alpha-Galactosylceramide as a Therapeutic Agent for Pulmonary Mycobacterium tuberculosis Infection

Rationale: Invariant natural killer T (iNKT) cells are a unique subset of T cells that recognize lipid antigens presented by CD1d molecules. Recent studies have shown that iNKT cells can protect mice against Mycobacterium tuberculosis (Mtb) infection. We sought to determine whether pharmacological activation of iNKT cells by alpha-galactosylceramide (alpha-GalCer) could be used to treat tuberculosis (TB). Objectives: We hypothesized that alpha-GalCer, either alone or in combination with isoniazid, could be used to treat pulmonary TB. Methods: The ability of alpha-GalCer activated iNKT cells to suppress Mtb replication was evaluated using an in vitro coculture system. To test its potency in vivo, mice infected with virulent Mtb were treated with alpha-GalCer alone or in combination with isoniazid. Measurements and Main Results: Quantitative colony-forming unit counts were compared for both experimental systems. Our results show that alpha-GalCer plus isoniazid controls bacterial growth better than alpha-GalCer or INH alone, and single or multiple alpha-GalCer administrations prolong the survival of the mice infected via the aerosol route. Conclusions: Our results demonstrate that alpha-GalCer administration can improve the outcome of Mtb infection, even when transmitted by the aerosol route. However, a combination of isoniazid and alpha-GalCer treatment has a synergistic effect on infection control. We conclude that more efficient treatment of TB will be achieved through a combination of classic chemotherapy and modulation of the host immune response.