Host-Directed Therapeutic Strategies for Tuberculosis

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of morbidity and mortality in humans worldwide. Currently, the standard treatment for TB involves multiple antibiotics administered for at least 6 months. Although multiple antibiotics therapy is necessary to prevent the development of drug resistance, the prolonged duration of treatment, combined with toxicity of drugs, contributes to patient non-compliance that can leads to the development of drug-resistant Mtb (MDR and XDR) strains. The existence of comorbid conditions, including HIV infection, not only complicates TB treatment but also elevates the mortality rate of patients. These facts underscore the need for the development of new and/or improved TB treatment strategies. Host-directed therapy (HDT) is a new and emerging concept in the treatment of TB, where host response is modulated by treatment with small molecules, with or without adjunct antibiotics, to achieve better control of TB. Unlike antibiotics, HDT drugs act by directly modulating host cell functions; therefore, development of drug resistance by infecting Mtb is avoided. Thus, HDT is a promising treatment strategy for the management of MDR- and XDR-TB cases as well as for patients with existing chronic, comorbid conditions such as HIV infection or diabetes. Functionally, HDT drugs fine-tune the antimicrobial activities of host immune cells and limit inflammation and tissue damage associated with TB. However, current knowledge and clinical evidence is insufficient to implement HDT molecules as a stand-alone, without adjunct antibiotics, therapeutic modality to treat any form of TB in humans. In this review, we discuss the recent findings on small molecule HDT agents that target autophagy, vitamin D pathway, and anti-inflammatory response as adjunctive agents along with standard antibiotics for TB therapy. Data from recent publications show that this approach has the potential to improve clinical outcome and can help to reduce treatment duration. Thus, HDT can contribute to global TB control programs by potentially increasing the efficiency of anti-TB treatment.

Keywords: adjunct therapy-tuberculosis; anti-tuberculosis drugs; autophagy; host–pathogen interactions; infant; tuberculosis; vitamin D.

Figure 1

Potential host therapeutic targets against Mycobacterium tuberculosis. (A) Host-directed therapeutic (HDT) drugs change the integrity of granuloma and enhance drug accessibility. (B) Some HDT agents upregulate production of antimicrobial peptides, reactive oxygen and induce autophagy in infected cells. (C) HDT drugs suppress proinflammatory responses, which decrease inflammation and tissue damage during active stage of the disease. (D) HDT agents regulate cell-mediated immune responses, including antigen-specific T cell responses. (E) Monoclonal antibody administration IS other emerging HDT concept for TB treatment. VEGF, vascular endothelial growth factor; PBA, phenylbutyrate; CAMP, cathelicidin antimicrobial peptide; ATG5, autophagy-related protein 5; BECN1, beclin-1; AMPK, AMP-activated protein kinase; COX1/2, cyclooxygenase-1/2; GR, glucocorticoid receptor; PDE, phosphodiesterases; MMPs, matrix metalloproteinases; KLF, Kruppel-like factor; PD-1, programmed cell death 1 receptor; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; LAG3, lymphocyte activation gene 3; LAM, Lipoarabinomannan.