, Tuberculosis, Vaccine, ESAT-6, Recombinant, Live-attenuated
Copyright Information: © 2021 Elsevier Ltd. All rights reserved.
Funders: National Health and Medical Research Council of Australia (NHMRC), Australian Institute of Tropical Health and Medicine (AITHM)
Projects and Grants: NHMRC APP1140709, NHMRC APP1120808
Date Deposited: 01 Nov 2021 23:57
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: 28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280102 Expanding knowledge in the biological sciences @ 65%
20 HEALTH > 2001 Clinical health > 200104 Prevention of human diseases and conditions @ 35%
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