Proviral role of human respiratory epithelial cell‐derived small extracellular vesicles in SARS‐CoV‐2 infection
François Berry
(1)
,
Margot Morin-Dewaele
(2)
,
Amene Majidipur
(3)
,
Thibaud Jamet
(4)
,
Sophie Bartier
(5)
,
Eva Ignjatovic
,
Donatella Toniutti
(6)
,
Jeanne Gaspar Lopes
(3)
,
Pascale Soyeux-Porte
(6, 3)
,
Pascale Maillé
(7)
,
Carolina Saldana
(8, 3)
,
Rozenn Brillet
(2)
,
Nazim Ahnou
(2)
,
Laurent Softic
(6)
,
Benoit Couturaud
(9)
,
Éric Huet
(10, 11, 3)
,
Abdelhakim Ahmed-Belkacem
(6)
,
Slim Fourati
(10, 7, 12)
,
Bruno Louis
(5, 13)
,
André Coste
(7, 14)
,
Émilie Béquignon
(2, 15, 13, 7, 16)
,
Alexandre de la Taille
(3)
,
Damien Destouches
(3)
,
Francis Vacherot
(3)
,
Jean‐michel Pawlotsky
,
Virginie Firlej
(3)
,
Patrice Bruscella
1
IP -
Institut Pascal
2 Inserm U955 - Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18)
3 TRePCa - Résistances Thérapeutiques du Cancer de la Prostate
4 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
5 U955 Inserm - UPEC - IMRB - "Biomechanics and Respiratory Apparatus" [Créteil]
6 IMRB - Institut Mondor de Recherche Biomédicale
7 Hôpital Henri Mondor
8 CHU Henri Mondor [Créteil]
9 ICMPE - Institut de Chimie et des Matériaux Paris-Est
10 UPEC UP12 - Université Paris-Est Créteil Val-de-Marne - Paris 12
11 IUT-UPEC - IUT Creteil-Vitry
12 U955 Inserm - UPEC - IMRB - VHC/"Viruses-Hepatology-Cancers" [Créteil]
13 BAR - Biomécanique & Appareil Respiratoire
14 CHIC - Centre Hospitalier Intercommunal de Créteil
15 UPE - Université Paris-Est
16 CHI Créteil
2 Inserm U955 - Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18)
3 TRePCa - Résistances Thérapeutiques du Cancer de la Prostate
4 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
5 U955 Inserm - UPEC - IMRB - "Biomechanics and Respiratory Apparatus" [Créteil]
6 IMRB - Institut Mondor de Recherche Biomédicale
7 Hôpital Henri Mondor
8 CHU Henri Mondor [Créteil]
9 ICMPE - Institut de Chimie et des Matériaux Paris-Est
10 UPEC UP12 - Université Paris-Est Créteil Val-de-Marne - Paris 12
11 IUT-UPEC - IUT Creteil-Vitry
12 U955 Inserm - UPEC - IMRB - VHC/"Viruses-Hepatology-Cancers" [Créteil]
13 BAR - Biomécanique & Appareil Respiratoire
14 CHIC - Centre Hospitalier Intercommunal de Créteil
15 UPE - Université Paris-Est
16 CHI Créteil
Eva Ignjatovic
- Fonction : Auteur
Jean‐michel Pawlotsky
- Fonction : Auteur
Patrice Bruscella
- Fonction : Auteur
Résumé
Abstract Small Extracellular Vesicles (sEVs) are 50–200 nm in diameter vesicles delimited by a lipid bilayer, formed within the endosomal network or derived from the plasma membrane. They are secreted in various biological fluids, including airway nasal mucus. The goal of this work was to understand the role of sEVs present in the mucus (mu‐sEVs) produced by human nasal epithelial cells (HNECs) in SARS‐CoV‐2 infection. We show that uninfected HNECs produce mu‐sEVs containing SARS‐CoV‐2 receptor ACE2 and activated protease TMPRSS2. mu‐sEVs cleave prefusion viral Spike proteins at the S1/S2 boundary, resulting in higher proportions of prefusion S proteins exposing their receptor binding domain in an ‘open’ conformation, thereby facilitating receptor binding at the cell surface. We show that the role of nasal mu‐sEVs is to complete prefusion Spike priming performed by intracellular furin during viral egress from infected cells. This effect is mediated by vesicular TMPRSS2 activity, rendering SARS‐CoV‐2 virions prone to entry into target cells using the ‘early’, TMPRSS2‐dependent pathway instead of the ‘late’, cathepsin‐dependent route. These results indicate that prefusion Spike priming by mu‐sEVs in the nasal cavity plays a role in viral tropism. They also show that nasal mucus does not protect from SARS‐CoV‐2 infection, but instead facilitates it.