Anti-Cancer Drug HMBA Acts as an Adjuvant during Intracellular Bacterial Infections by Inducing Type I IFN through STING

Abstract

The anti-proliferative agent hexamethylene bisacetamide (HMBA) belongs to a class of hybrid bipolar compounds developed more than 30 y ago for their ability to induce terminal differentiation of transformed cells. Recently, HMBA has also been shown to trigger HIV transcription from latently infected cells, via a CDK9/HMBA inducible protein-1 dependent process. However, the effect of HMBA on the immune response has not been explored. We observed that pretreatment of human peripheral blood mononuclear cells with HMBA led to a markedly increased production of IL-12 and IFN-γ, but not of TNF-α, IL-6, and IL-8 upon subsequent infection with and HMBA treatment was also associated with better intracellular bacterial control. HMBA significantly improved IL-12p70 production from CD14 monocytes during infection partly via the induction of type I IFN in these cells, which primed an increased transcription of the p35 subunit of IL-12p70 during infection. HMBA also increased early type I IFN transcription in human monocytic and epithelial cell lines, but this was surprisingly independent of its previously reported effects on positive transcription elongation factor b and HMBA inducible protein-1. Instead, the effect of HMBA was downstream of a calcium influx, and required the pattern recognition receptor and adaptor STING but not cGAS. Our work therefore links the STING-IRF3 axis to enhanced IL-12 production and intracellular bacterial control in primary monocytes. This raises the possibility that HMBA or related small molecules may be explored as therapeutic adjuvants to improve disease outcomes during intracellular bacterial infections.

cGAS-STING Pathway Performance in the Vulnerable Atherosclerotic Plaque

“…The inhibition of NF-kB and IRF3 cytokine secretion can also be reversed by agents that increase the cytosolic Ca 2+ such as valinomycin and thapsigargin [ 25 ]. TypeIIFN expression, induced by STING activation, is sensitive to intracellular Ca 2+ levels [ 26 ]. Moreover, Ca 2+ signaling is shown to be a prerequisite for activation of STING and IRF3 during HCMV (human cytomegalovirus) invasion [ 27 ].…”

STING, the Endoplasmic Reticulum, and Mitochondria: Is Three a Crowd or a Conversation?

“…For instance, during dsDNA-stimulated STING activation in macrophages, calcium chelators such as BAPTA and mitochondrial calcium export inhibitors (CGP37157 sodium pump inhibitor) both reduce IRF3 and NF-κB activation ( 183 ). W-7, a potent calmodulin inhibitor also reduced STING activation by a pharmacologic STING-stimulating adjuvant ( 184 ). Early sensing of HCMV (human cytomegalovirus) and Sendai virus membrane perturbations and ensuing STING activation is calcium dependent ( 185 ).…”

The treatment of melioidosis: is there a role for repurposed drugs? A proposal and review

“…In the clinical setting, thalidomide is mainly used to treat leprosy [103]. Thalidomide therapy is not without disadvantages; it has had a long and troubled past with regard to its chiral form's teratogenetic affect [104] and is a known contraindication of a drug of interest to this manuscript (anakinra).…”