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

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 establishes BLOS1 as a novel immune defense factor whose activity is hijacked by diverse pathogens.

Trefoil Factor Family (TFF) Peptides and their Different Roles in the Mucosal Innate Immune Defense and More: An Update

: Mucous epithelia are protected by complex mucus barrier layers, which are part of the innate immune defense. Trefoil factor family peptides TFF1, TFF2, and TFF3 have lectin activities and are predominantly co-secreted together with mucins from these epithelia. TFF1 and TFF2 are mainly expressed in the gastric mucosa; whereas TFF3 is rather widely secreted from most mucous epithelia and their glands. TFF1 and TFF3 consist of a single TFF domain and an additional free 7th cysteine residue; whereas TFF2 contains two TFF domains. Systematic analyses of the molecular forms of TFFs gave new insights into their diverse molecular functions. TFF1 mainly exists as a monomer with an unusual free thiol group and only minor amounts form a disulfide linked homodimer as well as heterodimers with gastrokine-2 and IgG-Fc-binding protein (FCGBP). TFF3 mainly forms a heterodimer with FCGBP in vivo, but binds also Deleted in Malignant Brain Tumors/gp340 (DMBT1gp340) in vitro. In contrast, TFF2 binds as a lectin to a conserved O-linked carbohydrate moiety of the mucin MUC6. Both FCGBP and DMBT1gp340 are secreted from most mucous epithelia and their glands and are involved in mucosal innate immunity. Thus, a new picture emerged pointing to functions of TFF3-FCGBP (and TFF1-FCGBP) for mucosal innate immune defense, e.g. supporting the clearing of microorganisms. Such a function could be well be supported by DMBT1gp340. In contrast, the TFF2/MUC6 complex probably stabilizes physically the inner adherent gastric mucus layer. Furthermore, there are indications that TFF3-FCGBP might play also a role in blood vessels.

The Role of CARD9 Deficiency in Neutrophils

Neutrophils play a critical role in innate immune defense and directly contribute to infectious and autoimmune ailments. Great efforts are underway to better understand the nature of neutrophilic inflammation. Of note, CARD9, a myeloid cell-specific signaling protein that mainly expresses in macrophages and dendritic cells, is also present in neutrophils, emerging as a critical mediator for intercellular communication. CARD9–deficiency neutrophils display an increased susceptibility to fungal infection that primarily localize to the central nervous system, subcutaneous, and skin tissue. Additionally, CARD9–deficiency neutrophils are associated with some autoimmune diseases and even provide protection against a few bacteria. Here, the review summarizes recent preclinical and clinical advances that have provided a novel insight into the pathogenesis of CARD9 deficiency in neutrophils.