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Infections can lead to persistent or long-term symptoms and diseases such as shingles after varicella zoster, cancers after human papillomavirus, or rheumatic fever after streptococcal infections(1,2). Similarly, infection by SARS-CoV-2 can result in Long COVID, a condition characterized by symptoms of fatigue and pulmonary and cognitive dysfunction(3-5). The biological mechanisms that contribute to the development of Long COVID remain to be clarified. We leveraged the COVID-19 Host Genetics Initiative(6,7) to perform a genome-wide association study for Long COVID including up to 6,450 Long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We identified the first genome-wide significant association for Long COVID at the FOXP4 locus. FOXP4 has been previously associated with COVID-19 severity(6), lung function(8), and cancers(9), suggesting a broader role for lung function in the pathophysiology of Long COVID. While we identify COVID-19 severity as a causal risk factor for Long COVID, the impact of the genetic risk factor located in the FOXP4 locus could not be solely explained by its association to severe COVID-19. Our findings further support the role of pulmonary dysfunction and COVID-19 severity in the development of Long COVID.
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Infecciones Estreptocócicas , Enfermedades Pulmonares , Neoplasias , Infecciones por Papillomavirus , COVID-19 , Trastornos del Conocimiento , Fiebre ReumáticaRESUMEN
Background The severity of chest X-ray (CXR) findings is a prognostic factor in patients with coronavirus disease 2019 (COVID-19). However, the prognostic impact of deterioration of CXR findings and the clinical characteristics of patients with worsening CXR findings remain unclear. We aimed to investigate the clinical and genetic characteristics, as well as the prognosis, of patients with worsening CXR findings during early hospitalisation.Methods We retrospectively included 1656 consecutive Japanese patients with COVID-19 recruited through the Japan COVID-19 Task Force. Rapid deterioration of CXR findings was defined as increased pulmonary infiltrates in ≥ 50% of the lung fields within 48 h of admission.Results Rapid deterioration of CXR findings was an independent risk factor for death, most severe illness, tracheal intubation, and intensive care unit admission. The presence of consolidation on CXR, comorbid cardiovascular and chronic obstructive pulmonary diseases; high body temperature (≥ 37.7°C); and increased levels of serum aspartate aminotransferase (≥ 30 IU/L), potassium (≥ 4.3 mEq/L), and C-reactive protein (≥ 2.53 mg/dL) were independent risk factors for rapid deterioration of CXR findings. The risk variant at the ABO locus (rs529565-C) was associated with rapid deterioration of CXR findings in all patients with COVID-19. Further, the population-specific risk variant at the DOCK2 locus (rs60200309-A) was nominally associated with rapid deterioration of CXR findings in patients aged < 65 years.Conclusions This study revealed the clinical features, genetic features, and risk factors for rapid deterioration of CXR findings in patients with COVID-19. Rapid deterioration of CXR findings is a poor prognostic factor for patients with COVID-19.
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Enfermedad Pulmonar Obstructiva Crónica , Muerte , COVID-19RESUMEN
Background: An association between coronavirus disease 2019 (COVID-19) and ABO blood group has been reported. However, such an association has not been studied in the Japanese population on a large scale. Additionally, little is known about the association between COVID-19 and ABO genotype. Therefore, the present study aimed to investigate the association between COVID-19 and ABO blood group/genotype in a large Japanese population. Methods: All Japanese patients diagnosed with COVID-19 were recruited through the Japan COVID-19 Task Force between February 2020 and October 2021. We conducted a retrospective cohort study involving 1,790 COVID-19 Japanese patients whose DNA was used for genome-wide association study. We compared the ABO blood group/genotype in healthy population (n = 611, control) and COVID-19 patients, and then analyzed the association between the ABO blood group/genotype and clinical outcomes. Results: Blood group A was significantly more prevalent (41.6% vs. 36.8%) and group O was significantly less prevalent (26.2% vs. 30.8%) in the COVID-19 group than in the control group. Moreover, genotype OO was significantly less common in the COVID-19 group. Further, blood group AB was identified as an independent risk factor for most severe diseases compared with blood group O [aOR (95% CI) = 1.84 (1.00–3.37)]. Similarly, in ABO genotype analysis, only genotype AB was an independent risk factor for most severe disease compared with genotype OO. Conclusions: Blood group O is protective, whereas blood group A is associated with the risk of infection. Moreover, blood group AB is associated with the risk of ‘most’ severe disease.
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COVID-19RESUMEN
The use of therapeutic neutralizing antibodies against SARS-CoV-2 infection has been highly effective. However, there remain few practical antibodies against viruses that are acquiring mutations. In this study, we created 494 monoclonal antibodies from COVID-19-convalescent patients, and identified antibodies that exhibited comparable neutralizing ability to clinically used antibodies in the neutralization assay using pseudovirus and authentic virus including variants of concerns. These antibodies have different profiles against various mutations, which were confirmed by cell-based assay and cryo-electron microscopy. To prevent antibody-dependent enhancement, N297A modification was introduced, and showed a reduction of lung viral RNAs by therapeutic administration in a hamster model. In addition, an antibody cocktail consisting of three antibodies was also administered therapeutically to a macaque model, which resulted in reduced viral titers of swabs and lungs and reduced lung tissue damage scores. These results showed that our antibodies have sufficient antiviral activity as therapeutic candidates.
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COVID-19RESUMEN
The detailed mechanisms of COVID-19 infection pathology remain poorly understood. To improve our understanding of SARS-CoV-2 pathology, we performed a multi-omics analysis of an immunologically naive SARS-CoV-2 clinical cohort from the plasma of uninfected controls, mild, and severe infections. A comparison of healthy controls and patient samples showed activation of neutrophil degranulation pathways and formation of neutrophil extracellular trap (NET) complexes that were activated in a subset of the mild infections and more prevalent in severe infections (containing multiple NET proteins in individual patient samples). As a potential mechanism to suppress NET formation, multiple redox enzymes were elevated in the mild and severe symptom population. Analysis of metabolites from the same cohort showed a 24- and 60-fold elevation in plasma L-cystine, the oxidized form of cysteine, which is a substrate of the powerful antioxidant glutathione, in mild and severe patients, respectively. Unique to patients with mild infections, the carnosine dipeptidase modifying enzyme (CNDP1) was up-regulated. The strong protein and metabolite oxidation signatures suggest multiple compensatory pathways working to suppress oxidation and NET formation in SARS-CoV-2 infections.
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COVID-19 , Síndrome Respiratorio Agudo GraveRESUMEN
The gastrointestinal tract is constitutively exposed to proteases including trypsin, a serine protease originating from the pancreas1. Elevated trypsin levels in the large intestine have been implicated in pathological conditions including infectious and inflammatory bowel disease2-4. Here we show that trypsin is regulated via degradation by members of the gut microbiota. After passing through the small intestine, trypsin activity is markedly reduced in the caecum of specific pathogen-free (SPF) mice, whereas germ-free (GF) mice have high luminal trypsin levels. We have successfully identified and isolated Paraprevotella strains from the faecal microbiome of healthy human donors as potent trypsin-degrading commensals. Mechanistically, Paraprevotella recruit trypsin to the bacterial surface through type IX secretion system-dependent polysaccharide-anchoring proteins and 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, a mouse coronavirus dependent on trypsin and trypsin-like proteases for entry into host cells5,6. Congruently, carriage of putative genes involved in trypsin degradation in the gut microbiome was associated with reduced diarrhoea severity in patients with SARS-CoV2 infection. Therefore, trypsin-degrading commensal colonization may contribute to the maintenance of intestinal homeostasis and protection from pathogen infection.
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To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (<65 years of age) patients with a genome-wide significant p-value of 1.2 x 10-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.
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Obesidad , COVID-19RESUMEN
Background: It is well known that SARS-CoV-2 genome accumulates point mutations constantly. However, whether non-synonymous mutations affect COVID-19 severity through altering viral protein function remains unknown.Methods: We performed SARS-CoV-2 genome sequencing in 90 patients with COVID-19 admitted at Keio University Hospital in Tokyo Metropolitan area between March and August 2020. Viral haplotypes were examined by counting the number of non-synonymous mutations to analyse phylogenic trees and comparative amino acid sequence. Statistically relevant non-synonymous mutations were functionally evaluated with structural analyses.Findings: The number of non-synonymous mutations correlated inversely with the COVID-19 severity. Phylogenic tree analyses identified two predominant groups which were differentiated by a set of six point mutations (four non-synonymous amino acid mutations). Among them, Pro108Ser in 3 chymotrypsin-like protease (3CLpro) and Pro151Leu in nucleocapsid protein occurred at conserved locations among β-coronaviruses. Patients with these mutations indicated significantly lower odds ratio for developing hypoxia which required supplemental oxygen (adjusted odds ratio 0·24 [95% CI 0·07-0·88, p-value = 0·032]) after adjustments for age and sex, versus those lacking this haplotype in the canonical Clade 20B spread in Japan. The Pro108Ser 3CLpro enzyme decreases in the activity by 58%, and the hydrogen/deuterium exchange mass spectrometry reveals that mechanisms for decline-of-function involve structural perturbation at the substrate-binding region which is positioned behind and distant from the 108th amino acid residue of the enzyme.Interpretation: Viral genome sequencing in Tokyo showed that the specific mutant strain containing Pro108Ser mutation in 3CLpro, ameliorates the COVID-19 severity. This Pro108Ser mutant in 3CLpro reduces the catalytic activity of the protein by 50%. The mutant strain rapidly outcompeted pre-existing variants to become the dominant one in Japan. Our results may benefit the efforts under way to design small molecular compounds or antibodies targeting 3CLpro.Funding: Keio Gijuku Academic Development Funds and AMED (Grant Number JP20he0622043)Declaration of Interests: Authors have no conflicts of interests.Ethics Approval Statement: The study protocol was approved by the Ethics Committee of Keio University School of Medicine (approval number: 20200062).
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Discapacidades para el Aprendizaje , Hipoxia , COVID-19RESUMEN
Background: SARS-CoV-2 genome accumulates point mutations in a constant manner. Whether the accumulation of point mutations is correlated with milder manifestations of COVID-19 remains unknown. Methods: We performed SARS-CoV-2 genome sequencing in 90 patients with COVID-19 infection treated at a tertiary medical center in Tokyo between March and August 2020. The possible association between disease severity and viral haplotype was then assessed by counting the number of mutations in addition to performing phylogenic tree analysis, comparative amino acid sequence analysis among {beta}-coronaviruses, and mathematical prediction of the functional relevance of amino acid substitutions. Results: The number of non-synonymous mutations was inversely correlated with COVID-19 severity, as defined by requiring oxygen supplementation. Phylogenic tree analysis identified two predominant groups which were separated by a set of 6 single nucleotide substitutions, including four leading to non-synonymous amino acid substitutions. Among those four, Pro108Ser in 3 chymotrypsin-like protease (3CLpro) and Pro151Leu in nucleocapsid protein occurred at conserved locations and were predicted to be deleterious. Patients with Pro108Ser in 3CLpro and Pro151Leu in nucleocapsid protein had a lower odds ratio for developing hypoxia requiring supplemental oxygen (odds ratio of 0.24 [95% confidence interval of 0.07-0.88, P-value = 0.032]) after adjustments for age and sex, compared with patients lacking this haplotype in Clade 20B. Conclusion: Viral genome sequencing in 90 patients treated in the Tokyo Metropolitan area showed that the accumulation of point mutations, including Pro108Ser in 3CLpro and Pro151Leu in nucleocapsid protein, was inversely correlated with COVID-19 severity. Further in vitro research is awaited.