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2.
Virologie ; 26(2):186, 2022.
Article in English | EMBASE | ID: covidwho-1912865

ABSTRACT

Bats are natural reservoirs for numerous coronaviruses, including the potential ancestor of SARS-CoV-2. Knowledge concerning the interaction of coronaviruses and bat cells is, however, sparse. There is thus a need to develop bat cellular models to understand cell tropism, viral replication and virus-induced cell responses. Here, we report the first molecular study of SARS-CoV-2 infection in chiropteran cells. We investigated the ability of primary cells from Rhinolophus and Myotis species, as well as of established and novel cell lines from Myotis myotis, Eptesicus serotinus, Tadarida brasiliensis and Nyctalus noctula, to support SARS-CoV-2 replication. None of these cells were permissive to infection, not even the ones expressing detectable levels of angiotensin-converting enzyme 2 (ACE2), which serves as the viral receptor in many mammalian species including humans. The resistance to infection was overcome by expression of human ACE2 (hACE2) in three cell lines, suggesting that the restriction to viral replication was due to a low expression of bat ACE2 (bACE2) or absence of bACE2 binding in these cells. By contrast, multiple restriction factors to viral replication exist in the three N. noctula cells since hACE2 expression was not sufficient to permit infection. Infectious virions were produced but not released from hACE2-transduced M. myotis brain cells. E. serotinus brain cells and M. myotis nasal epithelial cells expressing hACE2 efficiently controlled viral replication, which correlated with a potent interferon response. Together, our data highlight the existence of species-specific molecular barriers to viral replication in bat cells. Our newly developed chiropteran cellular models are useful tools to investigate the interplay between viruses belonging to the SARS-CoV- 2 lineage and their natural reservoir, including the identification of factors responsible for viral restriction.

3.
Topics in Antiviral Medicine ; 30(1 SUPPL):122, 2022.
Article in English | EMBASE | ID: covidwho-1880385

ABSTRACT

Background: More than 10% of patients infected with SARS-CoV-2 experience a Long COVID syndrome, characterized by the persistence of a diverse array of symptoms where fatigue predominates. The role of the adaptive immune response in Long COVID remains poorly understood, with contrasting hypotheses suggesting either an insufficient antiviral response or an excessive immune response that would trigger autoimmune damage. To address this issue, we set to characterize humoral and cellular responses in Long COVID patients prior to SARS-CoV-2 vaccination. Methods: Long COVID patients (n=36) were included based on (1) an initial SARS-CoV-2 infection documented by PCR or the conjunction of two major signs of COVID-19 and (2) the persistence or resurgence of symptoms for over 3 months. They were compared to convalescent COVID patients with resolved symptoms (n=23) and uninfected control individuals (n=20). IgG and IgA antibodies specific to the SARS-CoV-2 spike were detected by a sensitive S-flow assay, which measures antibody binding to spike-expressing 293T cells. For CD4+ T cell response analyses, cytokine production was measured by intracellular staining on primary T cell lines stimulated by immunodominant peptides derived from the S, M, and N viral proteins. Results: Antibody analyses revealed either strong or very low/undetectable amounts of spike-specific IgG in sera from Long COVID patients, thus distinguishing a seropositive and a seronegative group. Seropositive Long COVID patients (n=21) showed strong CD4 responses that tended to be of higher magnitude than those of convalescents (P<0.05 for 2 immunodominant peptides). In contrast, seronegative Long COVID patients (n=15) showed low or undetectable CD4+ T cells responses, with 4/15 patients showing responses above those observed in healthy donors. CD4+ T cell responses correlated with spike-specific IgG responses in seropositive Long COVID patients (P≤0.002) but not in convalescents, pointing to differences in immune memory persistence. Conclusion: These findings highlight divergent adaptive immune responses among Long COVID patients, with a group characterized by seroconversion and particularly strong CD4+ T cell responses, and a second group characterized by low or undetectable antibody and cellular responses. Further studies are warranted to determine whether the etiology and the duration of symptoms differ in these two groups of Long COVID patients.

4.
Embase; 2022.
Preprint in English | EMBASE | ID: ppcovidwho-338083

ABSTRACT

Memory B-cell and antibody responses to the SARS-CoV-2 spike protein contribute to long-term immune protection against severe COVID-19, which can also be prevented by antibody-based interventions. Here, wide SARS-CoV-2 immunoprofiling in COVID-19 convalescents combining serological, cellular and monoclonal antibody explorations, revealed humoral immunity coordination. Detailed characterization of a hundred SARS-CoV-2 spike memory B-cell monoclonal antibodies uncovered diversity in their repertoire and antiviral functions. The latter were influenced by the targeted spike region with strong Fc-dependent effectors to the S2 subunit and potent neutralizers to the receptor binding domain. Amongst those, Cv2.1169 and Cv2.3194 antibodies cross-neutralized SARS-CoV-2 variants of concern including Omicron BA.1 and BA.2. Cv2.1169, isolated from a mucosa-derived IgA memory B cell, demonstrated potency boost as IgA dimers and therapeutic efficacy as IgG antibodies in animal models. Structural data provided mechanistic clues to Cv2.1169 potency and breadth. Thus, potent broadly neutralizing IgA antibodies elicited in mucosal tissues can stem SARS-CoV-2 infection, and Cv2.1169 and Cv2.3194 are prime candidates for COVID-19 prevention and treatment.

5.
Embase;
Preprint in English | EMBASE | ID: ppcovidwho-326820

ABSTRACT

The SARS-CoV-2 Omicron variant was first identified in November 2021 in Botswana and South Africa 1,2. It has in the meantime spread to many countries and is expected to rapidly become dominant worldwide. The lineage is characterized by the presence of about 32 mutations in the Spike, located mostly in the N-terminal domain (NTD) and the receptor binding domain (RBD), which may enhance viral fitness and allow antibody evasion. Here, we isolated an infectious Omicron virus in Belgium, from a traveller returning from Egypt. We examined its sensitivity to 9 monoclonal antibodies (mAbs) clinically approved or in development3, and to antibodies present in 90 sera from COVID-19 vaccine recipients or convalescent individuals. Omicron was totally or partially resistant to neutralization by all mAbs tested. Sera from Pfizer or AstraZeneca vaccine recipients, sampled 5 months after complete vaccination, barely inhibited Omicron. Sera from COVID-19 convalescent patients collected 6 or 12 months post symptoms displayed low or no neutralizing activity against Omicron. Administration of a booster Pfizer dose as well as vaccination of previously infected individuals generated an anti-Omicron neutralizing response, with titers 5 to 31 fold lower against Omicron than against Delta. Thus, Omicron escapes most therapeutic monoclonal antibodies and to a large extent vaccine-elicited antibodies.

6.
La Revue de Médecine Interne ; 42:A339-A340, 2021.
Article in French | ScienceDirect | ID: covidwho-1531776

ABSTRACT

Introduction L’émergence de nouvelles souches du SARS-CoV-2, telles que le variant Delta, présentant une réplication virale augmentée et la capacité d’échapper à la réponse immune soulève des inquiétudes chez les patients immunodéprimés. Cette étude avait pour objectif d’évaluer le taux de séroconversion, de neutralisation de différents variants, et la réponse lymphocytaire T en réponse à la vaccination par le BNT162b2 chez des patients avec maladies auto-immunes en fonction des traitements reçus. Patients et méthodes Étude prospective monocentrique réalisée à l’Hôpital Cochin (Paris) incluant des patients avec maladies auto-immunes traités par immunosuppresseurs et/ou immunomodulateurs, et des professionnels de santé comme contrôles. Les cas et les contrôles étaient exclus s’ils avaient une sérologie Covid-19 positive à l’inclusion. Le critère de jugement principal était la proportion d’anticorps anti-Spike et les titres de neutralisation croisée contre les variants Alpha et Delta à 3 mois (après deux doses de vaccin). Les critères de jugements secondaires étaient la réponse lymphocytaire T spécifique, la proportion d’infections à SARS-CoV-2 symptomatiques et la tolérance du vaccin. Résultats Soixante-quatre cas et 32 contrôles avec un âge médian respectif de 56 (39,5-59,5) et 52 (37,8-66,3) ans étaient inclus. Quatre groupes de traitements étaient défini: patients traités par rituximab (n=22), methotrexate (n=16), immunosuppresseurs conventionnels hors methotrexate (n=19), patients recevant des traitements connus pour ne pas avoir d’impact sur la réponse vaccinale (n=7). L’ensemble des cas avaient une production diminuée et retardée d’IgG et d’IgA anti-spike après vaccination par le BNT162b2, ceci de façon plus prononcée dans le groupe rituximab. Alors que 2 doses de vaccin induisaient une réponse humorale neutralisante contre les variants Alpha et Delta chez 100 % des contrôles, un seul patient sous rituximab (5 %) neutralisait Alpha et aucun Delta. Les autres groupes de traitements avaient une activité neutralisante partielle contre Alpha, et significativement diminuée contre Delta. Les réponses lymphocytaires T spécifiques étaient similaires entre les contrôles et les cas, à l’exception des patients sous metrotrexate qui avaient une réponse complètement abrogée après 1 dose et considérablement diminuée après 2 doses. Après 3 mois de suivi, 2 patients traités par rituximab présentaient une infection symptomatique peu sévère à SARS-CoV-2, 4 à 7jours après la seconde dose de vaccin. Quatre patients (6,3 %) présentaient une poussée de leur maladie auto-immune conduisant à une modification thérapeutique. Conclusion Le rituximab et le methotrexate impactent de façon différente l’immunogénicité du vaccin BNT162b2, en altérant respectivement les réponses humorales et cellulaires. Le variant Delta échappe complètement à la réponse humorale chez les patients traités par rituximab. Ces résultats soulignent la nécéssité de protocoles vaccinaux particuliers et d’autres traitements préventifs de l’infection dans cette population de patients.

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