Aspergillus fumigatus Infection in Humans With STAT3-Deficiency Is Associated With Defective Interferon-Gamma and Th17 Responses

François Danion (1, 2) , Vishukumar Aimanianda (2) , Jagadeesh Bayry (3) , Amélie Duréault (1) , Sarah Sze Wah Wong (2) , Marie-Elisabeth Bougnoux (4, 5) , Colas Tcherakian (6) , Marie-Alexandra Alyanakian (7) , Hélène Guegan (8, 9) , Anne Puel (10, 11) , Capucine Picard (12, 13) , Olivier Lortholary (1, 14, 15) , Fanny Lanternier (1, 10) , Jean-Paul Latgé (2)

1 Centre d'infectiologie Necker-Pasteur [CHU Necker]
2 Aspergillus
3 Immuno-pathologie et immuno-intervention thérapeutique = Immunopathology and Therapeutic Immuno-intervention [CRC]
4 Unité de Parasitologie-Mycologie, Service de Microbiologie [Hôpital Necker-Enfants-Malades, Paris]
5 BPF - Biologie et Pathogénicité fongiques - Fungal Biology and Pathogenicity
6 Service de pneumologie [Hôpital Foch]
7 Immunologie biologique [CHU Necker]
8 Irset - Institut de recherche en santé, environnement et travail
9 Service de Parasitologie-Mycologie [Rennes]
10 Rockefeller University [New York]
11 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
12 CEREDIH - Centre de Référence Déficits Immunitaires Héréditaires
13 UPCité - Université Paris Cité
14 CNRMA - Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals
15 Mycologie moléculaire - Molecular Mycology

In humans, loss-of-function mutation in the gene is frequently associated with susceptibility to bacterial as well as fungal infections including aspergillosis, although its pathogenesis remains largely unknown. In the present study, we investigated the immune responses obtained after stimulation with in STAT3-deficient patients. conidial killing efficiencies of both monocytes and neutrophils isolated from whole blood samples of STAT3-deficient patients were not different compared to those of healthy controls. After stimulation with conidia, lower concentrations of adaptive cytokines (IFN-γ, IL-17 and IL-22) were secreted by peripheral blood mononuclear cells from STAT3-deficient patients compared to those from healthy controls. Moreover, the frequency of IFN-γ and IL-17 producing CD4+ T cells was lower in STAT3-deficient patients vs. healthy controls. Among the STAT3-deficient patients, those with aspergillosis showed further lower secretion of IFN-γ upon stimulation of their PBMCs with conidia compared to the patients without aspergillosis. Together, our study indicated that STAT3-deficiency leads to a defective adaptive immune response against infection, particularly with a lower IFN-γ and IL-17 responses in those with aspergillosis, suggesting potential therapeutic benefit of recombinant IFN-γ in STAT3-deficient patients with aspergillosis.

Keywords: loss-of-function mutation; signal transducer and activator of transcription 3 (STAT3); Aspergillus; IgE; IgG; aspergillosis; autosomal dominant hyper-IgE syndrome (AD-HIES); innate/adaptive immunity

Domains: Life Sciences [q-bio]; Life Sciences [q-bio]; Human health and pathology; Life Sciences [q-bio]; Human health and pathology; Infectious diseases

François Danion, Vishukumar Aimanianda, Jagadeesh Bayry, Amélie Duréault, Sarah Sze Wah Wong, et al.. Aspergillus fumigatus Infection in Humans With STAT3-Deficiency Is Associated With Defective Interferon-Gamma and Th17 Responses. Frontiers in Immunology, 2020, 11, pp.38. ⟨10.3389/fimmu.2020.00038⟩. ⟨pasteur-02501359⟩