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2.
J Cell Biol ; 221(7)2022 07 04.
Article in English | MEDLINE | ID: covidwho-2082890

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal pathogen of the ongoing global pandemic of coronavirus disease 2019 (COVID-19). Loss of smell and taste are symptoms of COVID-19, and may be related to cilia dysfunction. Here, we found that the SARS-CoV-2 ORF10 increases the overall E3 ligase activity of the CUL2ZYG11B complex by interacting with ZYG11B. Enhanced CUL2ZYG11B activity by ORF10 causes increased ubiquitination and subsequent proteasome-mediated degradation of an intraflagellar transport (IFT) complex B protein, IFT46, thereby impairing both cilia biogenesis and maintenance. Further, we show that exposure of the respiratory tract of hACE2 mice to SARS-CoV-2 or SARS-CoV-2 ORF10 alone results in cilia-dysfunction-related phenotypes, and the ORF10 expression in primary human nasal epithelial cells (HNECs) also caused a rapid loss of the ciliary layer. Our study demonstrates how SARS-CoV-2 ORF10 hijacks CUL2ZYG11B to eliminate IFT46 and leads to cilia dysfunction, thereby offering a powerful etiopathological explanation for how SARS-CoV-2 causes multiple cilia-dysfunction-related symptoms specific to COVID-19.


Subject(s)
Cilia , SARS-CoV-2 , Ubiquitin-Protein Ligases , Animals , Cells, Cultured , Cilia/metabolism , Cilia/pathology , Cytoskeletal Proteins , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Mice , SARS-CoV-2/pathogenicity , Smell , Ubiquitin-Protein Ligases/metabolism
3.
Genome Med ; 14(1): 18, 2022 02 21.
Article in English | MEDLINE | ID: covidwho-1688773

ABSTRACT

BACKGROUND: Measuring host gene expression is a promising diagnostic strategy to discriminate bacterial and viral infections. Multiple signatures of varying size, complexity, and target populations have been described. However, there is little information to indicate how the performance of various published signatures compare to one another. METHODS: This systematic comparison of host gene expression signatures evaluated the performance of 28 signatures, validating them in 4589 subjects from 51 publicly available datasets. Thirteen COVID-specific datasets with 1416 subjects were included in a separate analysis. Individual signature performance was evaluated using the area under the receiving operating characteristic curve (AUC) value. Overall signature performance was evaluated using median AUCs and accuracies. RESULTS: Signature performance varied widely, with median AUCs ranging from 0.55 to 0.96 for bacterial classification and 0.69-0.97 for viral classification. Signature size varied (1-398 genes), with smaller signatures generally performing more poorly (P < 0.04). Viral infection was easier to diagnose than bacterial infection (84% vs. 79% overall accuracy, respectively; P < .001). Host gene expression classifiers performed more poorly in some pediatric populations (3 months-1 year and 2-11 years) compared to the adult population for both bacterial infection (73% and 70% vs. 82%, respectively; P < .001) and viral infection (80% and 79% vs. 88%, respectively; P < .001). We did not observe classification differences based on illness severity as defined by ICU admission for bacterial or viral infections. The median AUC across all signatures for COVID-19 classification was 0.80 compared to 0.83 for viral classification in the same datasets. CONCLUSIONS: In this systematic comparison of 28 host gene expression signatures, we observed differences based on a signature's size and characteristics of the validation population, including age and infection type. However, populations used for signature discovery did not impact performance, underscoring the redundancy among many of these signatures. Furthermore, differential performance in specific populations may only be observable through this type of large-scale validation.


Subject(s)
Bacterial Infections/diagnosis , Datasets as Topic/statistics & numerical data , Host-Pathogen Interactions/genetics , Transcriptome , Virus Diseases/diagnosis , Adult , Bacterial Infections/epidemiology , Bacterial Infections/genetics , Biomarkers/analysis , COVID-19/diagnosis , COVID-19/genetics , Child , Cohort Studies , Diagnosis, Differential , Gene Expression Profiling/statistics & numerical data , Genetic Association Studies/statistics & numerical data , Humans , Publications/statistics & numerical data , SARS-CoV-2/pathogenicity , Validation Studies as Topic , Virus Diseases/epidemiology , Virus Diseases/genetics
4.
G Ital Cardiol (Rome) ; 23(9): 651-662, 2022 Sep.
Article in Italian | MEDLINE | ID: covidwho-2065242

ABSTRACT

Recent evidence shows that a range of persistent or new symptoms can manifest after 4-12 weeks in a subset of patients who have recovered from acute SARS-CoV-2 infection, and this condition has been coined long COVID by COVID-19 survivors among social support groups. Long COVID can affect the whole spectrum of people with COVID-19, from those with very mild acute disease to the most severe forms. Like the acute form, long COVID has multisystemic aspects. Patients can manifest with a very heterogeneous multitude of symptoms, including fatigue, post-exertional malaise, dyspnea, cognitive impairment, sleep disturbances, anxiety and depression, muscle pain, brain fog, anosmia/dysgeusia, headache, and limitation of functional capacity, which impact their quality of life. Because of the extreme clinical heterogeneity, and also due to the lack of a shared, specific definition, it is very difficult to know the real prevalence and incidence of this condition. Risk factors for developing long COVID would be female sex, initial severity, and comorbidities. Globally, with the re-emergence of new waves, the population of people infected with SARS-CoV-2 continues to expand rapidly, necessitating a more thorough understanding of potential sequelae of COVID-19. This review summarizes up to date definitions and epidemiological aspects of long COVID.


Subject(s)
COVID-19 , COVID-19/complications , COVID-19/epidemiology , COVID-19/physiopathology , COVID-19/psychology , Humans , Quality of Life , Risk Factors , SARS-CoV-2/pathogenicity , Survivors
5.
Cornea ; 40(11): 1502-1504, 2021 Nov 01.
Article in English | MEDLINE | ID: covidwho-2063050

ABSTRACT

ABSTRACT: The coronavirus disease 2019 global pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several ophthalmic manifestations have been reported to be associated with SARS-CoV-2 infection, including conjunctivitis, acute sixth nerve palsy, and multiple cranial neuropathies. We present a unique case of unilateral phlyctenular keratoconjunctivitis in a 5-year-old boy in the setting of SARS-CoV-2 infection.


Subject(s)
COVID-19/diagnosis , Conjunctivitis, Viral/diagnosis , Eye Infections, Viral/diagnosis , Keratoconjunctivitis/diagnosis , SARS-CoV-2/pathogenicity , Administration, Oral , Anti-Bacterial Agents/administration & dosage , Ascorbic Acid/administration & dosage , Azithromycin/administration & dosage , COVID-19/drug therapy , COVID-19/virology , COVID-19 Nucleic Acid Testing , Child, Preschool , Conjunctivitis, Viral/drug therapy , Conjunctivitis, Viral/virology , Drug Therapy, Combination , Eye Infections, Viral/drug therapy , Eye Infections, Viral/virology , Fluorometholone/therapeutic use , Glucocorticoids/therapeutic use , Humans , Keratoconjunctivitis/drug therapy , Keratoconjunctivitis/virology , Male , Ophthalmic Solutions , Slit Lamp Microscopy , Tomography, Optical Coherence , Visual Acuity/physiology
6.
J Virol ; 96(17): e0096122, 2022 09 14.
Article in English | MEDLINE | ID: covidwho-2053119

ABSTRACT

Omicron (B.1.1.529) is the most recent SARS-CoV-2 variant of concern, which emerged in late 2021 and rapidly achieved global predominance by early 2022. In this study, we compared the infection dynamics, tissue tropism, and pathogenesis and pathogenicity of SARS-CoV-2 D614G (B.1), Delta (B.1.617.2), and Omicron BA.1.1 (B.1.1.529) variants in a highly susceptible feline model of infection. Although D614G- and Delta-inoculated cats became lethargic and showed increased body temperatures between days 1 and 3 postinfection (pi), Omicron-inoculated cats remained subclinical and, similar to control animals, gained weight throughout the 14-day experimental period. Intranasal inoculation of cats with D614G- and the Delta variants resulted in high infectious virus shedding in nasal secretions (up to 6.3 log10 TCID50.Ml-1), whereas strikingly lower level of viruses shedding (<3.1 log10 TCID50.Ml-1) was observed in Omicron-inoculated animals. In addition, tissue distribution of the Omicron variant was markedly reduced in comparison to the D614G and Delta variants, as evidenced by lower in situ viral RNA detection, in situ viral immunofluorescence staining, and viral loads in tissues on days 3, 5, and 14 pi. Nasal turbinate, trachea, and lung were the main-but not the only-sites of replication for all three viral variants. However, only scarce virus staining and lower viral titers suggest lower levels of viral replication in tissues from Omicron-infected animals. Notably, while D614G- and Delta-inoculated cats presented pneumonia, histologic examination of the lungs from Omicron-infected cats revealed mild to modest inflammation. Together, these results demonstrate that the Omicron variant BA.1.1 is less pathogenic than D614G and Delta variants in a highly susceptible feline model. IMPORTANCE The SARS-CoV-2 Omicron (B.1.1.529) variant of concern emerged in South Africa late in 2021 and rapidly spread across the world causing a significant increase in the number of infections. Importantly, this variant was also associated with an increased risk of reinfections. However, the number of hospitalizations and deaths due to COVID-19 did not follow the same trends. These early observations suggested effective protection conferred by immunizations and/or overall lower virulence of the highly mutated variant virus. In this study we present novel evidence demonstrating that the Omicron BA.1.1 variant of concern presents a lower pathogenicity when compared to D614G- or Delta variants in cats. Clinical, virological, and pathological evaluations revealed lower disease severity, viral replication, and lung pathology in Omicron-infected cats when compared with D614G and Delta variant inoculated animals, confirming that Omicron BA.1.1 is less pathogenic in a highly susceptible feline model of infection.


Subject(s)
COVID-19/virology , SARS-CoV-2 , Animals , Cats , Disease Models, Animal , Humans , SARS-CoV-2/pathogenicity , Virulence , Virus Replication
8.
Nature ; 610(7931): 381-388, 2022 10.
Article in English | MEDLINE | ID: covidwho-2050416

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and caused the devastating global pandemic of coronavirus disease 2019 (COVID-19), in part because of its ability to effectively suppress host cell responses1-3. In rare cases, viral proteins dampen antiviral responses by mimicking critical regions of human histone proteins4-8, particularly those containing post-translational modifications required for transcriptional regulation9-11. Recent work has demonstrated that SARS-CoV-2 markedly disrupts host cell epigenetic regulation12-14. However, how SARS-CoV-2 controls the host cell epigenome and whether it uses histone mimicry to do so remain unclear. Here we show that the SARS-CoV-2 protein encoded by ORF8 (ORF8) functions as a histone mimic of the ARKS motifs in histone H3 to disrupt host cell epigenetic regulation. ORF8 is associated with chromatin, disrupts regulation of critical histone post-translational modifications and promotes chromatin compaction. Deletion of either the ORF8 gene or the histone mimic site attenuates the ability of SARS-CoV-2 to disrupt host cell chromatin, affects the transcriptional response to infection and attenuates viral genome copy number. These findings demonstrate a new function of ORF8 and a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation. Further, this work provides a molecular basis for the finding that SARS-CoV-2 lacking ORF8 is associated with decreased severity of COVID-19.


Subject(s)
COVID-19 , Epigenesis, Genetic , Histones , Host Microbial Interactions , Molecular Mimicry , SARS-CoV-2 , Viral Proteins , COVID-19/genetics , COVID-19/metabolism , COVID-19/virology , Chromatin/genetics , Chromatin/metabolism , Chromatin Assembly and Disassembly , Epigenome/genetics , Histones/chemistry , Histones/metabolism , Humans , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Viral Proteins/chemistry , Viral Proteins/genetics , Viral Proteins/metabolism
9.
J Virol ; 96(19): e0130122, 2022 10 12.
Article in English | MEDLINE | ID: covidwho-2038240

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remained genetically stable during the first 3 months of the pandemic, before acquiring a D614G spike mutation that rapidly spread worldwide and then generating successive waves of viral variants with increasingly high transmissibility. We set out to evaluate possible epistatic interactions between the early-occurring D614G mutation and the more recently emerged cleavage site mutations present in spike of the Alpha, Delta, and Omicron variants of concern. The P681H/R mutations at the S1/S2 cleavage site increased spike processing and fusogenicity but limited its incorporation into pseudoviruses. In addition, the higher cleavage rate led to higher shedding of the spike S1 subunit, resulting in a lower infectivity of the P681H/R-carrying pseudoviruses compared to those expressing the Wuhan wild-type spike. The D614G mutation increased spike expression at the cell surface and limited S1 shedding from pseudovirions. As a consequence, the D614G mutation preferentially increased the infectivity of P681H/R-carrying pseudoviruses. This enhancement was more marked in cells where the endosomal route predominated, suggesting that more stable spikes could better withstand the endosomal environment. Taken together, these findings suggest that the D614G mutation stabilized S1/S2 association and enabled the selection of mutations that increased S1/S2 cleavage, leading to the emergence of SARS-CoV-2 variants expressing highly fusogenic spikes. IMPORTANCE The first SARS-CoV-2 variant that spread worldwide in early 2020 carried a D614G mutation in the viral spike, making this protein more stable in its cleaved form at the surface of virions. The Alpha and Delta variants, which spread in late 2020 and early 2021, respectively, proved increasingly transmissible and pathogenic compared to the original strain. Interestingly, Alpha and Delta both carried the mutations P681H/R in a cleavage site that made the spike more cleaved and more efficient at mediating viral fusion. We show here that variants with increased spike cleavage due to P681H/R were even more dependent on the stabilizing effect of the D614G mutation, which limited the shedding of cleaved S1 subunits from viral particles. These findings suggest that the worldwide spread of the D614G mutation was a prerequisite for the emergence of more pathogenic SARS-CoV-2 variants with highly fusogenic spikes.


Subject(s)
COVID-19 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , COVID-19/virology , Humans , Mutation , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics
11.
Nature ; 611(7935): 346-351, 2022 11.
Article in English | MEDLINE | ID: covidwho-2036837

ABSTRACT

Clinical outcomes of severe acute respiratory syndrome 2 (SARS-CoV-2) infection are highly heterogeneous, ranging from asymptomatic infection to lethal coronavirus disease 2019 (COVID-19). The factors underlying this heterogeneity remain insufficiently understood. Genetic association studies have suggested that genetic variants contribute to the heterogeneity of COVID-19 outcomes, but the underlying potential causal mechanisms are insufficiently understood. Here we show that common variants of the apolipoprotein E (APOE) gene, homozygous in approximately 3% of the world's population1 and associated with Alzheimer's disease, atherosclerosis and anti-tumour immunity2-5, affect COVID-19 outcome in a mouse model that recapitulates increased susceptibility conferred by male sex and advanced age. Mice bearing the APOE2 or APOE4 variant exhibited rapid disease progression and poor survival outcomes relative to mice bearing the most prevalent APOE3 allele. APOE2 and APOE4 mice exhibited increased viral loads as well as suppressed adaptive immune responses early after infection. In vitro assays demonstrated increased infection in the presence of APOE2 and APOE4 relative to APOE3, indicating that differential outcomes are mediated by differential effects of APOE variants on both viral infection and antiviral immunity. Consistent with these in vivo findings in mice, our results also show that APOE genotype is associated with survival in patients infected with SARS-CoV-2 in the UK Biobank (candidate variant analysis, P = 2.6 × 10-7). Our findings suggest APOE genotype to partially explain the heterogeneity of COVID-19 outcomes and warrant prospective studies to assess APOE genotyping as a means of identifying patients at high risk for adverse outcomes.


Subject(s)
Apolipoproteins E , COVID-19 , Human Genetics , Mice, Transgenic , SARS-CoV-2 , Animals , Humans , Male , Mice , Apolipoprotein E2/genetics , Apolipoprotein E3/genetics , Apolipoprotein E4/genetics , Apolipoproteins E/genetics , COVID-19/genetics , COVID-19/mortality , COVID-19/virology , Mice, Transgenic/genetics , Mice, Transgenic/virology , Prospective Studies , SARS-CoV-2/pathogenicity , Disease Models, Animal
12.
Sci Rep ; 12(1): 1724, 2022 02 02.
Article in English | MEDLINE | ID: covidwho-1663979

ABSTRACT

This study introduces localized surface plasmon resonance (L-SPR) mediated heating filter membrane (HFM) for inactivating universal viral particles by using the photothermal effect of plasmonic metal nanoparticles (NPs). Plasmonic metal NPs were coated onto filter membrane via a conventional spray-coating method. The surface temperature of the HFM could be controlled to approximately 40-60 °C at room temperature, owing to the photothermal effect of the gold (Au) NPs coated on them, under irradiation by visible light-emitting diodes. Due to the photothermal effect of the HFMs, the virus titer of H1Npdm09 was reduced by > 99.9%, the full inactivation time being < 10 min, confirming the 50% tissue culture infective dose (TCID50) assay. Crystal violet staining showed that the infectious samples with photothermal inactivation lost their infectivity against Mardin-Darby Canine Kidney cells. Moreover, photothermal inactivation could also be applied to reduce the infectivity of SARS-CoV-2, showing reduction rate of 99%. We used quantitative reverse transcription polymerase chain reaction (qRT-PCR) techniques to confirm the existence of viral genes on the surface of the HFM. The results of the TCID50 assay, crystal violet staining method, and qRT-PCR showed that the effective and immediate reduction in viral infectivity possibly originated from the denaturation or deformation of membrane proteins and components. This study provides a new, simple, and effective method to inactivate viral infectivity, leading to its potential application in various fields of indoor air quality control and medical science.


Subject(s)
COVID-19/virology , Hot Temperature , Light , Metal Nanoparticles , Micropore Filters , SARS-CoV-2 , Surface Plasmon Resonance/methods , Virion , Virus Inactivation , Air Pollution, Indoor , Animals , Cells, Cultured , Dogs , Gold/chemistry , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity
13.
Front Public Health ; 10: 952916, 2022.
Article in English | MEDLINE | ID: covidwho-2022976

ABSTRACT

With the COVID-19 pandemic continuing, more contagious SARS-CoV-2 variants, including Omicron, have been emerging. The mutations, especially those that occurred on the spike (S) protein receptor-binding domain (RBD), are of significant concern due to their potential capacity to increase viral infectivity, virulence, and breakthrough antibodies' protection. However, the molecular mechanism involved in the pathophysiological change of SARS-CoV-2 mutations remains poorly understood. Here, we summarized 21 RBD mutations and their human angiotensin-converting enzyme 2 (hACE2) and/or neutralizing antibodies' binding characteristics. We found that most RBD mutations, which could increase surface positive charge or polarity, enhanced their hACE2 binding affinity and immune evasion. Based on the dependence of electrostatic interaction of the epitope residue of virus and docking protein (like virus receptors or antibodies) for its invasion, we postulated that the charge and/or polarity changes of novel mutations on the RBD domain of S protein could affect its affinity for the hACE2 and antibodies. Thus, we modeled mutant S trimers and RBD-hACE2 complexes and calculated their electrotactic distribution to study surface charge changes. Meanwhile, we emphasized that heparan sulfate proteoglycans (HSPGs) might play an important role in the hACE2-mediated entry of SARS-CoV-2 into cells. Those hypotheses provide some hints on how SARS-CoV-2 mutations enhance viral fitness and immune evasion, which may indicate potential ways for drug design, next-generation vaccine development, and antibody therapies.


Subject(s)
COVID-19 , Heparan Sulfate Proteoglycans , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , COVID-19/genetics , Heparan Sulfate Proteoglycans/genetics , Humans , Mutation , Pandemics , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics
14.
Proc Natl Acad Sci U S A ; 119(37): e2204717119, 2022 09 13.
Article in English | MEDLINE | ID: covidwho-2017032

ABSTRACT

The ongoing COVID-19 pandemic is a major public health crisis. Despite the development and deployment of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pandemic persists. The continued spread of the virus is largely driven by the emergence of viral variants, which can evade the current vaccines through mutations in the spike protein. Although these differences in spike are important in terms of transmission and vaccine responses, these variants possess mutations in the other parts of their genome that may also affect pathogenesis. Of particular interest to us are the mutations present in the accessory genes, which have been shown to contribute to pathogenesis in the host through interference with innate immune signaling, among other effects on host machinery. To examine the effects of accessory protein mutations and other nonspike mutations on SARS-CoV-2 pathogenesis, we synthesized both viruses possessing deletions in the accessory genes as well as viruses where the WA-1 spike is replaced by each variant spike gene in a SARS-CoV-2/WA-1 infectious clone. We then characterized the in vitro and in vivo replication of these viruses and compared them to both WA-1 and the full variant viruses. Our work has revealed that the accessory proteins contribute to SARS-CoV-2 pathogenesis and the nonspike mutations in variants can contribute to replication of SARS-CoV-2 and pathogenesis in the host. This work suggests that while spike mutations may enhance receptor binding and entry into cells, mutations in accessory proteins may alter clinical disease presentation.


Subject(s)
COVID-19 , Mutation , SARS-CoV-2 , Viral Regulatory and Accessory Proteins , Virulence , COVID-19/virology , Humans , SARS-CoV-2/classification , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Viral Regulatory and Accessory Proteins/genetics , Virulence/genetics , Virus Replication/genetics
15.
Nature ; 611(7934): 139-147, 2022 11.
Article in English | MEDLINE | ID: covidwho-2016757

ABSTRACT

Severe SARS-CoV-2 infection1 has been associated with highly inflammatory immune activation since the earliest days of the COVID-19 pandemic2-5. More recently, these responses have been associated with the emergence of self-reactive antibodies with pathologic potential6-10, although their origins and resolution have remained unclear11. Previously, we and others have identified extrafollicular B cell activation, a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity12,13, as a dominant feature of severe and critical COVID-19 (refs. 14-18). Here, using single-cell B cell repertoire analysis of patients with mild and severe disease, we identify the expansion of a naive-derived, low-mutation IgG1 population of antibody-secreting cells (ASCs) reflecting features of low selective pressure. These features correlate with progressive, broad, clinically relevant autoreactivity, particularly directed against nuclear antigens and carbamylated proteins, emerging 10-15 days after the onset of symptoms. Detailed analysis of the low-selection compartment shows a high frequency of clonotypes specific for both SARS-CoV-2 and autoantigens, including pathogenic autoantibodies against the glomerular basement membrane. We further identify the contraction of this pathway on recovery, re-establishment of tolerance standards and concomitant loss of acute-derived ASCs irrespective of antigen specificity. However, serological autoreactivity persists in a subset of patients with postacute sequelae, raising important questions as to the contribution of emerging autoreactivity to continuing symptomology on recovery. In summary, this study demonstrates the origins, breadth and resolution of autoreactivity in severe COVID-19, with implications for early intervention and the treatment of patients with post-COVID sequelae.


Subject(s)
Autoantibodies , B-Lymphocytes , COVID-19 , Humans , Autoantibodies/immunology , B-Lymphocytes/immunology , B-Lymphocytes/pathology , COVID-19/immunology , COVID-19/pathology , COVID-19/physiopathology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Immunoglobulin G/immunology , Single-Cell Analysis , Autoantigens/immunology , Basement Membrane/immunology
16.
Nature ; 609(7927): 582-589, 2022 09.
Article in English | MEDLINE | ID: covidwho-2016756

ABSTRACT

Increased levels of proteases, such as trypsin, in the distal intestine have been implicated in intestinal pathological conditions1-3. However, the players and mechanisms that underlie protease regulation in the intestinal lumen have remained unclear. Here we show that Paraprevotella strains isolated from the faecal microbiome of healthy human donors are potent trypsin-degrading commensals. Mechanistically, Paraprevotella recruit trypsin to the bacterial surface through type IX secretion system-dependent polysaccharide-anchoring proteins to promote trypsin autolysis. Paraprevotella colonization protects IgA from trypsin degradation and enhances the effectiveness of oral vaccines against Citrobacter rodentium. Moreover, Paraprevotella colonization inhibits lethal infection with murine hepatitis virus-2, a mouse coronavirus that is dependent on trypsin and trypsin-like proteases for entry into host cells4,5. Consistently, carriage of putative genes involved in trypsin degradation in the gut microbiome was associated with reduced severity of diarrhoea in patients with SARS-CoV-2 infection. Thus, trypsin-degrading commensal colonization may contribute to the maintenance of intestinal homeostasis and protection from pathogen infection.


Subject(s)
Gastrointestinal Microbiome , Intestine, Large , Symbiosis , Trypsin , Administration, Oral , Animals , Bacterial Secretion Systems , Bacterial Vaccines/administration & dosage , Bacterial Vaccines/immunology , Bacteroidetes/isolation & purification , Bacteroidetes/metabolism , COVID-19/complications , Citrobacter rodentium/immunology , Diarrhea/complications , Feces/microbiology , Gastrointestinal Microbiome/genetics , Humans , Immunoglobulin A/metabolism , Intestine, Large/metabolism , Intestine, Large/microbiology , Mice , Murine hepatitis virus/metabolism , Murine hepatitis virus/pathogenicity , Proteolysis , SARS-CoV-2/pathogenicity , Trypsin/metabolism , Virus Internalization
18.
Nature ; 609(7929): 994-997, 2022 09.
Article in English | MEDLINE | ID: covidwho-1991628

ABSTRACT

Accurate and timely detection of recombinant lineages is crucial for interpreting genetic variation, reconstructing epidemic spread, identifying selection and variants of interest, and accurately performing phylogenetic analyses1-4. During the SARS-CoV-2 pandemic, genomic data generation has exceeded the capacities of existing analysis platforms, thereby crippling real-time analysis of viral evolution5. Here, we use a new phylogenomic method to search a nearly comprehensive SARS-CoV-2 phylogeny for recombinant lineages. In a 1.6 million sample tree from May 2021, we identify 589 recombination events, which indicate that around 2.7% of sequenced SARS-CoV-2 genomes have detectable recombinant ancestry. Recombination breakpoints are inferred to occur disproportionately in the 3' portion of the genome that contains the spike protein. Our results highlight the need for timely analyses of recombination for pinpointing the emergence of recombinant lineages with the potential to increase transmissibility or virulence of the virus. We anticipate that this approach will empower comprehensive real-time tracking of viral recombination during the SARS-CoV-2 pandemic and beyond.


Subject(s)
COVID-19 , Genome, Viral , Pandemics , Phylogeny , Recombination, Genetic , SARS-CoV-2 , COVID-19/epidemiology , COVID-19/transmission , COVID-19/virology , Genome, Viral/genetics , Humans , Mutation , Recombination, Genetic/genetics , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Selection, Genetic/genetics , Spike Glycoprotein, Coronavirus/genetics , Virulence/genetics
20.
Viruses ; 14(8)2022 08 12.
Article in English | MEDLINE | ID: covidwho-1987990

ABSTRACT

In the majority of cases, patients infected with the SARS-CoV-2 virus experience a complete resolution of symptoms within six weeks of acquiring the infection, but an increasing number of patients report persistent symptoms. This study aimed to analyse the prevalence of self-reported smell and/or taste disorders (STDs) in a group of convalescent patients after infection with the SARS-CoV-2 virus and to identify risk factors for the disease. The study included 2218 COVID-19 convalescents after both inpatient and outpatient treatment. The sample group was analysed with regard to chronic diseases, place of isolation and clinical symptoms occurring during COVID-19 along with their duration. The assessment also included the most common symptoms of COVID-19 and the severity of the disease course. A total of 98 patients reported persistent smell and taste disorders up to three months after the end of isolation (67.4% of men and 32.6% of women). The mean age of the participants was 53.8 ± 13.5 years (49.19 ± 14.68 in patients with an STD vs. 54.01 ± 13.44 in patients without an STD). The patients treated for COVID-19 at home (p < 0.001) constituted almost the entire group of patients with persistent smell and taste disorders (97%). Among the patients with persistent smell and taste disorders, 57.1% suffered from at least one chronic condition (vs. 71.4% of patients without an STD). In patients with an STD, the number of symptoms per patient was higher than in the other group at 8.87 ± 3.65 (p = 0.018), while the most common clinical symptoms during the acute phase of COVID-19 were smell and taste disorders (84%) (p < 0.001), significant weakness (70%), headache (60%), cough (55%), arthralgia (51%) (p = 0.034) and back muscle pain (51%). Based on the results obtained, the following conclusions were drawn: the risk of developing persistent smell and taste disorders after COVID-19 is greater in younger people with less comorbidities and a higher number of symptoms during the acute phase of COVID-19. The risk is associated with clinical symptoms occurring during the acute phase of COVID-19, i.e., smell and taste disorders and arthralgia. In addition, this risk is higher in patients receiving outpatient treatment for COVID-19.


Subject(s)
COVID-19 , Cardiovascular Diseases , Olfaction Disorders , Taste Disorders , Adult , Aged , Arthralgia , COVID-19/complications , COVID-19/epidemiology , Cardiovascular Diseases/complications , Female , Humans , Male , Middle Aged , Olfaction Disorders/diagnosis , Olfaction Disorders/epidemiology , Olfaction Disorders/etiology , Poland/epidemiology , SARS-CoV-2/pathogenicity , Smell , Taste Disorders/diagnosis , Taste Disorders/epidemiology , Taste Disorders/etiology
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