CWHM-12, an Antagonist of Integrin-Mediated Transforming Growth Factor-Beta Activation Confers Protection During Early Mycobacterium tuberculosis Infection in Mice.

Abstract

Tuberculosis (TB) caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb) is one of the most lethal infectious diseases in the world. Presently, Bacillus Calmette-Guerin, the vaccine approved for use against TB, does not offer complete protection against the disease, which necessitates the development of new therapeutics to treat this infection. Overexpression of transforming growth factor beta (TGF-β) is associated with pulmonary profibrotic changes. The inactive TGF-β secreted is activated through its cleavage and release by αv integrins. Integrin-mediated regulation of TGF-β is considered as a master switch in the profibrotic process and a potential therapeutic target. Thus, in this study, we sought to determine if treatment with a broad range antagonist of integrins, CWHM-12, has the potency to inhibit pulmonary fibrosis and enhance Mtb control in a highly susceptible mouse model of Mtb infection, namely the C3Heb/FeJ (FeJ). CWHM-12 treatment at the early stages of Mtb infection was efficacious in reducing disease severity and inflammation associated with decreased iNOS, MIP-2, and IL-10 production without degradation of collagen. This suggests a potential for CWHM-12 targeting of TGF-β to be explored as an adjunct therapeutic for early Mtb infection.