Th17/Treg Imbalance in Murine Cystic Fibrosis Is Linked to Indoleamine 2,3-Dioxygenase Deficiency but Corrected by Kynurenines

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Hypoxia Promotes Danger-mediated Inflammation via Receptor for Advanced Glycation End Products in Cystic Fibrosis

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Come sottomettere una proposta progettuale in Horizon Europe. Aspetti amministrativi e finanziari

In questo documento verranno indicati i passaggi, la documentazione e le informazioni necessari a sottomettere proposte progettuali in risposta alle Call del Programma Horizon Europe nell’ambito della Programmazione 2021-2027 della Commissione Europea. Queste linee guida sono state sviluppate per venire incontro alle richieste d’informazione dei ricercatori, come ausilio per la presentazione di proposte progettuali. Esse sono state elaborate a partire dall’AGA–Annotated Model Grant Agreement (versione del 31/11/2021), dalla Standard Application Form (versione del 21/01/2022), dalla normativa di riferimento nazionale, dalle direttive del Consiglio Nazionale delle Ricerche, dalla partecipazione a giornate informative europee e dal confronto con il National Contact Point di APRE (Agenzia per la Promozione della Ricerca Europea)

Come Parti diverse dai Beneficiari possono partecipare a Horizon Europe. Altre Parti-Organizzazioni che partecipano a progetti di Horizon Europe senza firmare il Grant Agreement

Al fine di armonizzare la terminologia e le regole con altri programmi dell’Unione Europea (UE), la Commissione Europea ha sistematizzato e cambiato la nomenclatura utilizzata per la definizione dei ruoli di altre parti diverse dai beneficiari, coinvolte nei progetti di Horizon Europe. Tali parti sono: Affiliated Entities, Associated Partners, Third Parties giving in-kind contributions, Subcontractors, Recipients of financial support to third Parties. A differenza dei Beneficiari, esse non firmano il Grant Agreement con la Commissione Europea, ma il loro coinvolgimento e contributo nel progetto deve essere previsto e dichiarato fin dalla preparazione della proposta progettuale. Queste linee guida sono state sviluppate per venire incontro alle richieste d’informazione dei ricercatori, come ausilio per la presentazione di proposte progettuali in Horizon Europe. Esse sono state elaborate a partire dall’AGA–Annotated Model Grant Agreement (versione del 23/07/2021), dalla Standard Application Form (versione del 26/05/2021), dalla normativa di riferimento nazionale, dalle direttive del Consiglio Nazionale delle Ricerche, dalla partecipazione a giornate informative europee e dal confronto con il National Contact Point di APRE (Agenzia per la Promozione della Ricerca Europea)

Il Timesheet integrato ISPC per il monitoraggio e la rendicontazione del tempo produttivo del personale impiegato su progetti di ricerca

Il rapporto tecnico descrive la struttura, le funzionalità e le modalità di utilizzo del Timesheet integrato sviluppato e messo a disposizione del personale dell’Istituto di Scienze del Patrimonio Culturale del Consiglio Nazionale delle Ricerche (Timesheet integrato ISPC). Il Timesheet integrato ISPC è stato sviluppato per supportare il personale dell’Istituto nella gestione del proprio tempo produttivo ed è stato elaborato tenendo conto dell’esperienza acquisita, di quanto previsto dall’AGA–Annotated Model Grant Agreement (versione del 30/11/2021), dalla normativa di riferimento nazionale, dalle direttive del Consiglio Nazionale delle Ricerche, dalla partecipazione a giornate informative europee e dal confronto con il National Contact Point di APRE (Agenzia per la Promozione della Ricerca Europea)

CD4+ T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease

Aspergillus fumigatus is a model fungal pathogen and a common cause of infection in individuals with the primary immunodeficiency chronic granulomatous disease (CGD). Although primarily considered a deficiency of innate immunity, CGD is also linked to dysfunctional T cell reactivity. Both CD4+ and CD8+ T cells mediate vaccine-induced protection from experimental aspergillosis, but the molecular mechanisms leading to the generation of protective immunity and whether these mechanisms are dysregulated in individuals with CGD have not been determined. Here, we show that activation of either T cell subset in a mouse model of CGD is contingent upon the nature of the fungal vaccine, the involvement of distinct innate receptor signaling pathways, and the mode of antigen routing and presentation in DCs. Aspergillus conidia activated CD8+ T cells upon sorting to the Rab14+ endosomal compartment required for alternative MHC class I presentation. Cross-priming of CD8+ T cells failed to occur in mice with CGD due to defective DC endosomal alkalinization and autophagy. However, long-lasting antifungal protection and disease control were successfully achieved upon vaccination with purified fungal antigens that activated CD4+ T cells through the endosome/lysosome pathway. Our study thus indicates that distinct intracellular pathways are exploited for the priming of CD4+ and CD8+ T cells to A. fumigatus and suggests that CD4+ T cell vaccination may be able to overcome defective antifungal CD8+ T cell memory in individuals with CGD

IL-22 and IDO1 Affect Immunity and Tolerance to Murine and Human Vaginal Candidiasis

<div><p>The ability to tolerate <i>Candida albicans</i>, a human commensal of the gastrointestinal tract and vagina, implicates that host defense mechanisms of resistance and tolerance cooperate to limit fungal burden and inflammation at the different body sites. We evaluated resistance and tolerance to the fungus in experimental and human vulvovaginal candidiasis (VVC) as well as in recurrent VVC (RVVC). Resistance and tolerance mechanisms were both activated in murine VVC, involving IL-22 and IL-10-producing regulatory T cells, respectively, with a major contribution by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 was responsible for the production of tolerogenic kynurenines, such that replacement therapy with kynurenines restored immunoprotection to VVC. In humans, two functional genetic variants in <i>IL22</i> and <i>IDO1</i> genes were found to be associated with heightened resistance to RVVC, and they correlated with increased local expression of IL-22, IDO1 and kynurenines. Thus, IL-22 and IDO1 are crucial in balancing resistance with tolerance to <i>Candida</i>, their deficiencies are risk factors for RVVC, and targeting tolerance via therapeutic kynurenines may benefit patients with RVVC.</p></div

Vaginal candidiasis in IL-17A- or IL-17F-deficient mice.

<p>(<b>A</b>) Vaginal fungal burden in C57BL/6, IL-17A- or IL-17F-deficient mice (<i>n</i> = 6) intravaginally inoculated with 5×10⁶<i>C. albicans</i> blastospores. CFU were quantified by culturing serial dilutions of vaginal fluid (VF) from each mouse at different days post-infection (dpi) and expressed as Log₁₀ CFU/100 µl VF ± s.e.m. Pooled data from 3 experiments. (<b>B</b>) Histological analysis of periodic acid-Schiff-stained vaginal sections and inflammatory cell recruitment in vaginal fluids (May–Grünwald Giemsa staining in the insets) at 3 dpi. Representative images (out of 3 experiments) of histology sections and vaginal fluids were acquired with a 40× and 100× objective respectively. Scale bars, 100 µm. (<b>C</b>) Polymorphonuclear cells (PMNs) quantification in the vaginal fluids at different dpi. PMNs were identified by nuclear morphology and enumerated per field at ×100 magnification. Each point represents an individual mouse, and horizontal bar indicates the means. (<b>D</b>) Cytokine levels (pg/mg, cytokine/total proteins for each sample) in the vaginal fluids of naïve or infected (3 dpi) mice. Data are pooled or representative (histology) from 3 independent experiments. * <i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001, knockout <i>vs.</i> wild-type mice. N.S., not significant.</p

Vaginal candidiasis in IL-22- or IDO1-deficient mice.

<p>C57BL/6, IL-22- or IDO1-deficient mice (<i>n</i> = 6) were intravaginally inoculated with 5×10⁶<i>C. albicans</i> blastoconidia. (<b>A</b>) Periodic acid-Schiff-staining of vaginal sections and inflammatory cell recruitment in vaginal fluids (May–Grünwald Giemsa staining in the insets) at different days post-infection (dpi). Representative images of histology sections and vaginal fluids were acquired with a 40× and 100× objective respectively. Scale bars, 100 µm. (<b>B</b>) Polymorphonuclear cells (PMNs) quantification in the vaginal fluids. PMNs were identified by nuclear morphology and enumerated per field at ×100 magnification. Each point represents an individual mouse, and horizontal bar indicates the means. **<i>P</i><0.01 and ***<i>P</i><0.001, IDO1- or IL-22-deficient <i>vs.</i> wild-type mice at the indicated days. (<b>C</b>) <i>S100a8</i> and <i>S100a9</i> mRNA expression in vaginal tissue by real-time RT-PCR. The mRNA-normalized data were expressed as relative mRNA in IDO1- or IL-22-deficient <i>vs.</i> wild-type mice. *<i>P</i><0.05 and **<i>P</i><0.01, IDO1- or IL-22-deficient <i>vs.</i> wild-type mice at the indicated days. (<b>D</b>) Levels of calprotectin during vaginal candidiasis. **<i>P</i><0.01, IDO1- or IL-22-deficient <i>vs.</i> wild-type mice. (<b>E</b>) Vaginal fungal burden in mice at different dpi. CFU were quantified by culturing serial dilutions of vaginal fluids (VF) from each mouse and expressed as Log₁₀ CFU/100 µl VF ± s.e.m. *<i>P</i><0.05, IDO1- or IL-22-deficient <i>vs.</i> wild-type mice at the days indicated. Data are pooled or representative (histology) from four independent experiments. (<b>F</b>) Cytokine levels (pg/mg, cytokine/total proteins for each sample) in the vaginal fluids (at 3 dpi for IL-17F and IL-17A). Results represent mean cytokine levels (± s.e.m.) from samples pooled from three experiments (<i>n</i> = 4–6 total samples per group). *<i>P</i><0.05, IDO1- or IL-22-deficient <i>vs.</i> wild-type mice. (<b>G</b>) Levels of IL-22 (pg/mg, cytokine/total proteins) and (<b>H</b>) fungal growth (at 3 dpi) in mice treated with 300 µg of mAb neutralizing IL-22 or isotype control mAb (None) given intraperitoneally the day of and 1 day after the primary infection. (<b>I</b>) Fungal growth (at 3 dpi) in mice treated intravaginally with rIL-22 or PBS (None) the day of and 1 and 2 days after the infection. Pooled data from two experiments (<i>n</i> = 6). *<i>P</i><0.05 and ***<i>P</i><0.001, treated <i>vs.</i> untreated mice. N.S., not significant.</p