Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants

Anosmia was identified as a hallmark of COVID-19 early in the pandemic, however, with the emergence of variants of concern, the clinical profile induced by SARS-CoV-2 infection has changed, with anosmia being less frequent. Several studies have focused on the neuropathogenesis of the original SARS-CoV-2, but little is known about the neuropathological potential of the variants. Here, we assessed the clinical, olfactory and inflammatory conditions of golden hamsters infected with the original SARS-CoV-2, its ORF7-deleted mutant, and three variants: Gamma, Delta and Omicron/BA.1. We show that infected animals developed a variant-dependent clinical disease, and that the ORF7 of SARS-CoV-2 contribute to causing olfactory disturbances. Conversely, all SARS-CoV-2 variants were found to be neuroinvasive, regardless of the clinical presentation they induce. With newly-generated nanoluciferase-expressing SARS-CoV-2, we validated the olfactory pathway as a main entry point towards the brain, confirming that neuroinvasion and anosmia are independent phenomena upon SARS-CoV-2 infection. Graphical asbtract O_FIG O_LINKSMALLFIG WIDTH=150 HEIGHT=200 SRC="FIGDIR/small/505985v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1dd3fd3org.highwire.dtl.DTLVardef@896aeaorg.highwire.dtl.DTLVardef@1ca6157org.highwire.dtl.DTLVardef@1bcd84c_HPS_FORMAT_FIGEXP M_FIG C_FIG

Identification of DAXX As A Restriction Factor Of SARS-CoV-2 Through A CRISPR/Cas9 Screen

Interferon restricts SARS-CoV-2 replication in cell culture, but only a handful of Interferon Stimulated Genes with antiviral activity against SARS-CoV-2 have been identified. Here, we describe a functional CRISPR/Cas9 screen aiming at identifying SARS-CoV-2 restriction factors. We identified DAXX, a scaffold protein residing in PML nuclear bodies known to limit the replication of DNA viruses and retroviruses, as a potent inhibitor of SARS-CoV-2 and SARS-CoV replication in human cells. Basal expression of DAXX was sufficient to limit the replication of SARS-CoV-2, and DAXX over-expression further restricted infection. In contrast with most of its previously described antiviral activities, DAXX-mediated restriction of SARS-CoV-2 was independent of the SUMOylation pathway. SARS-CoV-2 infection triggered the re-localization of DAXX to cytoplasmic sites and promoted its degradation. Mechanistically, this process was mediated by the viral papain-like protease (PLpro) and the proteasome. Together, these results demonstrate that DAXX restricts SARS-CoV-2, which in turn has evolved a mechanism to counteract its action.

Cluster of COVID-19 in northern France: A retrospective closed cohort study

BackgroundThe Oise department in France has been heavily affected by COVID-19 in early 2020. MethodsBetween 30 March and 4 April 2020, we conducted a retrospective closed cohort study among pupils, their parents and siblings, as well as teachers and non-teaching staff of a high-school located in Oise. Participants completed a questionnaire that covered history of fever and/or respiratory symptoms since 13 January 2020 and had blood tested for the presence of anti-SARS-CoV-2 antibodies. The infection attack rate (IAR) was defined as the proportion of participants with confirmed SARS-CoV-2 infection based on antibody detection. Blood samples from two blood donor centres collected between 23 and 27 March 2020 in the Oise department were also tested for presence of anti-SARS-CoV-2 antibodies. FindingsOf the 661 participants (median age: 37 years), 171 participants had anti-SARS-CoV-2 antibodies. The overall IAR was 25.9% (95% confidence interval (CI) = 22.6-29.4), and the infection fatality rate was 0% (one-sided 97.5% CI = 0 - 2.1). Nine of the ten participants hospitalised since mid-January were in the infected group, giving a hospitalisation rate of 5.3% (95% CI = 2.4 -9.8). Anosmia and ageusia had high positive predictive values for SARS-CoV-2 infection (84.7% and 88.1%, respectively). Smokers had a lower IAR compared to non-smokers (7.2% versus 28.0%, P <0.001). The proportion of infected individuals who had no symptoms during the study period was 17.0% (95% CI = - 23.4). The proportion of donors with anti-SARS-CoV-2 antibodies in two nearby blood banks of the Oise department was 3.0% (95% CI = 1.1 - 6.4). InterpretationThe relatively low IAR observed in an area where SARS-CoV-2 actively circulated weeks before confinement measures indicates that establishing herd immunity will take time, and that lifting these measures in France will be long and complex. FundingInstitut Pasteur, CNRS, Universite de Paris, Sante publique France, Labex IBEID (ANR-10-LABX-62-IBEID), REACTing, EU grant Recover, INCEPTION project (PIA/ANR-16-CONV-0005). Research in contextO_ST_ABSEvidence before the studyC_ST_ABSThe first COVID-19 cases in France were reported on 24 January 2020. Substantial transmission has occurred since then, with the Oise department, north of Paris, one of the heaviest affected areas in the early stages of the epidemic in France. As of 13 April 2020, 98,076 cases had been diagnosed in France, including 5,379 deaths. Epidemiological and clinical characteristics of patients with COVID-19 have been widely reported, but this has largely been centred on cases requiring medical care. What remains unclear at this stage is the extent to which SARS-CoV-2 infections may be asymptomatic or present as subclinical, non-specific symptoms. While extensive contact tracing has identified asymptomatic infections using RT-PCR testing, serologic detection of anti-SARS-CoV-2 antibodies is needed to determine the real infection attack rate and the proportion of all infections that are asymptomatic or subclinical. Added value of this studyUsing a combination of serologic assays with high sensitivity and specificity for anti-SARS-CoV-2 antibodies, we conducted a retrospective closed cohort study. In a high school linked to a cluster of COVID-19 in the Oise department, we showed an overall infection attack rate (IAR) of 40.9% in the high school group, and 10.9% in parents and siblings of the pupils. The proportion of infected individuals who had no symptoms during the study period was 17.0%. Implications of all of the available evidenceThe relatively low IAR in this area where SARS-CoV-2 actively circulated before confinement measures were introduced indicates that establishing herd immunity will take time, and that the lifting of these measures in France will be long and complex.