Vorinostat (SAHA) promotes innate and adaptive immunity to Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis ( Mtb) is increasingly resistant to antibiotics. Therefore, it is paramount to develop host-directed therapies (HDT) aimed at activating the host immune response to promote bacterial killing. Mtb is phagocytosed by alveolar macrophages (AM) and infiltrating monocyte-derived macrophages (MDM) in the lung which upregulate effector functions by epigenetic modifications to enable transcription. Suberanilohydroxamic acid (Vorinostat; SAHA), an FDA-approved histone deacetylase inhibitor, can modulate these changes and support immunity.

Human AM were purified from bronchoalveolar lavage. MDM were obtained from blood of healthy donors and patients with TB. Macrophages were infected with Mtb in the presence of SAHA. After 24 hours, cytokine secretion was quantified. Macrophages were washed and co-cultured with CFSE-labelled PBMC from IGRA positive donors. T-cell responses were analysed by flow cytometry and ELISA. Macrophages were lysed and colony forming units were enumerated.

SAHA increased IL-1β and decreased IL-10 in human AM and MDM infected with Mtb. Proliferating T-helper cells co-cultured with Mtb-infected, SAHA-treated AM or MDM exhibited enhanced IFN-γ and GMCSF co-production. SAHA promotes proinflammatory immune responses to Mtb infection in human AM and MDM, with a subsequent effect on T cell responses. SAHA may therefore be beneficial as a host-directed therapy or vaccine adjunct against TB.