Gasdermin D associates with cellular regions bordering NETosis enrichment in human TB granulomas

Abstract Programmed cell death is an important part of maintaining homeostasis. However, other forms of cell death can also be the cause of tissue damage and be manipulated during infection to benefit the invading pathogen. A granuloma is a pathological hallmark of tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb). NETosis is a cell death mediated by neutrophils and has been associated with granulomas in humans and mice. Gasdermin D (GSDMD) has recently been reported to be vital driver of NETosis. Using immunohistochemistry, ELISA and in-vitro infection models, we assessed the presence and abundance of GSDMD in lungs of TB patients and whether targeting this pathway reduced NETosis. We show that GSDMD is present within cellular regions surrounding necrotic caseum and that GSDMD is detectable in the plasma of individuals with TB. In addition, we show that plasma GSDMD correlated with IL-1b in individuals with LTBI or TB. Targeting GSDMD with a pharmaceutical inhibitor significantly reduced NETosis induced by Mtb H37Rv infection. Here, we show that GSDMD is associated with TB pathology and may be explored as a target for HDT aimed to reduce lung tissue damage mediated by NETosis.