Identification of CTL Epitopes on Efflux Pumps of the ATP-Binding Cassette and the Major Facilitator Superfamily of Mycobacterium tuberculosis

Abstract

Tuberculosis is the world’s most deadly infectious disease, with 10 million people falling ill and 1.5 million people dying from the disease every year. With the increasing number of drug-resistant Mycobacterium tuberculosis (MTB) strains and prevalence of coinfection of MTB with human immunodeficiency virus, many challenges remain in the prevention and treatment of tuberculosis. Therefore, the development of safe and effective tuberculosis vaccines is an urgent issue. In this study, we identified cytotoxic T lymphocyte epitopes on drug resistance-associated membrane protein efflux pumps of MTB, the ATP-binding cassette and the major facilitator superfamilies. First, three online software were used to predict HLA-A2-restricted epitopes. Then, the candidate epitopes were confirmed with the T2A2 cell binding affinity and peptide/MHC (pMHC) complex stability assays and in vitro immune activity experiments. Two drug-resistant T lymphocyte epitopes, designated Rv1218c-p24 and Rv2477c-p182, were selected, and their immunogenic activities studied in vivo in genetically engineered mice. The immune activities of these two epitopes were improved with the help of complete Freund’s adjuvant (CFA). The epitopes identified here provide a foundation for the diagnosis and treatment of patients infected with drug resistant and the future development of a multiepitope vaccine.

Structure-Aware Mycobacterium tuberculosis Functional Annotation Uncloaks Resistance, Metabolic, and Virulence Genes

“…These putative transporters might contribute to intrinsic efflux-mediated drug resistance and tolerance in M. tuberculosis ( 11 ). Other putative novel transport proteins may serve important homeostatic roles in the dynamic host microenvironment ( 61 , 62 ) and could make attractive drug ( 63 ) and vaccine ( 64 ) targets.…”

Pangenome and genomic signatures linked to the dominance of the lineage-4 of Mycobacterium tuberculosis isolated from extrapulmonary tuberculosis patients in western Ethiopia

“…Moreover, the functions of PE_PGRS6 / Rv0532 [ 72 ], Rv2994 [ 73 ], arsB1 / Rv2685 [ 74 ], TB27 . 3 / Rv0577 [ 75 ], and PE_PGRS42 [ 76 ] are not fully understood, but previous studies have identified them as promising antigens/epitopes for a TB vaccine.…”

CTLs: Killers of intracellular bacteria

“…Drug resistance induced by intracellular bacteria becomes a problem in the treatment of their infections. Developing safe and effective vaccines to address the increasing challenges of these drug-resistant strains is an urgent issue ( Lin et al., 2021 ). CTLs play an important role in the clearance of intracellular bacteria; thus, the development of CTLs-oriented vaccines may be a feasible and promising therapeutic approach to control intracellular bacterial infections ( Reinherz et al., 2014 ).…”