Mycobacterium tuberculosis strain with deletions in menT3 and menT4 is attenuated and confers protection in mice and guinea pigs

Tannu Priya Gosain, Saurabh Chugh, Zaigham Abbas Rizvi, Neeraj Kumar Chauhan, Saqib Kidwai, Krishan Gopal Thakur, Amit Awasthi and Ramandeep Singh ()
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Tannu Priya Gosain: NCR Biotech Science Cluster
Saurabh Chugh: NCR Biotech Science Cluster
Zaigham Abbas Rizvi: NCR Biotech Science Cluster
Neeraj Kumar Chauhan: NCR Biotech Science Cluster
Saqib Kidwai: NCR Biotech Science Cluster
Krishan Gopal Thakur: Council of Scientific and Industrial Research-Institute of Microbial Technology (CSIR-IMTECH)
Amit Awasthi: NCR Biotech Science Cluster
Ramandeep Singh: NCR Biotech Science Cluster

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract The genome of Mycobacterium tuberculosis encodes for a large repertoire of toxin-antitoxin systems. In the present study, MenT3 and MenT4 toxins belonging to MenAT subfamily of TA systems have been functionally characterized. We demonstrate that ectopic expression of these toxins inhibits bacterial growth and this is rescued upon co-expression of their cognate antitoxins. Here, we show that simultaneous deletion of menT3 and menT4 results in enhanced susceptibility of M. tuberculosis upon exposure to oxidative stress and attenuated growth in guinea pigs and mice. We observed reduced expression of transcripts encoding for proteins that are essential or required for intracellular growth in mid-log phase cultures of ΔmenT4ΔT3 compared to parental strain. Further, the transcript levels of proteins involved in efficient bacterial clearance were increased in lung tissues of ΔmenT4ΔT3 infected mice relative to parental strain infected mice. We show that immunization of mice and guinea pigs with ΔmenT4ΔT3 confers significant protection against M. tuberculosis infection. Remarkably, immunization of mice with ΔmenT4ΔT3 results in increased antigen-specific TH1 bias and activated memory T cell response. We conclude that MenT3 and MenT4 are important for M. tuberculosis pathogenicity and strains lacking menT3 and menT4 have the potential to be explored further as vaccine candidates.

Date: 2024
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DOI: 10.1038/s41467-024-49246-5

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