Guanylate Binding Proteins (GBPs) are some of the most abundantly interferon-induced proteins and have become a mainstay of recent tuberculosis (TB) whole blood transcriptional signature. Yet despite their presence as one of the strongest markers for TB disease risk, their role in TB pathogenesis remains elusive. Through mediating canonical and noncanonical inflammasome activation via caspase-1, -4 and -5, GBPs have recently been shown to induce Gasdermin D-mediated pyroptotic pro-inflammatory cell death. Noncanonical inflammasome activation of Gasdermin D, has also recently been linked to neutrophil extracellular trap formation (NETosis). Investigating whole blood signatures of TB patients, we found circulating monocytes and neutrophils were the predominant source of the GBP expression, and GBP1 expression highly correlated with serum LDH, a marker of cell death, in TB patients. We therefore hypothesized that underlying interferon activation, such as in individuals infected with HIV-1 who have increased TB risk, would lead to enhanced GBP production following Mycobacterium tuberculosis (Mtb) infection and subsequent Gasdermin D-mediated pyroptosis and NETosis. We have systematically characterised GBP1-7 production by human monocyte derived macrophages (MDM) and neutrophils, in response to type I, and II interferons, as well as HIV-1 and/or various clinical strains of Mtb, identifying cell specific patterns of regulation and internal localisation. Using CRISPR and siRNA GBP targeting and various inflammasome-related small molecule inhibitors we have found that heterogeneity in interferon-induced GBP production orchestrates a varied cascade of intracellular signalling which, under certain circumstances, elicits a cytopathic and potentially tissue destructive phenotype, positioning GBPs and their downstream effectors as ideal targets for host-directed prevention of TB pathogenesis.