Diverse pathogens activate the host RIDD pathway to subvert BLOS1-directed immune defense (preprint)

The phagocytosis and destruction of pathogens in lysosomes constitute central elements of innate immune defense. Here, we show that Brucella , the causative agent of brucellosis, the most prevalent bacterial zoonosis globally, subverts this immune defense pathway by activating regulated IRE1α-dependent decay (RIDD) of mRNAs encoding BLOS1, a protein that promotes endosome-lysosome fusion. RIDD-deficient cells and mice harboring a RIDD-incompetent variant of IRE1α were resistant to infection. Non-functional Blos1 struggled to assemble the BLOC-1-related complex (BORC), resulting in differential recruitment of BORC-related lysosome trafficking components, perinuclear trafficking of Brucella -containing vacuoles (BCVs), and enhanced susceptibility to infection. The RIDD-resistant Blos1 variant maintains the integrity of BORC and a higher-level association of BORC-related components that promote centrifugal lysosome trafficking, resulting in enhanced BCV peripheral trafficking and lysosomal-destruction, and resistance to infection. These findings demonstrate that host RIDD activity on BLOS1 regulates Brucella intracellular parasitism by disrupting BORC-directed lysosomal trafficking. Notably, coronavirus MHV also subverted the RIDD-BLOS1 axis to promote intracellular replication. Our work therefore establishes BLOS1 as a novel immune defense factor whose activity is hijacked by diverse pathogens.

COVID-Datathon: Biomarker identification for COVID-19 severity based on BALF scRNA-seq data (preprint)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emergence began in late 2019 and has since spread rapidly worldwide. The characteristics of respiratory immune response to this emerging virus is not clear. Recently, Single-cell RNA sequencing (scRNA-seq) transcriptome profiling of Bronchoalveolar lavage fluid (BALF) cells has been done to elucidate the potential mechanisms underlying in COVID-19. With the aim of better utilizing this atlas of BALF cells in response to the virus, here we propose a bioinformatics pipeline to identify candidate biomarkers of COVID-19 severity, which may help characterize BALF cells to have better mechanistic understanding of SARS-CoV-2 infection. The proposed pipeline is implemented in R and is available at https://github.com/namini94/scBALF_Hackathon.