A mathematical model of SARS-CoV-2 immunity predicts paxlovid rebound.

Nirmatrelvir/ritonavir (Paxlovid), an oral antiviral medication targeting SARS-CoV-2, remains an important treatment for COVID-19. Initial studies of nirmatrelvir/ritonavir were performed in SARS-CoV-2 unvaccinated patients without prior confirmed SARS-CoV-2 infection; however, most individuals have now either been vaccinated and/or have experienced SARS-CoV-2 infection. After nirmatrelvir/ritonavir became widely available, reports surfaced of "Paxlovid rebound," a phenomenon in which symptoms (and SARS-CoV-2 test positivity) would initially resolve, but after finishing treatment, symptoms and test positivity would return. We used a previously described parsimonious mathematical model of immunity to SARS-CoV-2 infection to model the effect of nirmatrelvir/ritonavir treatment in unvaccinated and vaccinated patients. Model simulations show that viral rebound after treatment occurs only in vaccinated patients, while unvaccinated (SARS-COV-2 naïve) patients treated with nirmatrelvir/ritonavir do not experience any rebound in viral load. This work suggests that an approach combining parsimonious models of the immune system could be used to gain important insights in the context of emerging pathogens.

Histone mRNA polyadenylation-mediated inflammation underlies various virus infections and cancers.

The mechanistic understanding of virus infection and inflammation in many diseases is incomplete. Normally, messenger RNA (mRNA) tails of replication-dependent histones (RDH) that safeguard naked nuclear DNAs are protected by a specialized stem-loop instead of polyadenylation. Here, we showed that infection by various RNA viruses (including severe acute respiratory syndrome coronavirus 2) induced aberrant polyadenylation of RDH mRNAs (pARDH) that resulted in inflammation or cellular senescence, based on which we constructed a pARDH inflammation score (pARIS). We further investigated pARIS elevation in various disease conditions, including different types of virus infection, cancer, and cellular senescence. Notably, we found that pARIS was positively correlated with coronavirus disease 2019 severity in specific immune cell types. We also detected a subset of HIV-1 elite controllers characterized by pARDH "flipping" potentially mediated by HuR. Importantly, pARIS was positively associated with transcription of endogenous retrovirus but negatively associated with most immune cell infiltration in tumors of various cancer types. Finally, we identified and experimentally verified two pARIS regulators, ADAR1 and ZKSCAN1, which was first linked to inflammation. The ZKSCAN1 was known as a transcription factor but instead was shown to regulate pARIS as a novel RNA binding protein. Both regulators were upregulated under most infection and inflammation conditions. In conclusion, we unraveled a potential antiviral mechanism underlying various types of virus infections and cancers.

Gilteritinib: Repurposing of AXL-targeting kinase inhibitors against COVID-19.

The coronavirus disease-19 (COVID-19) is an ongoing infection outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel positive single-stranded, enveloped RNA virus belonging to the genus Betacoronavirus. During the pandemic, the SARS-CoV-2 subvariants evolved rapidly with enhanced transmissibility, and became a global public health threat as its alarmingly rising rate of infection led to excessive mortality. According to the WHO data, COVID-19 caused more than 6 million deaths and affected 215 countries. Although vaccines are beneficial for preventing hospitalization, reducing severe illness and deaths from COVID-19, the constantly mutated Spike protein under high selection pressure leading to off-target or immune evasion which warrants additional therapeutic strategies. Therefore, it is important to identify and test potential therapeutic targets against proteins that are highly conserved among multiple coronaviruses for clinical drug development to combat SARS-COV-2. While research for new therapies continues, the cost-effective and rapid repurposing of existing therapeutics may provide a viable treatment alternative for COVID-19.

Genome-based comparison between the recombinant SARS-CoV-2 XBB and its parental lineages.

Recombination is the main contributor to RNA virus evolution, and SARS-CoV-2 during the pandemic produced several recombinants. The most recent SARS-CoV-2 recombinant is the lineage labeled XBB, also known as Gryphon, which arose from BJ.1 and BM.1.1.1. Here we performed a genome-based survey aimed to compare the new recombinant with its parental lineages that never became dominant. Genetic analyses indicated that the recombinant XBB and its first descendant XBB.1 show an evolutionary condition typical of an evolutionary blind background with no further epidemiologically relevant descendant. Genetic variability and expansion capabilities are slightly higher than parental lineages. Bayesian Skyline Plot indicates that XBB reached its plateau around October 6, 2022 and after an initial rapid growth the viral population size did not further expand, and around November 10, 2022 its levels of genetic variability decreased. Simultaneously with the reduction of the XBB population size, an increase of the genetic variability of its first sub-lineage XBB.1 occurred, that in turn reached the plateau around November 9, 2022 showing a kind of vicariance with its direct progenitors. Structure analysis indicates that the affinity for ACE2 surface in XBB/XBB.1 RBDs is weaker than for BA.2 RBD. In conclusion, at present XBB and XBB.1 do not show evidence about a particular danger or high expansion capability. Genome-based monitoring must continue uninterrupted to individuate if further mutations can make XBB more dangerous or generate new subvariants with different expansion capability.

Reply to Chan, et al.

We appreciate the comments from Chan et al. for our study, and have carefully responded to the comments of Chan et al. and are very grateful for their praise of our research. We agree that smoking might be a risk factor of the severity of COVID-19 as mentioned by Chan et al., but in our study, smoking was not so robust compared with our conclusion. Also, we strongly agreed with the opinion of Chan, et al. that COVID-19 patients with diabetes or other chronic diseases might worsen the situation of the disease. But these factors were out of the scope of our study and we had published other research on this topic related to diabetes. Because of the limited sample size and original medical records, our study could not cover many factors suggested as Chan, et al. But we wish our study will be a useful and meaningful pilot study for the future studies. This article is protected by copyright. All rights reserved.

Transplacental transmission of SARS-CoV-2 immunoglobulin G antibody to infants from maternal COVID-19 vaccine immunization before pregnancy.

The coronavirus disease 2019 (COVID-19) vaccine generates functional antibodies in maternal circulation that are detectable in infants, while the information is restricted to the usage of COVID-19 vaccine during pregnancy. In this study, we aimed to evaluate the effect of maternal COVID-19 vaccines before pregnancy. Infants were included from mothers with no inactivated COVID-19 vaccine, 1-, 2-, and 3-dose before pregnancy, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) antibodies were tested. Comparative analysis was done between the groups. A total of 130 infants were enrolled in the study. Significantly higher levels of SARS-CoV-2 IgG antibodies in infants born to mothers with 3-dose COVID-19 vaccine before pregnancy compared with 1- and 2-dose groups (p < 0.0001). The levels of antibodies decreased significantly with age in infants born to mothers with the 3-dose COVID-19 vaccine before pregnancy (r = -0.338, p = 0.035), and it was still higher than that 2-dose COVID-19 vaccine group. The maternal SARS-CoV-2 antibodies produced from the inactivated COVID-19 vaccine before pregnancy can be transferred to newborns via the placenta. Maternal immunization with 3-dose of the COVID-19 vaccine before pregnancy could be more beneficial for both mothers and infants.

Production of a versatile SARS-CoV-2 main protease biosensor based on a dimerization-dependent red fluorescent protein.

we designed a functionally active Mpro biosensor based on a dimerization-dependent red fluorescent protein (ddRFP) for the evaluation of Mpro inhibitors in vitro. This study provides an affordable strategy for rapid production of a versatile ddRFP biosensor, which would be a useful tool for the measurement and quantification of Mpro inhibitors This article is protected by copyright. All rights reserved.

SARS-CoV-2 ORF3a inhibits cGAS-STING-mediated autophagy flux and antiviral function.

Recognizing aberrant cytoplasmic dsDNA and stimulating cGAS-STING-mediated innate immunity is essential for the host defense against viruses. Recent studies have reported that SARS-CoV-2 infection, responsible for the COVID-19 pandemic, triggers cGAS-STING activation. cGAS-STING activation can trigger IRF3-Type I interferon (IFN) and autophagy-mediated antiviral activity. Although viral evasion of STING-triggered IFN-mediated antiviral function has been well studied, studies concerning viral evasion of STING-triggered autophagy-mediated antiviral function are scarce. In the present study, we have discovered that SARS-CoV-2 ORF3a is a unique viral protein that can interact with STING and disrupt the STING-LC3 interaction, thus blocking cGAS-STING-induced autophagy but not IRF3-Type I IFN induction. This novel function of ORF3a, distinct from targeting autophagosome-lysosome fusion, is a selective inhibition of STING-triggered autophagy to facilitate viral replication. We have also found that activation of bat STING can induce autophagy and antiviral activity despite its defect in IFN induction. Furthermore, ORF3a from bat coronaviruses can block bat STING-triggered autophagy and antiviral function. Interestingly, the ability to inhibit STING-induced autophagy appears to be an acquired function of SARS-CoV-2 ORF3a, since SARS-CoV ORF3a lacks this function. Taken together, these discoveries identify ORF3a as a potential target for intervention against COVID-19.

Liquid biomarkers of macrophage dysregulation and circulating spike protein illustrate the biological heterogeneity in patients with post-acute sequelae of COVID-19.

Post-acute sequelae of COVID-19 (PASC) are long-term consequences of SARS-CoV-2 infection that can substantially impair quality of life. Underlying mechanisms ranging from persistent virus to innate and adaptive immune dysregulation have been discussed. Here, we profiled plasma of 181 individuals from the cohort study for digital health research in Germany (DigiHero) including individuals after mild to moderate COVID-19 with or without PASC and uninfected controls. We focused on soluble factors related to monocyte/macrophage biology and on circulating SARS-CoV-2 spike (S1) protein as potential biomarker for persistent viral reservoirs. At a median time of eight months after infection, we found pronounced dysregulation in almost all tested soluble factors including both pro-inflammatory and pro-fibrotic cytokines. These immunological perturbations were remarkably independent of ongoing PASC symptoms per se, but further correlation and regression analyses suggested PASC specific patterns involving CCL2/MCP-1 and IL-8 that either correlated with sCD162, sCD206/MMR, IFN-α2, IL-17A and IL-33, or IL-18 and IL-23. None of the analyzed factors correlated with the detectability or levels of circulating S1 indicating that this represents an independent subset of patients with PASC. This data confirms prior evidence of immune dysregulation and persistence of viral protein in PASC and illustrates its biological heterogeneity that still awaits correlation with clinically defined PASC subtypes. This article is protected by copyright. All rights reserved.

The immunodominance of RBD antigen of delta variant as vaccine candidate against SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel subset of coronavirus that causes coronavirus disease 2019 (COVID-19), but vaccine development is hampered by the high mutation of virus This article is protected by copyright. All rights reserved.

Spike protein mediated membrane fusion during SARS-CoV-2 infection.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a serious threat to public health and has quickly become a global concern. The infection of SARS-CoV-2 begins with the binding of its spike protein to the receptor-angiotensin-converting enzyme 2 (ACE2), which, after a series of conformation changes, results in the fusion of viral-cell membranes and the release of the viral RNA genome into the cytoplasm. In addition, infected host cells can express spike protein on their cell surface, which will interact with ACE2 on neighboring cells, leading to cell membrane fusion and the formation of multinucleated cells or syncytia. Both viral entry and syncytia formation are mediated by spike-ACE2 interaction and share some common mechanisms of membrane fusion. Here in this review, we will summarize our current understanding of spike-mediated membrane fusion, which may shed light on future broad-spectrum antiviral development.

Higher SARS-CoV-2 shedding in exhaled aerosol probably contributed to the enhanced transmissibility of Omicron BA.5 subvariant.

The global pandemic of the BA.5 subvariant had moved from prediction to reality. In this study, we compared SARS-CoV-2 aerosol emissions from patients with BA.2 or BA.5 subvariant infection. First, patients with BA.2 subvariant infection had higher upper respiratory viral loads than patients with BA.5 subvariant infection. However, the average breath emission rate (BER) of patients with BA.5 subvariant infection, which represented the concentration of exhaled SARS-CoV-2 aerosols, was nearly 40 times higher than that of patients with BA.2 subvariant. Second, aerosols exhaled by patients with BA.5 subvariant infection exhibited SARS-CoV-2 RNA detection positive rate than patients with BA.1 or BA.2 subvariant infection. Meanwhile, for BA.5 subvariant infection, patients that exhaled infectious SARS-CoV-2 aerosols accounted for 14.8% of all patients. Third, since the onset of COVID-19, the SARS-CoV-2 RNA detection signals of throat swabs showed a gradual decline trend, although the decline process was accompanied by fluctuations. Overall, the monitoring of infectious SARS-CoV-2 aerosols may provide the data support for the transmissibility evaluation of the Omicron BA.5 subvariant. This article is protected by copyright. All rights reserved.

Positive SARS-CoV-2 RT-qPCR of a nasal swab spot after 30 days of conservation on filter paper at room temperature.

We tested the use of nasal swabs spotted onto filter paper (Whatman 3M) for the molecular diagnosis of SARS-CoV-2 infection. Spots of a positive nasal swab in conservation medium (B.1.177 strain, 21Ct) were still positive (duo E-gene/IP4) after 10, 20, and 30 days of conservation at room temperature, with Ct values of 28, 27, and 26, respectively. Direct spotting of the swab at bedside (omicron strain) still gave a positive result after 10 days in two RT-qPCR systems: 33.7 Ct using duo E-gene/IP4, and 34.8 using a specific Omicron system. Spotting of a dilution range of media spiked with the Delta (strain 2021/FR/0610, lineage B 1.617.2) and Omicron strains (strain UVE/SARS-CoV-2/2021/FR/1514) showed a threshold of 0.04 TCID50 after 10 days of conservation. We show, for the first time, that this simple and low-cost conservation method can be used to store samples for RT-qPCR against SARS-CoV-2 for up to at least 1 month.

Twelve-month clinical, functional, and radiological outcomes in patients hospitalized for SARS-CoV-2 pneumonia.

To assess long-term clinical, radiological, and functional follow-up of patients hospitalized for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pneumonia of different grades of severity. Two-hundred-thirty and three patients (Group 1, patients needed invasive mechanical ventilation, n = 69; Group 2, patients needed noninvasive mechanical ventilation, n = 78; Group 3, patients needed <12 L/min of O2 supply, n = 96) with a postdischarge follow-up >12 months were studied. Follow-up visits, chest computed tomography (CT) scan and pulmonary function tests (diffusing capacity of the lung for carbon monoxide [DLCO], 6-min walking tests [6MWT], spirometry) were done at 3, 6, and 12 months after discharge. Male sex was more frequent in Group 1 (n = 50, 72.5%) compared with Group 2 (n = 49, 62.5%) and Group 3 (n = 44, 51.2%), p = 0.024. Group 2 patients had more comorbidities and higher BMI compared with others. At Month 12, the main reported symptoms were fatigue (mainly in Group 3) and dyspnea; most symptoms resolved during follow-up, except brain fog, memory loss, and anosmia/dysgeusia that, when present at Month 3, usually persisted at Month 12. DLCO and 6MWT normalized at Month 12 in almost all patients. Only nine patients (13%) in Group 1 had a normal chest CT at Month 12, while 20 (29%) had >3 abnormalities, compared with 14 (17.9%) in Group 2 and 11 (11.4%) in Group 3, respectively (p = 0.04). Different clinical symptoms persist up to 12 months in patients hospitalized for SARS-CoV-2 pneumonia. Despite the persistence of abnormalities at chest CT scan after 12 months, an impairment of pulmonary function persists only in a minority of subjects. A longer follow-up is needed to assess the evolution of radiological abnormalities in COVID-19 population.

Changes in endemic patterns of respiratory syncytial virus infection in pediatric patients under the pressure of nonpharmaceutical interventions for COVID-19 in Beijing, China.

A series of nonpharmaceutical interventions (NPIs) was launched in Beijing, China, on January 24, 2020, to control coronavirus disease 2019. To reveal the roles of NPIs on the respiratory syncytial virus (RSV), respiratory specimens collected from children with acute respiratory tract infection between July 2017 and Dec 2021 in Beijing were screened by capillary electrophoresis-based multiplex PCR (CEMP) assay. Specimens positive for RSV were subjected to a polymerase chain reaction (PCR) and genotyped by G gene sequencing and phylogenetic analysis using iqtree v1.6.12. The parallel and fixed (paraFix) mutations were analyzed with the R package sitePath. Clinical data were compared using SPSS 22.0 software. Before NPIs launched, each RSV endemic season started from October/November to February/March of the next year in Beijing. After that, the RSV positive rate abruptly dropped from 31.93% in January to 4.39% in February 2020; then, a dormant state with RSV positive rates ≤1% from March to September, a nearly dormant state in October (2.85%) and November (2.98%) and a delayed endemic season in 2020, and abnormal RSV positive rates remaining at approximately 10% in summer until September 2021 were detected. Finally, an endemic RSV season returned in October 2021. There was a game between Subtypes A and B, and RSV-A replaced RSV-B in July 2021 to become the dominant subtype. Six RSV-A and eight RSV-B paraFix mutations were identified on G. The percentage of severe pneumonia patients decreased to 40.51% after NPIs launched. NPIs launched in Beijing seriously interfered with the endemic season of RSV.

Genetic and Structural Data on the SARS-CoV-2 Omicron BQ.1 Variant Reveal Its Low Potential for Epidemiological Expansion.

The BQ.1 SARS-CoV-2 variant, also known as Cerberus, is one of the most recent Omicron descendant lineages. Compared to its direct progenitor BA.5, BQ.1 has some additional spike mutations in some key antigenic sites, which confer further immune escape ability over other circulating lineages. In such a context, here, we perform a genome-based survey aimed at obtaining a complete-as-possible nuance of this rapidly evolving Omicron subvariant. Genetic data suggest that BQ.1 represents an evolutionary blind background, lacking the rapid diversification that is typical of a dangerous lineage. Indeed, the evolutionary rate of BQ.1 is very similar to that of BA.5 (7.6 × 10-4 and 7 × 10-4 subs/site/year, respectively), which has been circulating for several months. The Bayesian Skyline Plot reconstruction indicates a low level of genetic variability, suggesting that the peak was reached around 3 September 2022. Concerning the affinity for ACE2, structure analyses (also performed by comparing the properties of BQ.1 and BA.5 RBD) indicate that the impact of the BQ.1 mutations may be modest. Likewise, immunoinformatic analyses showed moderate differences between the BQ.1 and BA5 potential B-cell epitopes. In conclusion, genetic and structural analyses on SARS-CoV-2 BQ.1 suggest no evidence of a particularly dangerous or high expansion capability. Genome-based monitoring must continue uninterrupted for a better understanding of its descendants and all other lineages.

Ribovirus classification by a polymerase barcode sequence.

RNA viruses encoding a polymerase gene (riboviruses) dominate the known eukaryotic virome. High-throughput sequencing is revealing a wealth of new riboviruses known only from sequence, precluding classification by traditional taxonomic methods. Sequence classification is often based on polymerase sequences, but standardised methods to support this approach are currently lacking. To address this need, we describe the polymerase palmprint, a segment of the palm sub-domain robustly delineated by well-conserved catalytic motifs. We present an algorithm, Palmscan, which identifies palmprints in nucleotide and amino acid sequences; PALMdb, a collection of palmprints derived from public sequence databases; and palmID, a public website implementing palmprint identification, search, and annotation. Together, these methods demonstrate a proof-of-concept workflow for high-throughput characterisation of RNA viruses, paving the path for the continued rapid growth in RNA virus discovery anticipated in the coming decade.

What are the long-term holistic health consequences of COVID-19 among survivors? An umbrella systematic review.

Many people who have survived COVID-19 have experienced negative persistent impacts on health. Impacts on health have included persistent respiratory symptoms, decreased quality of life, fatigue, impaired functional capacity, memory deficits, psychological impacts, and difficulties in returning to paid employment. Evidence is yet to be pooled to inform future directions in research and practice, to determine the physical, psychological, social, and spiritual impacts of the illness which extend beyond the acute phase of COVID-19 survivors. This umbrella review (review of systematic reviews) critically synthesized physical (including abnormal laboratory parameters), psychological, social, and spiritual impacts which extended beyond the acute phase of COVID-19 survivors. The search strategy was based on the sample, phenomena of interest, design, evaluation, research model and all publications were double screened independently by four review authors for the eligibility criteria. Data extraction and quality assessment were conducted in parallel independently. Eighteen systematic reviews were included, which represented a total of 493 publications. Sample sizes ranged from n = 15 to n = 44 799 with a total of n = 295 455 participants. There was incomplete reporting of several significant data points including the description of the severe acute respiratory syndrome coronavirus 2 variant, COVID-19 treatments, and key clinical and demographic data. A number of physical, psychological, and social impacts were identified for individuals grappling with post-COVID condition. The long term sequalae of acute COVID-19 and size of the problem is only beginning to emerge. Further investigation is needed to ensure that those affected by post-COVID condition have their informational, spiritual, psychological, social, and physical needs met in the future.