Matrix Metalloproteinase 13a: An early host protective factor during mycobacterial infection

Abstract

Tuberculosis (TB) is a bacterial disease caused by Mycobacterium tuberculosis (Mtb). Despite the availability of antibiotics, it remains an insidious problem worldwide, and the rise of drug resistant strains has threatened the ability to treat and eradicate the disease. We are looking to target host pathways as adjunct therapies to shorten drug treatment and improve survival. Our lab studies host pathways involved in immunity and pathogenesis of TB using the zebrafish-M. marinum (Mm) model of infection. Matrix metalloproteinases (MMPs), a class of proteases that are known to participate in inflammation and immunity, are upregulated during Mm and Mtb infection. Since MMPs are correlated to severity of infection, we wanted to what roles they play during tuberculosis. We have previously published that mmp9 is subverted by mycobacteria to enhance granuloma formation and bacterial spread. Here, we have found that mmp13a is induced in response to infection with bacteria that express the ESX-1 virulence factor, similar to mmp9. However, unlike mmp9, mmp13a knockdown causes hypersusceptibility, indicating that it is a host-protective factor. Indeed, mmp13a expression enhances bactericidal activity by macrophages. The knockdown phenotype for mmp13a is similar to that of tnf signaling deficiency. We show that MMP13a can cleave TNF in vitro, and that it may be an important TNF sheddase during mycobacterial infection. MMP13a may act by regulating the amount of bio-active TNF that is available during infection, and is a viable target for inhibition to treat hyper-inflammatory TB patients.