Full text

Turn on search term navigation

© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Natural killer (NK) cells mount an immune response against hepatitis C virus (HCV) infection and can be activated by several cytokines, including interleukin-2 (IL-2), IL-15, and interferon-alpha (IFN-α). By exploiting the Huh7.5 hepatoma cell line infected with the HCV JFH1 genome, we provide novel insights into the antiviral effector functions of human primary NK cells after cytokine stimulation. NK cells activated with IFN-α (IFNα-NKs) had enhanced contact-dependent and -independent responses as compared with NK cells activated with IL-2/IL-15 (IL2/IL15-NKs) and could inhibit HCV replication both in vitro and in vivo. Importantly, IFN-α, but not IL-2/IL-15, protected NK cells from the functional inhibition exerted by HCV. By performing flow cytometry, multiplex cytokine profiling, and mass-spectrometry-based proteomics, we discovered that IFNα-NKs secreted high levels of galectin-9 and interferon-gamma (IFN-γ), and by conducting neutralization assays, we confirmed the major role of these molecules in HCV suppression. We speculated that galectin-9 might act extracellularly to inhibit HCV binding to host cells and downstream infection. In silico approaches predicted the binding of HCV envelope protein E2 to galectin-9 carbohydrate-recognition domains, and co-immunoprecipitation assays confirmed physical interaction. IFN-γ, on the other hand, triggered the intracellular expressions of two antiviral gate-keepers in target cells, namely, myxovirus-1 (MX1) and interferon-induced protein with tetratricopeptide repeats 1 (IFIT1). Collectively, our data add more complexity to the antiviral innate response mediated by NK cells and highlight galectin-9 as a key molecule that might be exploited to neutralize productive viral infection.

Details

Title
Galectin-9 and Interferon-Gamma Are Released by Natural Killer Cells upon Activation with Interferon-Alpha and Orchestrate the Suppression of Hepatitis C Virus Infection
Author
Carreca, Anna Paola 1   VIAFID ORCID Logo  ; Gaetani, Massimiliano 2 ; Busà, Rosalia 3   VIAFID ORCID Logo  ; Francipane, Maria Giovanna 1   VIAFID ORCID Logo  ; Gulotta, Maria Rita 1   VIAFID ORCID Logo  ; Perricone, Ugo 1 ; Iannolo, Gioacchin 3   VIAFID ORCID Logo  ; Russelli, Giovanna 3   VIAFID ORCID Logo  ; Carcione, Claudia 1 ; Conaldi, Pier Giulio 3   VIAFID ORCID Logo  ; Badami, Ester 4   VIAFID ORCID Logo 

 Fondazione Ri.MED, 90133 Palermo, Italy; [email protected] (A.P.C.); [email protected] (M.G.); [email protected] (M.G.F.); [email protected] (M.R.G.); [email protected] (U.P.); [email protected] (C.C.) 
 Fondazione Ri.MED, 90133 Palermo, Italy; [email protected] (A.P.C.); [email protected] (M.G.); [email protected] (M.G.F.); [email protected] (M.R.G.); [email protected] (U.P.); [email protected] (C.C.); Department of Research, IRCCS-ISMETT, Istituto Mediterraneo per i Trapianti e Terapie Ad Alta Specializzazione, 90127 Palermo, Italy; [email protected] (R.B.); [email protected] (G.I.); [email protected] (G.R.); [email protected] (P.G.C.); Chemical Proteomics, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Biomedicum, SE-17177 Stockholm, Sweden; SciLifeLab (Science for Life Laboratory), SE-17177 Stockholm, Sweden 
 Department of Research, IRCCS-ISMETT, Istituto Mediterraneo per i Trapianti e Terapie Ad Alta Specializzazione, 90127 Palermo, Italy; [email protected] (R.B.); [email protected] (G.I.); [email protected] (G.R.); [email protected] (P.G.C.) 
 Fondazione Ri.MED, 90133 Palermo, Italy; [email protected] (A.P.C.); [email protected] (M.G.); [email protected] (M.G.F.); [email protected] (M.R.G.); [email protected] (U.P.); [email protected] (C.C.); Department of Research, IRCCS-ISMETT, Istituto Mediterraneo per i Trapianti e Terapie Ad Alta Specializzazione, 90127 Palermo, Italy; [email protected] (R.B.); [email protected] (G.I.); [email protected] (G.R.); [email protected] (P.G.C.) 
First page
1538
Publication year
2022
Publication date
2022
Publisher
MDPI AG
e-ISSN
19994915
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2694082728
Copyright
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.