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.

Spanish Asthma Management Guidelines (GEMA) v.5.1. Highlights and Controversies

In this fifth phase of development, the contents of the Spanish Asthma Management Guidelines (GEMA), which include versions 5.0 and 5.1, have undergone a thorough review. The aim here is to set the main changes in context. These could be summarized as follows: DIAGNOSIS: new FENO cut-off and severity classification based on treatment needed to maintain control;INTERMITTENT ASTHMA: a more restrictive concept and treatment extended to include a glucocorticoid/adrenergic combination as needed;MILD ASTHMA: glucocorticoid/adrenergic therapy as needed as an alternative in case of low therapeutic adherence to conventional fixed-dose steroids;SEVERE ASTHMA: readjustment of phenotypes, incorporation of triple therapy in a single inhaler, and criteria for selection of a biologic in severe uncontrolled asthma;OTHERS: specific scoring in childhood asthma, incorporation of certain organizational aspects (care circuits, asthma units, telemedicine), new sections on COVID-19 and nasal polyposis. Resumen La quinta fase de la Guía Española para el Manejo del Asma (GEMA) que incluye las versiones 5.0 y 5.1, ha efectuado una profunda revisión de su contenido. El presente texto tiene como objetivo contextualizar los principales cambios. Estos se podrían resumir en: DIAGNÓSTICO: nuevo punto de corte de FENO y clasificación de gravedad basada en el tratamiento necesario para mantener el control;ASMA INTERMITENTE: concepto más restrictivo y tratamiento ampliado a combinación de glucocorticoide/adrenérgico a demanda;ASMA LEVE: tratamiento con glucocorticoide/adrenérgico a demanda como alternativa si baja adhesión terapéutica a esteroide fijo clásico;ASMA GRAVE: reajuste de los fenotipos, incorporación de la triple terapia en un solo inhalador y criterios para la selección del fármaco biológico en asma grave no controlada;OTROS: puntualizaciones concretas en asma infantil, incorporación de determinados aspectos organizativos (flujos entre niveles asistenciales, unidades de asma, telemedicina), nuevas secciones de COVID-19 y de poliposis nasal.