SARS-CoV-2 hijacks fragile X mental retardation proteins for efficient infection (preprint)

Viruses interact with numerous host factors to facilitate viral replication and to dampen antiviral defense mechanisms. We currently have a limited mechanistic understanding of how SARS-CoV-2 binds host factors and the functional role of these interactions. Here, we uncover a novel interaction between the viral NSP3 protein and the fragile X mental retardation proteins (FMRPs: FMR1 and FXR1-2). SARS-CoV-2 NSP3 mutant viruses preventing FMRP binding have attenuated replication in vitro and have delayed disease onset in vivo. We show that a unique peptide motif in NSP3 binds directly to the two central KH domains of FMRPs and that this interaction is disrupted by the I304N mutation found in a patient with fragile X syndrome. NSP3 binding to FMRPs disrupts their interaction with the stress granule component UBAP2L through direct competition with a peptide motif in UBAP2L to prevent FMRP incorporation into stress granules. Collectively, our results provide novel insight into how SARS-CoV-2 hijacks host cell proteins for efficient infection and provides molecular insight to the possible underlying molecular defects in fragile X syndrome.

Rehabilitation Needs Following COVID-19: Five-Month Post-Discharge Clinical Follow-Up of Individuals With Concerning Self-Reported Symptoms (preprint)

Background: This paper forms part of the Linköping COVID-19 Study (LinCoS) which includes all 745 individuals in Region Östergötland (RÖ) admitted to hospital for COVID-19 during March 1st – May 31st, 2020. This report aimed at describing and objectivizing the reported problems through clinical examination, and determining the required level of rehabilitation sevices according to rehabilitation complexity. Methods: In this ambidirectional cohort study, all 185 individuals who had reported concerning persisting symptoms were invited to a multi-professional clinical assessment of somatic, functional, affective, neuropsychological status and rehabilitation needs.Findings: A broad array of symptoms and signs attributable to COVID-19 involving respiratory, visual, auditory, motor, sensory and cognitive functions could be confirmed clinically at five months post-discharge in most patients. This translated into approximately 20% of survivors of the total regional cohort of hospitalised patients requiring further rehabilitative interventions at follow-up. Weakness in extremities was reported in 28·5%. On examination, clinically overt muscle weakness could be corroborated in 15 individuals (9·8%). 48% of cases reported cognitive symptoms, while the physician noted overt cognitive impairments in only 3%. Formal testing by a neuropsychologist showed that 39% performed 1.5 SD below the norm, indicating neurocognitive deficit. Fifty-five individuals (34·8%) reported new or aggravated pain. In three fourths of them, it exerted a ‘moderate’ detrimental effect or worse on their ability to work.Interpretation: Our study underscores the importance of providing extensive examination of cases with persisting problems after COVID-19, especially since symptoms such as fatigue and breathlessness are highly nonspecific, but may represent significant underlying functional impairments. Robust neurocognitive testing should be performed, as cognitive problems may easily be overlooked during routine medical consultation. Most rehabilitative interventions could be provided in a primary care setting. However, a substantial minority of patients should to be triaged to specialized rehabilitation services.Funding Information: The study was funded by the ALF grant and Region Östergötland.Declaration of Interests: The authors declare no conflicts of interest.Ethics Approval Statement: The Swedish Ethical Review Authority approved the study protocol (Dnr 2020-03029 and 2020-04443).

Large scale discovery of coronavirus-host factor protein interaction motifs reveals SARS-CoV-2 specific mechanisms and vulnerabilities (preprint)

Viral proteins make extensive use of short peptide interaction motifs to hijack cellular host factors. However, most current large-scale methods do not identify this important class of protein-protein interactions. Uncovering peptide mediated interactions provides both a molecular understanding of viral interactions with their host and the foundation for developing novel antiviral reagents. Here we describe a scalable viral peptide discovery approach covering 229 RNA viruses that provides high resolution information on direct virus-host interactions. We identify 269 peptide-based interactions for 18 coronaviruses including a specific interaction between the human G3BP1/2 proteins and an [FILV]xFG peptide motif in the SARS-CoV-2 nucleocapsid (N) protein. This interaction supports viral replication and through its [FILV]xFG motif N rewires the G3BP1/2 interactome to disrupt stress granules. A peptide-based inhibitor disrupting the G3BP1/2-N interaction blocks SARS-CoV-2 infection showing that our results can be directly translated into novel specific antiviral reagents.

Detection of asymptomatic SARS-CoV-2 exposed individuals by a sensitive S-based ELISA. (preprint)

To assess the current coronavirus pandemic, there is a pressing need to determine the exposure and seroconversion to SARS-CoV-2 on a local and global level. Here, we demonstrate a sensitive and specific S-protein based assay that is well suited for detection of weak SARS- CoV-2-directed IgG responses, and that could identify exposed individuals with asymptomatic infection without the requirement of PCR diagnostics. Our results raise the possibility that on- going population-based studies using less sensitive state-of-the-art serological assays may significantly underestimate the frequency of exposure and seroconversion to SARS-CoV-2.