A novel therapeutic strategy of lipidated promiscuous peptide against Mycobacterium tuberculosis by eliciting Th1 and Th17 immunity of host

Abstract

Regardless of the fact that potent drug-regimen is currently available, tuberculosis continues to kill 1.5 million people annually. Tuberculosis patients are not only inflicted by the trauma of disease but they also suffer from the harmful side-effects, immune suppression and drug resistance instigated by prolonged therapy. It is an exigency to introduce radical changes in the existing drug-regime and discover safer and better therapeutic measures. Hence, we designed a novel therapeutic strategy by reinforcing the efficacy of drugs to kill Mtb by concurrently boosting host immunity by L91. L91 is chimera of promiscuous epitope of Acr1 antigen of Mtb and TLR-2 agonist Pam2Cys. The adjunct therapy using drugs and L91 (D-L91) significantly declined the bacterial load in Mtb infected animals. The mechanism involved was through enhancement of IFN-γ+TNF-α+ polyfunctional Th1 cells and IL-17A+IFN-γ+ Th17 cells, enduring memory CD4 T cells and downregulation of PD-1. The down-regulation of PD-1 prevents CD4 T cells from undergoing exhaustion and improves their function against Mtb. Importantly, the immune response observed in animals could be replicated using T cells of tuberculosis patients on drug therapy. In future, D-L91 therapy can invigorate drugs potency to treat tuberculosis patients and reduce the dose and duration of drug-regime.

The crucial roles of Th17-related cytokines/signal pathways in M. tuberculosis infection

“…The decrease in IL-17A production, correlated with the exhaustion of T cells, may be due to the overexposure to Mtb antigens and hyperexpression of the exhausted marker programmed death-1 (PD-1). 12,13 Increased PD-1 expression appears to be relevant to the depressed production of IL-17A in TB because anti-PD-1 antibodies can enhance IL-17A production by Mtbstimulated CD4+ T cells of TB patients. 14 Anti-TB therapy can decrease PD-1 expression and increase IL-17A production by CD4+ T cells.…”

PD-1 modulating Mycobacterium tuberculosis-specific polarized effector memory T cells response in tuberculosis pleurisy

“…Although up‐regulated PD‐1 in active TB infection impedes T cell responses, blocking this PD1/PD‐Ls pathway can functionally rescue these T cells. Abs blocking PD‐1/PD‐Ls is able to enhance Ag‐specific IFN‐γ responses in cells from patients with TBP in vitro . We reported that PD‐1 was selectively up‐regulated by the activated CD4 + and CD8 + T cells.…”

“…Abs blocking PD-1/PD-Ls is able to enhance Ag-specific IFN-responses in cells from patients with TBP in vitro. 17,26,27 We reported that PD-1 was selectively upregulated by the activated CD4 + and CD8 + T cells. Therefore, we 28,31 When transferred into uninfected animals, these cells persist, mount a robust recall response, and provide superior protection to M.tb re-challenge when compared to terminally differentiated Th1 cells that reside preferentially in the lung-associated vasculature.…”

The self‐curing phenomenon of schistosome infection in rhesus macaques: insight from in vitro studies

“…These findings suggest that multifunctional cellular immune responses might be involved in the self‐cure process. Several studies have demonstrated the protective roles of host polyfunctional cells against numerous infectious organisms . For example, the frequency of Plasmodium falciparium ‐specific polyfunctional T cells has been associated with protection in humans .…”

“…Several studies have demonstrated the protective roles of host polyfunctional cells against numerous infectious organisms. [53][54][55][56][57] For example, the frequency of Plasmodium falciparium-specific polyfunctional T cells has been associated with protection in humans. 58 Similarly, the importance of durable polyfunctional viral antigen-specific protective T cell responses has also been demonstrated in HIV-infected rhesus macaques.…”