Professor University of the Philippines Manila Manila, National Capital Region, Philippines
Abstract: Tuberculosis, a highly infectious disease affecting globally is caused by Mycobacterium tuberculosis (MTb), a microbe characterized by resilient cell wall with intricate strategies for immune evasion. Bacille Calmette-Guerin (BCG) the most common anti-TB vaccine has demonstrated variable efficacy from 0 to 80%, decreasing over time from 10-20 years and uses live-attenuated antigen, that pose risk to immunocompromised patients. Bronchiectasis, an MTb complication that results to lung fibrosis and impaired respiratory performance caused deteriorating quality of life to patients In this study, a combination of in-silico and in-vitro approach to design and evaluate preclinically a cell therapy composite for MTb bronchiectasis, using immunoinformatic tools in mapping cytotoxic (CTL) and helper (HTL) T-cell epitopes, antigenic peptides were designed from the sequences of Mtb secretory proteins as potential multi-epitope vaccine. Identification of highly conserved sequences of the target protein was done using the Protein Variability Server (PVS). Epitopes predicted to be allergenic, cross-reactive, and toxic were discarded. The population coverages of CD4+ and CD8+ epitopes were estimated for the Southeast Asia region. The candidate epitopes were evaluated for binding thru molecular docking to their corresponding MHC molecules. In vitro and in vivo assessment of the peptides, matured DC and primed mesenchymal stem cells were utilized to evaluate efficacy of the cell therapy composite. Five secretory proteins associated with MTb pathogenesis and virulence were identified. The epitopes have IC50 scores ≤500 nM and are considered to be good binders. The CD4+ and CD8+ epitopes were not found to have similar human proteome and allergen hits in the databases. The peptides bind promiscuously with various HLA alleles while the estimated population coverage of other candidate epitopes identified reached up to 94% in Southeast Asia. In vitro evaluation showed favorable uptake responses from dendritic cells derived from healthy volunteers and significant interferon-gamma levels. Mesenchymal stem cell priming with bronchiectasis lung extracts as well as in vivo fibrotic mouse challenge results showed promising results. The cell therapy composite affords a potential for the management of Mtb bronchiectasis
Funding Source: DOST-PCHRD and University of the Philippines-Manila
