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Pandemic influenza virus A(H1N1)pdm09 infection occurred in healthy children and young adults, but asthmatic patients presented more rapid progression of respiratory distress and plastic bronchitis. To investigate the pathogenesis of worsening respiratory symptoms after A(H1N1)pdm09 infection, we focused on matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1). MMP-9 and TIMP-1 levels in bronchoalveolar lavage fluid and serum from mice with and without asthma were evaluated after A(H1N1)pdm09 or seasonal A(H1N1) infection. MMP-9 levels were more elevated in Asthma/A(H1N1)pdm09-infected mice than in non-Asthma/A(H1N1)pdm09-infected mice on both 3 and 7 days post-infection. Immunohistochemical findings in this pneumonia model showed that MMP-9 and TIMP-1 positive cells were observed in blood vessels and bronchus of lung tissue in severe pathological findings of pneumonia with asthma. Microscopically, shedding cells and secretions were conspicuous in the trachea on days 3 and 7 post-infection, in the A(H1N1)pdm09-infected mice with asthma. Our results suggest that MMP-9 and TIMP-1 expressions are related to severe pneumonia in the A(H1N1)pdm09 infection with asthma, leading to cause epithelial cell shedding.

In parallel with vaccination, oral antiviral agents are highly anticipated to act as countermeasures for the treatment of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Oral antiviral medication demands not only high antiviral activity but also target specificity, favorable oral bioavailability, and high metabolic stability. Although a large number of compounds have been identified as potential inhibitors of SARS-CoV-2 infection in vitro, few have proven to be effective in vivo. Here, we show that oral administration of S-217622 (ensitrelvir), an inhibitor of SARS-CoV-2 main protease (M pro ; also known as 3C-like protease), decreases viral load and ameliorates disease severity in SARS-CoV-2–infected hamsters. S-217622 inhibited viral proliferation at low nanomolar to submicromolar concentrations in cells. Oral administration of S-217622 demonstrated favorable pharmacokinetic properties and accelerated recovery from acute SARS-CoV-2 infection in hamster recipients. Moreover, S-217622 exerted antiviral activity against SARS-CoV-2 variants of concern, including the highly pathogenic Delta variant and the recently emerged Omicron BA.5 and BA.2.75 variants. Overall, our study provides evidence that S-217622, an antiviral agent that is under evaluation in a phase 3 clinical trial (clinical trial registration no. jRCT2031210350), has remarkable antiviral potency and efficacy against SARS-CoV-2 and is a prospective oral therapeutic option for COVID-19.

A 72-year-old patient was admitted to the ICU due to acute respiratory distress syndrome caused by coronavirus disease 2019. On day 20, the patient experienced shock. The electrocardiogram showed ST segment elevation in leads V3–V6 and severe left ventricular dysfunction with an ejection fraction of 35%–40%. The left ventricle showed basal hypokinesis and apical akinesis, while the creatine kinase level was normal, indicating Takotsubo cardiomyopathy. On day 24, the patient died of multiple organ failure. In post-mortem biopsy, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen was detected in cardiomyocytes by immunostaining. Moreover, SARS-CoV-2 RNA was detected in heart tissue. We need to further analyze the direct link between SARS-CoV2 and cardiomyocytes.

We herein report a 67-year-old kidney transplant patient who died of COVID-19. He was treated with hydroxychloroquine and azithromycin and received mechanical ventilation that temporarily improved his respiratory status. Despite our efforts, however, he later developed respiratory failure and died 43 days after the disease onset. The autopsy revealed prominent organization of alveoli and alveolar ducts, with a massive accumulation of macrophages in the lungs. A few severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen-positive cells were detected in the lung, suggesting delayed virus clearance owing to his long-term immunosuppressed state, leading to constant lung damage and ultimately respiratory failure.

Purpose Recombinant human soluble thrombomodulin (rTM) has been used to treat disseminated intravascular coagulation (DIC). Recent studies have shown the efficacy of rTM through its anti-inflammatory effects for treatment of adults with acute respiratory distress syndrome (ARDS). However, the safety and efficacy of rTM in children with severe ARDS complicated by DIC have not been reported. In this preliminary study, we reported the feasibility of using rTM for the treatment of pneumonia-induced severe ARDS complicated by DIC in children. Methods Six children (age: median 10 months old) with pneumonia-induced severe ARDS complicated by DIC were enrolled in this preliminary study. rTM (380 U/kg) was administered for a maximum of 6 days, in addition to conventional therapies after diagnosis of severe ARDS complicated by DIC. After administration of rTM, we measured changes in the plasma TM concentration and evaluated the clinical course, status of DIC and ARDS, and other laboratory findings, including levels of cytokines, chemokines, and biomarkers. Results In all six children, the plasma concentration of TM increased and DIC scores decreased after administration of rTM. Four of the six children recovered from the severe ARDS complicated by DIC after treatment, and were discharged from the hospital with no complications. In survived children, levels of soluble receptors for advanced glycation end products, interleukin-6, interleukin-8 and monocyte chemotactic protein-1 decreased after administration of rTM compared to those before rTM. Conclusions The rTM administration is feasible as an adjunctive therapeutic strategy for children over 2 months with pneumonia-induced severe ARDS complicated by DIC. Supplementary Information The online version contains supplementary material available at 10.1007/s00540-021-02971-3.

Background Severe asthma exacerbation is an important comorbidity of the 2009 HIN1 pandemic (A(H1N1)pdm09) in asthmatic patients. However, the mechanisms underlying severe asthma exacerbation remain unknown. In this study, airway hyperresponsiveness (AHR) was measured in pediatric asthma patients infected with A(H1N1)pdm09. We also evaluated AHR in asthmatic mice with A(H1N1)pdm09 infection and those with seasonal influenza for comparison. Methods AHRs in asthmatic children were defined as the provocative acetylcholine concentration causing a 20% reduction in forced expiratory volume in 1 s (PC20). To investigate the pathophysiology using animal models, BALB/c mice aged 6‐8 weeks were sensitized and challenged with ovalbumin. Either mouse‐adapted A(H1N1)pdm09, seasonal H1N1 virus (1 × 105 pfu/20 μl), or mock treatment as a control was administered intranasally. At 3, 7, and 10 days after infection, each group of mice was evaluated for AHR by methacholine challenge using an animal ventilator, flexiVent. Lung samples were resected and observed using light microscopy to assess the degree of airway inflammation. Results AHRs in the children with bronchial asthma were temporarily increased, and alleviated by 3 months after discharge. AHR was significantly enhanced in A(H1N1)pdm09‐infected asthmatic mice compared to that in seasonal H1N1‐infected mice (p, AHR was significantly enhanced in asthmatic mice with A(H1N1)pdm09 infection compared with seasonal influenza infection. AHR and pulmonary inflammation of A(H1N1)pdm09‐infected mice showed peak at 7 days post infection and they were improved by 10 days postinfection. Also, AHR in asthmatic children after A(H1N1)pdm09 infection were temporarily increased, and alleviated by 3 months after discharge.

Objectives Transrectal laparoscopy (TRLS) using a flexible endoscope was recently proposed for peritoneal observation. Although previous studies have reported its feasibility, follow-up durations were insufficient to ascertain technical safety. Moreover, knowledge about the technical feasibility of collecting peritoneal cytological lavage or ascites during TRLS is limited. Thus, this study aimed to confirm the safety and efficacy of TRLS in a porcine survival model. Methods After creating artificial ascites in 10 animals, TRLS was performed as follows: submucosal tunnel creation on the anterior wall of the rectum, intentional perforation at the distal end of the tunnel, endoscopic ascites collection and intraperitoneal observation, and clip closure at the mucosal incision site. The pigs were administered antibiotics orally for 7 days after TRLS and killed for histological evaluation and bacterial culture after 28 days of observation. Results The technical success rates of insertion into the abdominal cavity, ascites collection, and clip closure were 100%. All frequent anatomical sites for peritoneal dissemination including the stomach, subdiaphragmatic space, and pelvic space were fully observable without adverse events. The median procedure time was 36.3 min. Full 28-day survival was observed in all cases without any infection. The autopsies showed no infection, including abscess formation. Bacterial cultures of the peritoneal cavity were negative 28 days after TRLS in all cases. Conclusions Transrectal laparoscopy enabled ascites collection and intraperitoneal observation without adverse events. All animals survived without peritonitis. Therefore, TRLS can be an option for intraperitoneal examination.

The avian influenza A(H7N9) virus has caused high mortality rates in humans, especially in the elderly; however, little is known about the mechanistic basis for this. In the current study, we used nonhuman primates to evaluate the effect of aging on the pathogenicity of A(H7N9) virus. We observed that A(H7N9) virus infection of aged animals (defined as age 20–26 years) caused more severe symptoms than infection of young animals (defined as age 2–3 years). In aged animals, lung inflammation was weak and virus infection was sustained. Although cytokine and chemokine expression in the lungs of most aged animals was lower than that in the lungs of young animals, 1 aged animal showed severe symptoms and dysregulated proinflammatory cytokine and chemokine production. These results suggest that attenuated or dysregulated immune responses in aged animals are responsible for the severe symptoms observed among elderly patients infected with A(H7N9) virus.

An autopsy of a patient in Japan with coronavirus disease indicated pneumonia lung pathology, manifested as diffuse alveolar damage. We detected severe acute respiratory syndrome coronavirus 2 antigen in alveolar epithelial cells and macrophages. Coronavirus disease is essentially a lower respiratory tract disease characterized by direct viral injury of alveolar epithelial cells.

In parallel with vaccination, oral antiviral agents are highly anticipated to act as countermeasures for the treatment of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Oral antiviral medication demands not only high antiviral activity but also target specificity, favorable oral bioavailability, and high metabolic stability. Although a large number of compounds have been identified as potential inhibitors of SARS-CoV-2 infection in vitro, few have proven to be effective in vivo. Here, we show that oral administration of S-217622, a novel inhibitor of SARS-CoV-2 main protease (Mpro, also known as 3C-like protease), decreases viral load and ameliorates the disease severity in SARS-CoV-2-infected hamsters. S-217622 inhibited viral proliferation at low nanomolar to sub-micromolar concentrations in cells. Oral administration of S-217622 demonstrated eminent pharmacokinetic properties and accelerated recovery from acute SARS-CoV-2 infection in hamster recipients. Moreover, S-217622 exerted antiviral activity against SARS-CoV-2 variants of concern (VOCs), including the highly pathogenic Delta variant and the recently emerged Omicron variant. Overall, our study provides evidence that S-217622, an antiviral agent that is under evaluation in a phase II/III clinical trial, possesses remarkable antiviral potency and efficacy against SARS-CoV-2 and is a prospective oral therapeutic option for COVID-19.

Polymerase chain reaction (PCR) is highly sensitive and is thus the standard method for diagnosing pertussis. Real-time PCR is widely used because of its accuracy and the simplicity of the simultaneous cycle threshold (Ct) value, which represents the copy numbers of the target gene. Little is known of the association of Ct value with pertussis severity in neonates and infants.This study determined Ct values in neonates and infants diagnosed with pertussis by real-time PCR using nasopharyngeal samples at Vietnam National Children's Hospital in Hanoi in 2017 and 2019. The association of disease severity and clinical parameters were analyzed using univariate and multivariate analyses.We evaluated 108 patients with pertussis [median age: 63 days, interquartile range (IQR): 41-92 days]. Only 6/108 (6%) received at least 1 dose of a pertussis-containing vaccine. Among them, 24 (22.2%) had severe disease requiring care in a pediatric intensive care unit, 16 (13.8%) required mechanical ventilation, and 3 (2.6%) died. The median Ct value was lower in patients with severe disease (19.0, IQR: 16.5-22.0, n = 24) than in those without severe disease (25.5, IQR: 20.0-30.0, n = 84) (P = 0.002). Logistic regression analyses demonstrated that PCR Ct value [odds ratio (OR): 1.783, 95% confidence interval (CI): 1.013-3.138, P = 0.045], age (OR: 3.118, 95% CI: 1.643-5.920, P = 0.001), and white blood cell counts (OR: 0.446, 95% CI: 0.261-0.763, P = 0.003) remained significantly associated with severe disease.Real-time PCR Ct values for pertussis might be useful as a predictor of severe disease in neonates and infants.

Despite the development and deployment of antibody and vaccine countermeasures, rapidly-spreading SARS-CoV-2 variants with mutations at key antigenic sites in the spike protein jeopardize their efficacy. The recent emergence of B.1.1.529, the Omicron variant1,2, which has more than 30 mutations in the spike protein, has raised concerns for escape from protection by vaccines and therapeutic antibodies. A key test for potential countermeasures against B.1.1.529 is their activity in pre-clinical rodent models of respiratory tract disease. Here, using the collaborative network of the SARS-CoV-2 Assessment of Viral Evolution (SAVE) program of the National Institute of Allergy and Infectious Diseases (NIAID), we evaluated the ability of multiple B.1.1.529 Omicron isolates to cause infection and disease in immunocompetent and human ACE2 (hACE2) expressing mice and hamsters. Despite modeling and binding data suggesting that B.1.1.529 spike can bind more avidly to murine ACE2, we observed attenuation of infection in 129, C57BL/6, and BALB/c mice as compared with previous SARS-CoV-2 variants, with limited weight loss and lower viral burden in the upper and lower respiratory tracts. Although K18-hACE2 transgenic mice sustained infection in the lungs, these animals did not lose weight. In wild-type and hACE2 transgenic hamsters, lung infection, clinical disease, and pathology with B.1.1.529 also were milder compared to historical isolates or other SARS-CoV-2 variants of concern. Overall, experiments from multiple independent laboratories of the SAVE/NIAID network with several different B.1.1.529 isolates demonstrate attenuated lung disease in rodents, which parallels preliminary human clinical data.

Despite various attempts to treat SARS-CoV-2-infected patients with COVID-19-convalescent plasmas, neither appropriate approach nor clinical utility has been established. We examined the efficacy of administration of highly-neutralizing COVID-19-convalescent plasma (hn-plasmas) and such plasma-derived IgG administration using the Syrian hamster COVID-19 model. Two hn-plasmas, which were in the best 1% of 340 neutralizing-activity-determined convalescent plasma samples, were intraperitoneally administered to SARS-CoV-2-infected hamsters, resulting in significant reduction of viral titers in lungs by up to 32-fold as compared to the viral titers in hamsters receiving control non-neutralizing plasma, while with two moderately neutralizing plasmas (mn-plasmas) administered, viral titer reduction was by up to 6-fold. IgG fractions purified from the two hn-plasmas also reduced viral titers in lungs than those from the two mn-plasmas. The severity of lung lesions seen in hamsters receiving hn-plasmas was minimal to moderate as assessed using micro-computerized tomography, which histological examination confirmed. Western blotting revealed that all four COVID-19-convalescent-plasmas variably contained antibodies against SARS-CoV-2 components including the receptor-binding domain and S1 domain. The present data strongly suggest that administering potent-neutralizing-activity-confirmed COVID-19-convalescent plasmas would be efficacious in treating patients with COVID-19. Importance Convalescent plasmas obtained from patients, who recovered from a specific infection, have been used as agents to treat other patients infected with the very pathogen. To treat using convalescent plasmas, despite that more than 10 randomized-controlled-clinical-trials have been conducted and more than 100 studies are currently ongoing, the effects of convalescent plasma against COVID-19 remained uncertain. On the other hand, certain COVID-19 vaccines have been shown to reduce the clinical COVID-19 onset by 94-95%, for which the elicited SARS-CoV-2-neutralizing antibodies are apparently directly responsible. Here, we demonstrate that highly-neutralizing-effect-confirmed convalescent plasmas significantly reduce the viral titers in the lung of SARS-CoV-2-infected Syrian hamsters and block the development of virally-induced lung lesions. The present data provide a proof-of-concept that the presence of highly-neutralizing antibody in COVID-19-convalescent plasmas is directly responsible for the reduction of viral replication and support the use of highly-neutralizing antibody-containing plasmas in COVID-19 therapy with convalescent plasmas.

The effects of simultaneous or serial infections with SARS-CoV-2 and influenza virus are unknown. Here, we report that, in a hamster model, SARS-CoV-2 infection at the same time as or prior to H3N2 influenza virus infection resulted in significantly reduced influenza virus titers in the lungs and nasal turbinates of infected animals. This interference of influenza virus replication may correlate with SARS-CoV-2-induced expression of the antiviral gene MX1.

Here we report the isolation of the influenza A/H1N1 2009 pandemic (A/H1N1pdm) and A/H3N2 viruses carrying an I38T mutation in the polymerase acidic protein-a mutation that confers reduced susceptibility to baloxavir marboxil-from patients before and after treatment with baloxavir marboxil in Japan. These variants showed replicative abilities and pathogenicity that is similar to those of wild-type isolates in hamsters; they also transmitted efficiently between ferrets by respiratory droplets.

BACKGROUND We examined treatment the efficacy and data on long-term outcomes in real-world Japanese patients infected with hepatitis C virus (HCV) genotype 2 treated with 12-week sofosbuvir/ribavirin combination therapy. PATIENTS AND METHODS In a total of 86 patients who were treated with sofosbuvir/ribavirin, sustained virological response (SVR) rates and long-term-outcomes were retrospectively analyzed. RESULTS The adherence to this combination therapy was 98.8%. The rates of SVR at week 24 (SVR24) achieved with this treatment according to the 'intention-to-treat' and 'per-protocol' analyses were 89.5% and 96.2%, respectively. Two patients who experienced relapse did not have any previously reported resistance-associated substitutions in the HCV non-structural protein 5B (NS5B) polymerase region. We did not observe any patients who experienced late relapse but did observe that 50% and 1.3% of patients with and without a previous history of hepatocellular carcinoma (HCC), respectively, developed HCC after achieving SVR24 (with a mean follow-up period of 2.7±0.8 years). CONCLUSION Patients with SVR should be carefully followed-up to screen for the occurrence of HCC, although it is infrequent.

Despite various attempts to treat SARS-CoV-2-infected patients with COVID-19-convalescent plasmas, neither appropriate approach nor clinical utility has been established. We examined the efficacy of administration of highly-neutralizing COVID-19-convalescent plasma (hn-plasmas) and such plasma-derived IgG administration using the Syrian hamster COVID-19 model. Two hn-plasmas, which were in the best 1% of 340 neutralizing-activity-determined convalescent plasma samples, were intraperitoneally administered to SARS-CoV-2-infected hamsters, resulting in significant reduction of viral titers in lungs by up to 32-fold as compared to the viral titers in hamsters receiving control non-neutralizing plasma, while with two moderately neutralizing plasmas (mn-plasmas) administered, viral titer reduction was by up to 6-fold. IgG fractions purified from the two hn-plasmas also reduced viral titers in lungs than those from the two mn-plasmas. The severity of lung lesions seen in hamsters receiving hn-plasmas was minimal to moderate as assessed using micro-computerized tomography, which histological examination confirmed. Western blotting revealed that all four COVID-19-convalescent-plasmas variably contained antibodies against SARS-CoV-2 components including the receptor-binding domain and S1 domain. The present data strongly suggest that administering potent-neutralizing-activity-confirmed COVID-19-convalescent plasmas would be efficacious in treating patients with COVID-19.ImportanceConvalescent plasmas obtained from patients, who recovered from a specific infection, have been used as agents to treat other patients infected with the very pathogen. To treat using convalescent plasmas, despite that more than 10 randomized-controlled-clinical-trials have been conducted and more than 100 studies are currently ongoing, the effects of convalescent plasma against COVID-19 remained uncertain. On the other hand, certain COVID-19 vaccines have been shown to reduce the clinical COVID-19 onset by 94-95%, for which the elicited SARS-CoV-2-neutralizing antibodies are apparently directly responsible. Here, we demonstrate that highly-neutralizing-effect-confirmed convalescent plasmas significantly reduce the viral titers in the lung of SARS-CoV-2-infected Syrian hamsters and block the development of virally-induced lung lesions. The present data provide a proof-of-concept that the presence of highly-neutralizing antibody in COVID-19-convalescent plasmas is directly responsible for the reduction of viral replication and support the use of highly-neutralizing antibody-containing plasmas in COVID-19 therapy with convalescent plasmas.

Significance Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are of concern, with the P.1 variants dominating in Brazil. Brazil is now seeing a record number of deaths. Here, we report that the pathogenicity in hamsters of a P.1 variant is similar to that of nonvariant SARS-CoV-2. However, it has an expanded host range as shown by its replication in mice. Prior infection with nonvariant SARS-CoV-2 strains efficiently prevented replication of the P.1 variant in the lower respiratory tract of hamsters upon reinfection. Convalescent sera from patients infected with nonvariants or sera from messenger RNA vaccinees showed comparable neutralization titers among the P.1 and previously circulating strains. These results suggest that previous SARS-CoV-2 infection and vaccines based on the original SARS-CoV-2 will provide some protection against P.1 infection., The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a key role in viral infectivity. It is also the major antigen stimulating the host's protective immune response, specifically, the production of neutralizing antibodies. Recently, a new variant of SARS-CoV-2 possessing multiple mutations in the S protein, designated P.1, emerged in Brazil. Here, we characterized a P.1 variant isolated in Japan by using Syrian hamsters, a well-established small animal model for the study of SARS-CoV-2 disease (COVID-19). In hamsters, the variant showed replicative abilities and pathogenicity similar to those of early and contemporary strains (i.e., SARS-CoV-2 bearing aspartic acid [D] or glycine [G] at position 614 of the S protein). Sera and/or plasma from convalescent patients and BNT162b2 messenger RNA vaccinees showed comparable neutralization titers across the P.1 variant, S-614D, and S-614G strains. In contrast, the S-614D and S-614G strains were less well recognized than the P.1 variant by serum from a P.1-infected patient. Prior infection with S-614D or S-614G strains efficiently prevented the replication of the P.1 variant in the lower respiratory tract of hamsters upon reinfection. In addition, passive transfer of neutralizing antibodies to hamsters infected with the P.1 variant or the S-614G strain led to reduced virus replication in the lower respiratory tract. However, the effect was less pronounced against the P.1 variant than the S-614G strain. These findings suggest that the P.1 variant may be somewhat antigenically different from the early and contemporary strains of SARS-CoV-2.

Objectives Pertussis is an infectious disease that causes epidemics and outbreaks and is associated with a high mortality rate, especially in infants, in both developed and developing countries. We aimed to characterize infants with pertussis with respiratory failure and shock and investigated the factors related to mortality. Design A retrospective, observational study conducted between January 2015 and October 2020. Setting This study was conducted at the Vietnam National Children's Hospital, which is a government hospital that serves as a tertiary care center in Hanoi, Vietnam. Patients Children who fulfilled the following inclusion criteria were included: 1) admitted to the PICU, 2) less than 16 years old, 3) pertussis confirmed by real-time polymerase chain reaction, and 4) treated with mechanical ventilation due to respiratory failure and shock. Interventions None. Measurement and main results Seventy-three mechanically ventilated children (40 boys; median age, 56 d), whereas 19 patients received extracorporeal membrane oxygenation support. Twenty-six patients (36%) died including 12 who received extracorporeal membrane oxygenation. Those who received extracorporeal membrane oxygenation support had higher leukocyte counts upon admission and were more frequently diagnosed with pulmonary hypertension and stage 3 acute kidney injury. Compared with survivors, nonsurvivors showed increased heart rates, leukocyte and neutrophil counts, and lower systolic and diastolic blood pressure at admission. Increased Vasoactive-Inotropic Score, stage 3 acute kidney injury, fluid overload, the use of renal replacement therapy, and extracorporeal membrane oxygenation use were prevalent among nonsurvivors. Conclusions In this study, around one third of mechanically ventilated patients with pertussis died. Those who received extracorporeal membrane oxygenation had higher leukocyte counts, a higher prevalence of pulmonary hypertension, and advanced stages of acute kidney injury. Higher Vasoactive-Inotropic Score and advanced stages of acute kidney injury were associated with a greater risk of mortality.

Postmortem lung pathology of a patient in Japan with severe acute respiratory syndrome coronavirus 2 infection showed diffuse alveolar damage as well as bronchopneumonia caused by Streptococcus pneumoniae infection. The distribution of each pathogen and the accompanying histopathology suggested the infections progressed in a mutually exclusive manner within the lung, resulting in fatal respiratory failure.

Changing with the timesPandemic spread of a virus in naïe populations can select for mutations that alter pathogenesis, virulence, and/or transmissibility. The ancestral form of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged from China has now been largely replaced by strains containing the mutation D614G (Asp614-to-Gly) in the viral spike protein. Houet al.compared the characteristics of the new variant against the ancestral form in a series of experiments in human cells and animal models. The variant is better at infecting upper-airway epithelial cells and replicates in greater numbers than the ancestral virus. Evidence indicates modest, if any, significant changes to virulence in animal models. Therefore, the virus appears to have evolved for greater transmissibility in humans rather than for greater pathogenicity. The mutation renders the new virus variant more susceptible to neutralizing antisera without altering the efficacy of vaccine candidates currently under development.Science, this issue p.1464

The D614G substitution in the S protein is most prevalent SARS-CoV-2 strain circulating globally, but its effects in viral pathogenesis and transmission remain unclear. We engineered SARS-CoV-2 variants harboring the D614G substitution with or without nanoluciferase. The D614G variant replicates more efficiency in primary human proximal airway epithelial cells and is more fit than wildtype (WT) virus in competition studies. With similar morphology to the WT virion, the D614G virus is also more sensitive to SARS-CoV-2 neutralizing antibodies. Infection of human ACE2 transgenic mice and Syrian hamsters with the WT or D614G viruses produced similar titers in respiratory tissue and pulmonary disease. However, the D614G variant exhibited significantly faster droplet transmission between hamsters than the WT virus, early after infection. Our study demonstrated the SARS-CoV2 D614G substitution enhances infectivity, replication fitness, and early transmission.

Background: Severe asthma exacerbation is an important comorbidity of the 2009 HIN1 pandemic [A(H1N1)pdm09] in asthmatic patients. However, the mechanisms underlying severe asthma exacerbation remain unknown. Using a mouse model of asthma, we evaluated airway hyperresponsiveness (AHR) in mice with A(H1N1)pdm09 infection and those with seasonal influenza for comparison. We also measured AHR in paediatric participants infected with A(H1N1)pdm09. Methods: BALB/c mice aged 6-8 weeks were sensitized and challenged with ovalbumin. Either mouse-adapted A(H1N1)pdm09, seasonal H1N1 virus (1×105 pfu/20 μL), or mock treatment as a control was administered intranasally. At 3, 7, and 10 days after infection, each group of mice was evaluated for AHR by methacholine challenge using an animal ventilator, flexiVent®. Lung samples were resected and observed using light microscopy to assess the degree of airway inflammation. AHRs in paediatric participants were defined as the provocative acetylcholine concentration causing a 20% reduction in FEV1.0 (PC20). Results: Airway resistance was significantly enhanced in A(H1N1)pdm09-infected asthmatic mice compared to that in seasonal H1N1-infected mice (p

Significance Since SARS-CoV-2 emerged in China, it has spread rapidly around the world. Effective vaccines and therapeutics for SARS-CoV-2−induced disease (coronavirus disease 2019;COVID-19) are urgently needed. We found that SARS-CoV-2 isolates replicate efficiently in the lungs of Syrian hamsters and cause severe pathological lesions in the lungs of these animals similar to commonly reported imaging features of COVID-19 patients with pneumonia. SARS-CoV-2−infected hamsters mounted neutralizing antibody responses and were protected against rechallenge with SARS-CoV-2. Moreover, passive transfer of convalescent serum to naïve hamsters inhibited virus replication in their lungs. Syrian hamsters are a useful small animal model for the evaluation of vaccines, immunotherapies, and antiviral drugs., At the end of 2019, a novel coronavirus (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2) was detected in Wuhan, China, that spread rapidly around the world, with severe consequences for human health and the global economy. Here, we assessed the replicative ability and pathogenesis of SARS-CoV-2 isolates in Syrian hamsters. SARS-CoV-2 isolates replicated efficiently in the lungs of hamsters, causing severe pathological lung lesions following intranasal infection. In addition, microcomputed tomographic imaging revealed severe lung injury that shared characteristics with SARS-CoV-2−infected human lung, including severe, bilateral, peripherally distributed, multilobular ground glass opacity, and regions of lung consolidation. SARS-CoV-2−infected hamsters mounted neutralizing antibody responses and were protected against subsequent rechallenge with SARS-CoV-2. Moreover, passive transfer of convalescent serum to naïve hamsters efficiently suppressed the replication of the virus in the lungs even when the serum was administrated 2 d postinfection of the serum-treated hamsters. Collectively, these findings demonstrate that this Syrian hamster model will be useful for understanding SARS-CoV-2 pathogenesis and testing vaccines and antiviral drugs.