Siglec15 and Siglec14 are new immune check point receptors during Mycobacterium tuberculosis infection of human macrophages 2259532

Abstract Introduction Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB) killing a million people each year. Mtb persists in macrophages and tissues from where reactivation of TB can occur. We found that Mtb upregulated several Siglec receptors in human macrophages (MDMs) and we hypothesized that they are immune check point receptors (ICPRs) Methods MDMs were infected with Mtb, and treated with specific MABs or IgG isotype and Mtb survival was measured along with cellular oxide responses and transcriptional responses using RNAseq post antibody treatment. Results 1) Blockade using specific MABs enhanced the ability of MDMs to kil intracellular Mtb; blockade of Siglec15 and Sigec14 were most potent followed by Siglec1,7,9 and 10. 2) MABs induced reactive oxygen species (ROS) in MDMs and their blockade enhanced the growth of Mtb suggesting that Siglec15 and Sigec14 regulate ROS response in MDMs. 3) Transcriptome analysis was done using KEGG, Gene Ontology and Reactome work flow. Unlike others, MAB-Siglec14/MAB-Siglec15 signal through DAP12 and enhanced gene expression of multiple modules of innate immunity in MDMs including cytokine-cytokine receptor, chemokines, TNF, TLR, CLR, NF-kB and JAK-STAT pathways. 4) MABs to Siglec1,7,9 and 10 also upregulated similar modules and in addition, genes of the IFN responsiveness. Conclusion Siglecs are novel ICPRs and targets for host directed therapy of TB Funding Source AI-161015 NIAID, NIH. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)