RESUMO
We assessed susceptibility of dogs to SARS-COV-2 Delta and Omicron variants by experimentally inoculating beagle dogs. Moreover, we investigated transmissibility of the variants from infected to naive dogs. The dogs were susceptible to infection without clinical signs and transmitted both strains to other dogs through direct contact.
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COVID-19 , Animais , Cães , COVID-19/veterinária , SARS-CoV-2RESUMO
BACKGROUND: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has challenged the effectiveness of current therapeutic regimens. Here, we aimed to develop a potent SARS-CoV-2 antibody with broad neutralizing effect by screening a scFv library with the spike protein receptor-binding domain (RBD) via phage display. METHODS: SKAI-DS84 was identified through phage display, and we performed pseudovirus neutralization assays, authentic virus neutralization assays, and in vivo neutralization efficacy evaluations. Furthermore, surface plasmon resonance (SPR) analysis was conducted to assess the physical characteristics of the antibody, including binding kinetics and measure its affinity for variant RBDs. RESULTS: The selected clones were converted to human IgG, and among them, SKAI-DS84 was selected for further analyses based on its binding affinity with the variant RBDs. Using pseudoviruses, we confirmed that SKAI-DS84 was strongly neutralizing against wild-type, B.1.617.2, B.1.1.529, and subvariants of SARS-CoV-2. We also tested the neutralizing effect of SKAI-DS84 on authentic viruses, in vivo and observed a reduction in viral replication and improved lung pathology. We performed binding and epitope mapping experiments to understand the mechanisms underlying neutralization and identified quaternary epitopes formed by the interaction between RBDs as the target of SKAI-DS84. CONCLUSIONS: We identified, produced, and tested the neutralizing effect of SKAI-DS84 antibody. Our results highlight that SKAI-DS84 could be a potential neutralizing antibody against SARS-CoV-2 and its variants.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Anticorpos Monoclonais , Testes de Neutralização , Receptores Virais/metabolismo , Anticorpos Neutralizantes , Anticorpos Antivirais , Glicoproteína da Espícula de Coronavírus/químicaRESUMO
Throughout the recent COVID-19 pandemic, South Korea led national efforts to develop vaccines and therapeutics for SARS-CoV-2. The project proceeded as follows: 1) evaluation system setup (including Animal Biosafety Level 3 (ABSL3) facility alliance, standardized nonclinical evaluation protocol, and laboratory information management system), 2) application (including committee review and selection), and 3) evaluation (including expert judgment and reporting). After receiving 101 applications, the selection committee reviewed pharmacokinetics, toxicity, and efficacy data and selected 32 final candidates. In the nonclinical efficacy test, we used golden Syrian hamsters and human angiotensin-converting enzyme 2 transgenic mice under a cytokeratin 18 promoter to evaluate mortality, clinical signs, body weight, viral titer, neutralizing antibody presence, and histopathology. These data indicated eight new drugs and one repositioned drug having significant efficacy for COVID-19. Three vaccine and four antiviral drugs exerted significant protective activities against SARS-CoV-2 pathogenesis. Additionally, two anti-inflammatory drugs showed therapeutic effects on lung lesions and weight loss through their mechanism of action but did not affect viral replication. Along with systematic verification of COVID-19 animal models through large-scale studies, our findings suggest that ABSL3 multicenter alliance and nonclinical evaluation protocol standardization can promote reliable efficacy testing against COVID-19, thus expediting medical product development.
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COVID-19 , Animais , Cricetinae , Camundongos , Humanos , SARS-CoV-2 , Pandemias , Anticorpos Neutralizantes , Mesocricetus , Modelos Animais de DoençasRESUMO
Adeno-associated virus (AAV)-mediated gene delivery holds great promise for gene therapy. However, the non-invasive delivery of AAV for lung tissues has not been adequately established. Here, we revealed that the intratracheal administration of an appropriate amount of AAV2/8 predominantly targets lung tissue. AAV-mediated gene delivery that we used in this study induced the expression of the desired protein in lung parenchymal cells, including alveolar type II cells. We harnessed the technique to develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-susceptible mice. Three kinds of immune function-relevant gene knockout (KO) mice were transduced with AAV encoding human angiotensin-converting enzyme 2 (hACE2) and then injected with SARS-CoV-2. Among these mice, type I interferon receptor (IFNAR) KO mice showed increased viral titer in the lungs compared to that in the other KO mice. Moreover, nucleocapsid protein of SARS-CoV-2 and multiple lesions in the trachea and lung were observed in AAV-hACE2-transduced, SARS-CoV-2-infected IFNAR KO mice, indicating the involvement of type I interferon signaling in the protection of SARS-CoV-2. In this study, we demonstrate the ease and rapidness of the intratracheal administration of AAV for targeting lung tissue in mice, and this can be used to study diverse pulmonary diseases.
Assuntos
COVID-19 , SARS-CoV-2 , Animais , COVID-19/terapia , Dependovirus/genética , Modelos Animais de Doenças , Suscetibilidade a Doenças , Pulmão/patologia , Camundongos , Camundongos Transgênicos , SARS-CoV-2/genéticaRESUMO
Germinal centers (GCs) elicit protective humoral immunity through a combination of antibody-secreting cells and memory B cells, following pathogen invasion or vaccination. However, the possibility of a GC response inducing protective immunity against reinfection following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unknown. We found GC activity was consistent with seroconversion observed in recovered macaques and humans. Rechallenge with a different clade of virus resulted in significant reduction in replicating virus titers in respiratory tracts in macaques with high GC activity. However, diffuse alveolar damage and increased fibrotic tissue were observed in lungs of reinfected macaques. Our study highlights the importance of GCs developed during natural SARS-CoV-2 infection in managing viral loads in subsequent infections. However, their ability to alleviate lung damage remains to be determined. These results may improve understanding of SARS-CoV-2-induced immune responses, resulting in better coronavirus disease 2019 (COVID-19) diagnosis, treatment, and vaccine development.
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COVID-19 , Centro Germinativo , Imunidade Humoral , Reinfecção/imunologia , Animais , Anticorpos Antivirais , COVID-19/imunologia , Humanos , Pulmão/patologia , Pulmão/virologia , Macaca , Células B de Memória , SoroconversãoRESUMO
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 pandemic. METHODS: In this study, the antiviral activity of a far-UVC (222 nm) microplasma flat lamp against SARS-CoV-2 was evaluated. RESULTS AND CONCLUSIONS: Immediate inactivation of up to 99.99% of the coronavirus was achieved with a dose of less than 8 mJ/cm2 and complete inactivation was observed by real-time RT-PCR; therefore, far-UVC (222 nm) is a promising candidate for the effective inactivation of SARS-CoV-2.
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COVID-19 , SARS-CoV-2 , Antivirais/farmacologia , Desinfecção , Humanos , Inativação de VírusRESUMO
Hepatitis E virus (HEV) is a zoonotic pathogen commonly considered an important foodborne virus. Pet dogs are important reservoirs of zoonotic agents. In the present study, the seroprevalence of HEV in pet dogs and pet veterinarians were found to be 28.2 and 5.0%, respectively. It remains unclear whether pet veterinarians are at higher risk of HEV transmission. However, pet animals and individuals who have contact with infected animals must be continually monitored for public health concerns.
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BACKGROUND: Canine noroviruses (CaNoVs) are classified into genogroups GIV, GVI, and GVII and have been detected in fecal samples from dogs since their first appearance in a dog with enteritis in Italy in 2007. CaNoVs may be a public health concern because pet animals are an integral part of the family and could be a potential reservoir of zoonotic agents. Nonetheless, there was no previous information concerning the epidemiology of CaNoV in South Korea. In the present study, we aimed to detect CaNoV antigens and to investigate serological response against CaNoV in dogs. RESULTS: In total, 459 fecal samples and 427 sera were collected from small animal clinics and animal shelters housing free-roaming dogs in geographically distinct areas in South Korea. For the detection of CaNoV, RT-PCR was performed using target specific primers, and nucleotide sequences of CaNoV isolates were phylogenetically analyzed. Seroprevalence was performed by ELISA based on P domain protein. CaNoVs were detected in dog fecal samples (14/459, 3.1%) and were phylogenetically classified into the same cluster as previously reported genogroup GIV CaNoVs. Seroprevalence was performed, and 68 (15.9%) of 427 total dog serum samples tested positive for CaNoV IgG antibodies. CONCLUSION: This is the first study identifying CaNoV in the South Korean dog population.
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Infecções por Caliciviridae/veterinária , Doenças do Cão/epidemiologia , Norovirus/fisiologia , Animais , Anticorpos Antivirais/sangue , Infecções por Caliciviridae/epidemiologia , Infecções por Caliciviridae/virologia , Cães , Ensaio de Imunoadsorção Enzimática , Fezes/virologia , Norovirus/classificação , Filogenia , República da Coreia , Estudos SoroepidemiológicosRESUMO
Equine influenza virus (EIV) causes a highly contagious disease in horses and other equids. Recently, we isolated an H3N8 EIV (A/equine/Kyonggi/SA1/2011) from a domestic horse in South Korea that exhibited symptoms of respiratory disease, and found that the EIV strain contained a naturally mutated NS gene segment encoding a truncated NS1 protein. In order to determine whether there was an association between the NS gene truncation and viral virulence, a reverse genetics system was applied to generate various NS gene recombinant viruses using the backbone of the H1N1 A/Puerto Rico/8/1934 (PR/8) virus. In a mouse model, the recombinant PR/8 virus containing the mutated NS gene of the Korean H3N8 EIV strain showed a dramatically reduced virulence: it induced no weight loss, no clinical signs and no histopathological lesions. However, the mice infected with the recombinant viruses with NS genes of PR/8 and H3N8 A/equine/2/Miami/1963 showed severe clinical signs including significant weight loss and 100% mortality. In addition, the levels of the pro-inflammatory cytokines; IL-6, CCL5, and IFN-γ, in the lungs of mice infected with the recombinant viruses expressing a full-length NS1 were significantly higher than those of mice infected with the virus with the NS gene from the Korean H3N8 EIV strain. In this study, our results suggest that the C-terminal moiety of NS1 contains a number of virulence determinants and might be a suitable target for the development of a vaccine candidate against equine influenza.
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Vírus da Influenza A Subtipo H3N8 , Infecções por Orthomyxoviridae/veterinária , Proteínas não Estruturais Virais/genética , Células A549 , Animais , Western Blotting , Citocinas/metabolismo , Cães , Células HEK293 , Doenças dos Cavalos/imunologia , Doenças dos Cavalos/virologia , Cavalos , Humanos , Vírus da Influenza A Subtipo H3N8/genética , Vírus da Influenza A Subtipo H3N8/patogenicidade , Pulmão/patologia , Pulmão/virologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Recombinação Genética/genética , Proteínas não Estruturais Virais/imunologia , Ensaio de Placa ViralRESUMO
An outbreak of a canine influenza virus (CIV) H3N2 reassortant derived from pandemic (pdm) H1N1 and CIV H3N2 in companion animals has underscored the urgent need to monitor CIV infections for potential zoonotic transmission of influenza viruses to humans. In this study, we assessed the virulence of a novel CIV H3N2 reassortant, VC378, which was obtained from a dog that was coinfected with pdm H1N1 and CIV H3N2, in ferrets, dogs, and mice. Significantly enhanced virulence of VC378 was demonstrated in mice, although the transmissibility and pathogenicity of VC378 were similar to those of classical H3N2 in ferrets and dogs. This is notable because mice inoculated with an equivalent dose of classical CIV H3N2 showed no clinical signs and no lethality. We found that the PA and NS gene segments of VC378 were introduced from pdmH1N1, and these genes included the amino acid substitutions PA-P224S and NS-I123V, which were previously found to be associated with increased virulence in mice. Thus, we speculate that the natural reassortment between pdm H1N1 and CIV H3N2 can confer virulence and that continuous surveillance is needed to monitor the evolution of CIV in companion animals.
Assuntos
Modelos Animais de Doenças , Cães , Furões , Vírus da Influenza A Subtipo H3N2/patogenicidade , Influenza Humana/virologia , Camundongos , Vírus Reordenados/patogenicidade , Animais , Cães/virologia , Furões/virologia , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H1N1/fisiologia , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/fisiologia , Influenza Humana/mortalidade , Camundongos/virologia , Camundongos Endogâmicos C57BL , Vírus Reordenados/genética , Vírus Reordenados/fisiologia , Proteínas Virais/genéticaRESUMO
We investigated the infectivity and transmissibility of the human seasonal H3N2, pandemic (pdm) H1N1 (2009) and B influenza viruses in dogs. Dogs inoculated with human seasonal H3N2 and pdm H1N1 influenza viruses exhibited nasal shedding and were seroconverted against the viruses; this did not occur in the influenza B virus-inoculated dogs. Transmission of human H3N2 virus between dogs was demonstrated by observing nasal shedding and seroconversion in naïve dogs after contact with inoculated dogs. The seroprevalence study offered evidence of human H3N2 infection occurring in dogs since 2008. Furthermore, serological evidence of pdm H1N1 influenza virus infection alone and in combination with canine H3N2 virus was found in the serum samples collected from field dogs during 2010 and 2011. Our results suggest that dogs may be hosts for human seasonal H3N2 and pdm H1N1 influenza viruses.
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Doenças do Cão/transmissão , Doenças do Cão/virologia , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Vírus da Influenza B/isolamento & purificação , Influenza Humana/virologia , Infecções por Orthomyxoviridae/veterinária , Animais , Anticorpos Antivirais/sangue , Reservatórios de Doenças , Doenças do Cão/patologia , Cães , Humanos , Vírus da Influenza A Subtipo H3N2/crescimento & desenvolvimento , Vírus da Influenza B/crescimento & desenvolvimento , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/transmissão , Infecções por Orthomyxoviridae/virologia , Eliminação de Partículas ViraisRESUMO
BACKGROUND: Since avian-origin H3N2 canine influenza virus (CIV) was first identified in South Korea in 2008, the novel influenza virus has been reported in several countries in Asia. Reverse zoonotic transmission of pandemic H1N1 (2009) influenza virus (pH1N1) has been observed in a broad range of animal species. Viral dominance and characterization of the reassortants of both viruses was undertaken in the present study. FINDINGS: Here we describe the viral dominance of 23 CIV reassortants between pH1N1 and canine H3N2 influenza viruses from a naturally co-infected dog. These results indicate that the M gene of pandemic H1N1 and the HA gene of canine H3N2 are predominant in the reassortants. Furthermore, unlike the original canine H3N2 virus, some reassortants showed high pathogenicity in mice. CONCLUSIONS: This study suggests that continuous monitoring of influenza infection in companion animals may be necessary to investigate the potential of the emergence of novel influenza viruses.
Assuntos
Coinfecção/veterinária , Doenças do Cão/virologia , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Infecções por Orthomyxoviridae/veterinária , Vírus Reordenados/isolamento & purificação , Animais , Coinfecção/virologia , Modelos Animais de Doenças , Cães , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H3N2/genética , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/virologia , Vírus Reordenados/genética , República da Coreia , Proteínas da Matriz Viral/genética , VirulênciaRESUMO
BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) causes a loss of approximately US$ 70 million every year to the South Korean pork industry. There are two distinct genotypes: European (type 1) and North American (type 2). In South Korea, type 1 and type 2 PRRSV are widely distributed and have evolved continuously since the infection was first described. Here, we present two field cases of type 1 PRRSV infection with unusually severe pathogenicity. CASE PRESENTATION: The first case farm was a two-site production system comprising farrow-to-grower and grower-to-finish units and was historically free from PRRSV infections. The PRRSV vaccine had not been used in both units. In October 2014, pigs in the grower-to-finish unit experienced severe respiratory distress with the mortality rate reaching to 22%. Despite antibiotic treatment, clinical signs were still noticed in most pigs. The second case farm was also a two-site production system, but had two separate farrow-to-grower units (unit A and unit B). Historically, type 1 PRRSV was continuously present in unit A, but unit B was free from PRRSV. Thus, all grower pigs of unit B were vaccinated before being moved to the grower-to-finish unit. In November 2014, severe respiratory distress was seen in pigs of the grower-to-finish unit. Significant respiratory distress was observed in only the grower herd moved from unit B, and the mortality of those pigs was ~50%. However, no disease was shown in the grower pigs from unit A. CONCLUSIONS: To our knowledge, the present study is the first observation of the cases of infection by highly pathogenic type 1 PRRSV in South Korea. The Korean type 1 PRRSV strains have undergone unique evolutionary dynamics for the last decade in this country. Although there are known to be three clusters of Korean type 1 PRRSV, their pathogenicity could not be categorized owing to their high level of genetic diversity. Therefore, further studies are needed to demonstrate the novel classification of Korean type 1 PRRSV strains according to their virulence factors.
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Criação de Animais Domésticos/métodos , Síndrome Respiratória e Reprodutiva Suína/patologia , Animais , Genótipo , Pulmão/patologia , Filogenia , Síndrome Respiratória e Reprodutiva Suína/epidemiologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/genética , Vírus da Síndrome Respiratória e Reprodutiva Suína/patogenicidade , República da Coreia/epidemiologia , Suínos , VirulênciaRESUMO
BACKGROUND: The predominant subtypes of swine influenza A virus (SIV) in Korea swine population are H1N1, H1N2, and H3N2. The viruses are genetically close to the classical U.S. H1N1 and triple-reassortant H1N2 and H3N2 viruses, respectively. Comparative pathogenesis caused by Korean H1N1, H1N2, and H3N2 SIV was evaluated in this study. FINDINGS: The H3N2 infected pigs had severe scores of gross and histopathological lesions at post-inoculation days (PID) 2, and this then progressively decreased. Both the H1N1 and H1N2 infected pigs lacked gross lesions at PID 2, but they showed moderate to severe pneumonia on PID 4, 7 and 14. The pigs infected with H1N1 had significant scores of gross and histopathological lesions when compared with the other pigs infected with H1N2, H3N2, and mock at PID 14. Mean SIV antigen-positive scores were rarely detected for pigs infected with H1N2 and H3N2 from PID 7, whereas a significantly increased amount of viral antigens were found in the bronchioles and alveolar epithelium of the H1N1infected pigs at PID 14. CONCLUSIONS: We demonstrated that Korean SIV subtypes had different pulmonary pathologic patterns. The Korean H3N2 rapidly induced acute lung lesions such as broncho-interstitial pneumonia, while the Korean H1N1 showed longer course of infection as compared to other strains.
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Vírus da Influenza A Subtipo H1N1/fisiologia , Vírus da Influenza A Subtipo H1N2/fisiologia , Vírus da Influenza A Subtipo H3N2/fisiologia , Infecções por Orthomyxoviridae/veterinária , Doenças dos Suínos/patologia , Animais , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Vírus da Influenza A Subtipo H1N2/isolamento & purificação , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Pulmão/patologia , Pulmão/virologia , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , República da Coreia , Suínos , Doenças dos Suínos/virologiaRESUMO
While an association between Parkinson's disease (PD) and viral infections has been recognized, the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on PD progression remains unclear. Here, we demonstrate that SARS-CoV-2 infection heightens the risk of PD using human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons and a human angiotensin-converting enzyme 2 (hACE2) transgenic (Tg) mouse model. Our findings reveal that SARS-CoV-2 infection exacerbates PD susceptibility and cellular toxicity in DA neurons pre-treated with human preformed fibrils (hPFFs). Additionally, nasally delivered SARS-CoV-2 infects DA neurons in hACE2 Tg mice, aggravating the damage initiated by hPFFs. Mice infected with SARS-CoV-2 display persisting neuroinflammation even after the virus is no longer detectable in the brain. A comprehensive analysis suggests that the inflammatory response mediated by astrocytes and microglia could contribute to increased PD susceptibility associated with SARS-CoV-2. These findings advance our understanding of the potential long-term effects of SARS-CoV-2 infection on the progression of PD.
Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Modelos Animais de Doenças , Neurônios Dopaminérgicos , Camundongos Transgênicos , Doença de Parkinson , SARS-CoV-2 , Animais , Neurônios Dopaminérgicos/patologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/virologia , Humanos , COVID-19/patologia , COVID-19/virologia , Doença de Parkinson/patologia , Doença de Parkinson/virologia , Camundongos , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Microglia/patologia , Microglia/metabolismo , Microglia/virologia , Células-Tronco Embrionárias Humanas/metabolismo , Astrócitos/patologia , Astrócitos/virologia , Astrócitos/metabolismo , Encéfalo/patologia , Encéfalo/virologiaRESUMO
The coronavirus disease 19 (COVID-19) pandemic, caused by the severe acute respiratory syndrome, coronavirus 2 (SARS-CoV-2), has resulted in unprecedented challenges to healthcare worldwide. In particular, the anthroponotic transmission of human coronaviruses has become a common concern among pet owners. Here, we experimentally inoculated beagle dogs with SARS-CoV-2 or Middle East respiratory syndrome (MERS-CoV) to compare their susceptibility to and the pathogenicity of these viruses. The dogs in this study exhibited weight loss and increased body temperatures and shed the viruses in their nasal secretions, feces, and urine. Pathologic changes were observed in the lungs of the dogs inoculated with SARS-CoV-2 or MERS-CoV. Additionally, clinical characteristics of SARS-CoV-2, such as increased lactate dehydrogenase levels, were identified in the current study.
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Avian influenza virus (AIV) causes acute infectious diseases in poultry, critically impacting food supply. Highly pathogenic avian influenza viruses (HPAIVs), in particular, cause morbidity and mortality, resulting in significant economic losses in the poultry industry. To prevent the spread of HPAIVs, detection at early stages is critical to implement effective countermeasures such as quarantine and isolation. Through a viral fusion mechanism, cell-mimetic nanoparticles (CMPs), developed in the current study, can rapidly detect HPAIV and low pathogenic AIV (LPAIV). The CMPs comprise polymeric nanoparticles, which are constructed using sialic acid and fluorescence resonance energy transfer (FRET) dye pairs that expose the FRET off signal in response to LPAIV and HPAIV, after activation by enzymatic cleavage in the endosomal environment. The CMPs detect a wide variety of LPAIVs and HPAIVs in biological environments. Additionally, the cross-reactivity of CMPs is determined by testing their function with different viral species. Therefore, these findings demonstrate the significant potential of the proposed strategy for mimicking viral infection in vitro and using them as a highly effective diagnostic assay to rapidly detect LPAIV and HPAIV, preventing economic losses associated with viral outbreaks.
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Técnicas Biossensoriais , Vírus da Influenza A , Influenza Aviária , Animais , Galinhas , Influenza Aviária/diagnóstico , Aves DomésticasRESUMO
Patients with recent pandemic coronavirus disease 19 (COVID-19) complain of neurological abnormalities in sensory functions such as smell and taste in the early stages of infection. Determining the cellular and molecular mechanism of sensory impairment is critical to understand the pathogenesis of clinical manifestations, as well as in setting therapeutic targets for sequelae and recurrence. The absence of studies utilizing proper models of human peripheral nerve hampers an understanding of COVID-19 pathogenesis. Here, we report that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly infects human peripheral sensory neurons, leading to molecular pathogenesis for chemosensory impairments. An in vitro system utilizing human embryonic stem cell (hESC)-derived peripheral neurons was used to model the cellular and molecular pathologies responsible for symptoms that most COVID-19 patients experience early in infection or may develop as sequelae. Peripheral neurons differentiated from hESCs expressed viral entry factor ACE2, and were directly infected with SARS-CoV-2 via ACE2. Human peripheral neurons infected with SARS-CoV-2 exhibited impaired molecular features of chemosensory function associated with abnormalities in sensory neurons of the olfactory or gustatory organs. Our results provide new insights into the pathogenesis of chemosensory dysfunction in patients with COVID-19.
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COVID-19/complicações , Transtornos do Olfato/etiologia , SARS-CoV-2 , Células Receptoras Sensoriais/virologia , Distúrbios do Paladar/etiologia , Enzima de Conversão de Angiotensina 2/fisiologia , HumanosRESUMO
The ongoing coronavirus disease 2019 pandemic and its overlap with the influenza season lead to concerns over severe disease caused by the influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) co-infections. Using a Syrian hamster co-infection model with SARS-CoV-2 and the pandemic influenza virus A/California/04/2009 (H1N1), we found (a) more severe disease in co-infected animals, compared to those infected with influenza virus alone but not SARS-CoV-2 infection alone; (b) altered haematological changes in only co-infected animals and (c) altered influenza virus tropism in the respiratory tracts of co-infected animals. Overall, our study revealed that co-infection with SARS-CoV-2 and influenza virus is associated with altered disease severity and tissue tropism, as well as haematological changes, compared to infection with either virus alone.