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COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice.

ABSTRACT: The ongoing coronavirus disease 2019 (COVID-19) pandemic is associated with substantial morbidity and mortality. Although much has been learned in the first few months of the pandemic, many features of COVID-19 pathogenesis remain to be determined. For example, anosmia is a common presentation, and many patients with anosmia show no or only minor respiratory symptoms¹. Studies in animals infected experimentally with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of COVID-19, provide opportunities to study aspects of the disease that are not easily investigated in human patients. Although the severity of COVID-19 ranges from asymptomatic to lethal², most experimental infections provide insights into mild disease³. Here, using K18-hACE2 transgenic mice that were originally developed for SARS studies⁴, we show that infection with SARS-CoV-2 causes severe disease in the lung and, in some mice, the brain. Evidence of thrombosis and vasculitis was detected in mice with severe pneumonia. Furthermore, we show that infusion of convalescent plasma from a recovered patient with COVID-19 protected against lethal disease. Mice developed anosmia at early time points after infection. Notably, although pre-treatment with convalescent plasma prevented most signs of clinical disease, it did not prevent anosmia. Thus, K18-hACE2 mice provide a useful model for studying the pathological basis of both mild and lethal COVID-19 and for assessing therapeutic interventions.

SUBMITTER: Zheng J

PROVIDER: S-EPMC7855185 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice.

Zheng Jian J Wong Lok-Yin Roy LR Li Kun K Verma Abhishek Kumar AK Ortiz Miguel E ME Wohlford-Lenane Christine C Leidinger Mariah R MR Knudson C Michael CM Meyerholz David K DK McCray Paul B PB Perlman Stanley S

Nature 20201109 7843

The ongoing coronavirus disease 2019 (COVID-19) pandemic is associated with substantial morbidity and mortality. Although much has been learned in the first few months of the pandemic, many features of COVID-19 pathogenesis remain to be determined. For example, anosmia is a common presentation, and many patients with anosmia show no or only minor respiratory symptoms<sup>1</sup>. Studies in animals infected experimentally with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cau ...[more]

PMID: 33166988

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Project description:SARS-CoV-2 emerged in late 2019 and resulted in the ongoing COVID-19 pandemic. Several animal models have been rapidly developed that recapitulate the asymptomatic to moderate disease spectrum. Now, there is a direct need for additional small animal models to study the pathogenesis of severe COVID-19 and for fast-tracked medical countermeasure development. Here, we show that transgenic mice expressing the human SARS-CoV-2 receptor (angiotensin-converting enzyme 2 [hACE2]) under a cytokeratin 18 promoter (K18) are susceptible to SARS-CoV-2 and that infection resulted in a dose-dependent lethal disease course. After inoculation with either 104 TCID50 or 105 TCID50, the SARS-CoV-2 infection resulted in rapid weight loss in both groups and uniform lethality in the 105 TCID50 group. High levels of viral RNA shedding were observed from the upper and lower respiratory tract and intermittent shedding was observed from the intestinal tract. Inoculation with SARS-CoV-2 resulted in upper and lower respiratory tract infection with high infectious virus titers in nasal turbinates, trachea and lungs. The observed interstitial pneumonia and pulmonary pathology, with SARS-CoV-2 replication evident in pneumocytes, were similar to that reported in severe cases of COVID-19. SARS-CoV-2 infection resulted in macrophage and lymphocyte infiltration in the lungs and upregulation of Th1 and proinflammatory cytokines/chemokines. Extrapulmonary replication of SARS-CoV-2 was observed in the cerebral cortex and hippocampus of several animals at 7 DPI but not at 3 DPI. The rapid inflammatory response and observed pathology bears resemblance to COVID-19. Additionally, we demonstrate that a mild disease course can be simulated by low dose infection with 102 TCID50 SARS-CoV-2, resulting in minimal clinical manifestation and near uniform survival. Taken together, these data support future application of this model to studies of pathogenesis and medical countermeasure development.

Project description:SARS-CoV-2 emerged in late 2019 and resulted in the ongoing COVID-19 pandemic. Several animal models have been rapidly developed that recapitulate the asymptomatic to moderate disease spectrum. Now, there is a direct need for additional small animal models to study the pathogenesis of severe COVID-19 and for fast-tracked medical countermeasure development. Here, we show that transgenic mice expressing the human SARS-CoV-2 receptor (angiotensin-converting enzyme 2 [hACE2]) under a cytokeratin 18 promoter (K18) are susceptible to SARS-CoV-2 and that infection resulted in a dose-dependent lethal disease course. After inoculation with either 10 4 TCID 50 or 10 5 TCID 50 , the SARS-CoV-2 infection resulted in rapid weight loss in both groups and uniform lethality in the 10 5 TCID 50 group. High levels of viral RNA shedding were observed from the upper and lower respiratory tract and intermittent shedding was observed from the intestinal tract. Inoculation with SARS-CoV-2 resulted in upper and lower respiratory tract infection with high infectious virus titers in nasal turbinates, trachea and lungs. The observed interstitial pneumonia and pulmonary pathology, with SARS-CoV-2 replication evident in pneumocytes, were similar to that reported in severe cases of COVID-19. SARS-CoV-2 infection resulted in macrophage and lymphocyte infiltration in the lungs and upregulation of Th1 and proinflammatory cytokines/chemokines. Extrapulmonary replication of SARS-CoV-2 was observed in the cerebral cortex and hippocampus of several animals at 7 DPI but not at 3 DPI. The rapid inflammatory response and observed pathology bears resemblance to COVID-19. Taken together, this suggests that this mouse model can be useful for studies of pathogenesis and medical countermeasure development. The disease manifestation of COVID-19 in humans range from asymptomatic to severe. While several mild to moderate disease models have been developed, there is still a need for animal models that recapitulate the severe and fatal progression observed in a subset of patients. Here, we show that humanized transgenic mice developed dose-dependent disease when inoculated with SARS-CoV-2, the etiological agent of COVID-19. The mice developed upper and lower respiratory tract infection, with virus replication also in the brain after day 3 post inoculation. The pathological and immunological diseases manifestation observed in these mice bears resemblance to human COVID-19, suggesting increased usefulness of this model for elucidating COVID-19 pathogenesis further and testing of countermeasures, both of which are urgently needed.

Project description:BackgroundNeurological damage caused by coronavirus disease 2019 (COVID-19) has attracted increasing attention. Recently, through autopsies of patients with COVID-19, the direct identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in their central nervous system (CNS) has been reported, indicating that SARS-CoV-2 might directly attack the CNS. The need to prevent COVID-19-induced severe injuries and potential sequelae is urgent, requiring the elucidation of large-scale molecular mechanisms in vivo.MethodsIn this study, we performed liquid chromatography-mass spectrometry-based proteomic and phosphoproteomic analyses of the cortex, hippocampus, thalamus, lungs, and kidneys of SARS-CoV-2-infected K18-hACE2 female mice. We then performed comprehensive bioinformatic analyses, including differential analyses, functional enrichment, and kinase prediction, to identify key molecules involved in COVID-19.FindingsWe found that the cortex had higher viral loads than did the lungs, and the kidneys did not have SARS-COV-2. After SARS-CoV-2 infection, RIG-I-associated virus recognition, antigen processing and presentation, and complement and coagulation cascades were activated to different degrees in all five organs, especially the lungs. The infected cortex exhibited disorders of multiple organelles and biological processes, including dysregulated spliceosome, ribosome, peroxisome, proteasome, endosome, and mitochondrial oxidative respiratory chain. The hippocampus and thalamus had fewer disorders than did the cortex; however, hyperphosphorylation of Mapt/Tau, which may contribute to neurodegenerative diseases, such as Alzheimer's disease, was found in all three brain regions. Moreover, SARS-CoV-2-induced elevation of human angiotensin-converting enzyme 2 (hACE2) was observed in the lungs and kidneys, but not in the three brain regions. Although the virus was not detected, the kidneys expressed high levels of hACE2 and exhibited obvious functional dysregulation after infection. This indicates that SARS-CoV-2 can cause tissue infections or damage via complicated routes. Thus, the treatment of COVID-19 requires a multipronged approach.InterpretationThis study provides observations and in vivo datasets for COVID-19-associated proteomic and phosphoproteomic alterations in multiple organs, especially cerebral tissues, of K18-hACE2 mice. In mature drug databases, the differentially expressed proteins and predicted kinases in this study can be used as baits to identify candidate therapeutic drugs for COVID-19. This study can serve as a solid resource for the scientific community. The data in this manuscript will serve as a starting point for future research on COVID-19-associated encephalopathy.FundingThis study was supported by grants from the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, the National Natural Science Foundation of China, and the Natural Science Foundation of Beijing.

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COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice.

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COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice.

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