Correspondence to Zhou, P. et al. Higher viral loads were also detected in lung tissue of aged rhesus macaques. Experimental transmission studies of SARS-CoV-2 in fruit bats, ferrets, pigs and chickens. These data suggest that susceptibility to infection may be a function of several factors, including genetic ACE2 composition, organ-specific ACE2 expression and other host factors (such as additional receptors and host immune responses). Daten über Ihr Gerät und Ihre Internetverbindung, darunter Ihre IP-Adresse, Such- und Browsingaktivität bei Ihrer Nutzung der Websites und Apps von Verizon Media. (2021), Cell Communication and Signaling Google Scholar. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Nature Lancet Infect. Peer review information Nature thanks Linda Saif and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Large-scale clinical trials are currently underway to test multiple candidate preventative and therapeutic interventions in humans. High-resolution micro-computed tomography scans showed airway dilation and substantial consolidations in the lungs of infected hamsters36. Weingartl, H. M. et al. Med. Rockx, B. et al. 26, 450–452 (2020). A summary of the current literature on COVID-19 animal models. Several vaccine candidates have shown protection in rhesus macaques57,58,59,60,61, and both the cynomolgus and rhesus macaque models have been useful for the testing of therapeutic agents82. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. SARS-CoV-2—as severe acute respiratory syndrome coronavirus (SARS-CoV)—uses the cellular surface protein angiotensin-converting enzyme 2 (ACE2) to bind and enter cells, and mouse ACE2 does not effectively bind the viral spike protein7. Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. ... Valentine's dinner ideas for a cozy, romantic night in Natl Acad. Nature https://doi.org/10.1038/s41586-020-2608-y (2020). Si, L. et al. Notably, these mice develop evidence of thrombosis and anosmia after infection with SARS-CoV-2 and have been used for studies of the innate and T cell responses16. Expression of chemokines and cytokines in the lungs of hamsters peaked at four days after infection, and then gradually resolved by seven days after infection. Finally, instead of permanent genetic modification, it is also possible to generate mice that are susceptible to infection with SARS-CoV-2 by sensitizing the respiratory tract of these mice to SARS-CoV-2 replication through transduction with adenovirus or adeno-associated virus that expresses human ACE2 (Ad5-hACE2 or AAV-hACE2, respectively). For example, the inoculation of the SARS-CoV-2 isolate CTan-H into juvenile (70–100 days old) and subadult cats (6–9 months old) through the intranasal route resulted in virus replication in the upper and lower respiratory tract, as well as in the gastrointestinal tract. These findings suggest that, although Rousettus bats are not the original reservoir species of SARS-CoV-2, experimental infection of these fruit bats could help to model the physiopathology of the virus in its host. Due to the coronavirus (COVID-19), wearing a face mask is mandatory in all indoor common areas. Shi, J. et al. Nat. Alternatively, SARS-CoV-2 can be adapted to infect mouse cells by using reverse genetics to modify the receptor-binding domain of the virus so that it can infect mouse cells via the mouse ACE2 protein. Tickets for each show are $32 plus … Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance. Sia, S. F. et al. Animal models are needed to assess vaccine-associated enhanced respiratory disease, and the establishment of a positive control for this disease will be important. Virus replication in ferrets appears to be restricted to the respiratory and gastrointestinal tracts. Biotechnol. To test these and other potential medical countermeasures, it is imperative to identify animal models for COVID-19 that provide measurable readouts for potential interventions and that use representative virus isolates6. In addition, advanced age in rhesus macaques was also associated with an increased number of radiological and histopathological changes. Tang, D., Comish, P. & Kang, R. The hallmarks of COVID-19 disease. J. Virol. During the first wave of the coronavirus disease (COVID-19) pandemic in Europe in spring 2020, several countries experienced extraordinarily high levels of excess mortality. USA 113, 3048–3053 (2016). A comprehensive description of SARS-CoV-2 pathogenesis in the Syrian hamster model and its applicability for transmission studies. Google Scholar. Google Scholar. 383, 120–128 (2020). These mice will then be useful for pathogenesis studies, and for studies of antiviral agents and vaccines. In future studies, it will be important to define key outcome measures that would allow comparison between candidate interventions in animal models and humans. Iwatsuki-Horimoto, K. et al. 'Happiness is the most rebellious act.' SARS-CoV-2 infection in farmed minks, the Netherlands, April and May 2020. The nearest airport is Dole - Jura Airport, 9.3 mi from De Pierre … Severe acute respiratory syndrome coronavirus infection of mice transgenic for the human angiotensin-converting enzyme 2 virus receptor. Severity of disease in humanized mice infected with Ebola virus or Reston virus is associated with magnitude of early viral replication in liver. By submitting a comment you agree to abide by our Terms and Community Guidelines. ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. A SARS-CoV-2 infection model in mice demonstrates protection by neutralizing antibodies. All authors contributed to writing this Review. To ensure such models are able to provide these readouts, it is important to attempt to induce vaccine-associated enhanced respiratory disease in models of COVID-19 challenge using suboptimal doses of candidate vaccines or antigenic preparations with the goal of inducing the required detrimental immune profile and associated lung pathology. Comparison of transgenic and adenovirus hACE2 mouse models for SARS-CoV-2 infection. Standardization of these measurements will be important for the future evaluation of vaccines and therapeutic agents. However, the limited experimental studies performed so far have suggested that chickens—including embryonated chicken eggs—and ducks are not susceptible to infection with SARS-CoV-249,50,71. In addition, haematological changes—with evidence of T cell activation, mild lymphopenia and neutrophilia—have been observed in infected non-human primates. J. Med. As they grapple with new realities, … All of these models will be useful for the evaluation of vaccines and antiviral agents, and some share features with the human disease. PubMed  Miao, J., Chard, L. S., Wang, Z. Cell Host Microbe 28, 124–133.e4 (2020). 21, 1508–1513 (2015). Many of the pathogenesis studies described in this Review have also highlighted an important caveat in COVID-19 research, which are the methods used to measure virus replication. Proc. Preprint at https://doi.org/10.1101/2020.05.02.073411 (2020). 11, 3496 (2020). The former French President - who led the country for a … PubMed Central  To obtain DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Dis. Preprint at https://ssrn.com/abstract=3578792 (2020). Conversely, previous studies have reported infection with SARS-CoV in pigs67. Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development. One strategy to achieve this modification is the sequential passaging of SARS-CoV-2 in mouse lung tissue8. Graham, B. S. Rapid COVID-19 vaccine development. Emerg. Age-related rhesus macaque models of COVID-19. SARS-like WIV1-CoV poised for human emergence. PubMed  Google Scholar. Conversely, previous studies showed that a SARS-like coronavirus did not replicate in fruit bats after experimental inoculation77. PLoS Genet. Viruses 12, 779 (2020). Winkler, E. S. et al. https://doi.org/10.1038/s41586-020-2787-6, DOI: https://doi.org/10.1038/s41586-020-2787-6, Veterinary Quarterly PubMed  100, 1065–1075 (2020). Transmission occurred to one out of three direct-contact animals. Israelow, B. et al. Shedding of SARS-CoV-2 virus is observed in nasal and oropharyngeal swabs47,48,49,50. The spike protein of SARS-CoV-2 can be modified to gain effective binding to mouse ACE2. ADS  In addition to animal models that are more commonly used in infectious disease research, recent studies have characterized infection with SARS-CoV-2 in other animals. PubMed Central  Since SARS-CoV-2 emerged in the human population in late 2019, it has spread via human-to-human transmission to most countries in the world, leading to a coronavirus pandemic of an unprecedented scale. 82, 7264–7275 (2008). There are a number of small and large animal models that investigators can use to explore important aspects of COVID-19, including pathology, transmission and host responses to SARS-CoV-2, as well as to help to establish the safety and efficacy of potential therapeutic agents and vaccines. 115, 69–92 (2012). J. Virol. Interferon-γ, and pro-inflammatory chemokines and cytokines, were potently induced at two and four days after infection, respectively, and dropped to the baseline level at seven days after infection. Pierre Sarkozy attends the Etam Winter 2019/Summer 2020 show Credit: Getty Images - Getty Pierre Sarkozy is also known as DJ Mosey, and - aside from gigs - works as a music producer. Cancer Res. PubMed Central  Mice sensitized via AAV-hACE2 delivery are also susceptible to infection with SARS-CoV-2, but virus replication seems to be lower than in mice transduced with Ad5-hACE223. J. Virol. Syrian hamsters (Mesocricetus auratus) are small mammals that have been used as models for infection with respiratory viruses, including SARS-CoV, influenza virus and adenovirus31,32,33,34. Multisystem inflammatory syndrome in U.S. children and adolescents. J. Virol. At the time of writing, 41 additional mink farms have confirmed infections with SARS-CoV-2 and thousands of mink have been culled in the Netherlands and Spain. Individuals at a higher risk of developing severe COVID-19 include those with underlying conditions, such as obesity, diabetes, hypertension, chronic respiratory disease and cardiovascular disease1. Despite the use of different isolates of SARS-CoV-2, the results have been notably consistent across all laboratories. Despite this caveat, the vaccines tested so far have induced binding and neutralizing antibodies and have resulted in substantial reductions of viral replication in the lower respiratory tract, and—to a lesser extent—the upper respiratory tract, following challenge with SARS-CoV-2. CAS  At least one in silico study using the informational spectrum methodology proposed chicken as an animal species that is potential susceptible to infection with SARS-CoV-270. The ongoing COVID-19 pandemic and ensuing shutdown have left many restaurants uncertain about their future. Identification of candidate COVID-19 therapeutics using hPSC-derived lung organoids. Infect. These studies underscored the importance of coronavirus surveillance studies in bats, as these animals are regarded as the natural reservoir of many coronaviruses—including SARS-CoV and SARS-CoV-275,76. Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques. SHREVEPORT, La. A mouse model of SARS-CoV-2 infection and pathogenesis. Google Scholar. Neither chickens nor ducks appear to represent suitable animal models for studies of SARS-CoV-2 infection. Physiol. Proc. N. Engl. The authors did not describe clinical signs in any of the infected cats, except that 2 juvenile cats (out of 10 in total) died (on day 3 and day 13 after infection)50. Sci. J. Clin. Chan, J. F.-W. et al. At necropsy, interstitial pneumonia, loss of cilia and epithelial necrosis, as well as inflammation in nasal turbinates and trachea, were observed. Presumably, Collaborative Cross studies could enable the exploration of an expanded range of SARS-CoV-2 phenotypes in mice that potentially better recapitulates human disease, as mouse-adapted strains become available. In the meantime, to ensure continued support, we are displaying the site without styles Nat. Virus transmission to cage-mates has also been observed35, which suggests that hamsters may be useful in transmission studies. In this regard, micro-engineered organs-on-chips and lung organoids have been shown to support key hallmarks of the cytopathology and inflammatory responses observed in human airways after infection with SARS-CoV-2 and have served to facilitate the study of human disease pathogenesis, test candidate COVID-19 therapeutic agents and expedite drug repurposing78,79. Histological examination of the lungs of patients showed bilateral diffuse alveolar damage, pulmonary oedema and formation of hyaline membranes3. Nature https://doi.org/10.1038/s41586-020-2607-z (2020). However, continued refinement may result in models even for these aspects of the human disease. This system, which was pioneered in studies of MERS21, allows the transient replication of SARS-CoV-2 in the lungs of mice for several days until immune clearance, and it has the advantage that it can be applied quickly to different strains of mice. Upon experimental intranasal infection, Syrian hamsters show mild-to-moderate disease with progressive weight loss that starts very early after infection (days 1–2 after inoculation). Preprint at https://doi.org/10.1101/2020.05.05.079095 (2020). Screengrab: KHOU A … Callaway, E. Labs rush to study coronavirus in transgenic animals — some are in short supply. J. Virol. CAS  https://de-de.facebook.com/SWRFernsehen/videos/250322196154503 10, 2329 (2019). This was proposed to be due to differences between species in the levels of ACE2 expression in the respiratory epithelium80. Muñoz-Fontela, C., Dowling, W.E., Funnell, S.G.P. Gralinski, L. E. et al. Preprint at https://doi.org/10.1101/2020.07.08.193045 (2020). PubMed Central  217, 58–63 (2018). Passive immunization of naive hamsters with samples of this convalescent serum resulted in significantly reduced viral loads in the respiratory tract, but no obvious improvement in clinical signs and histological changes. Infect. Mink are also naturally susceptible to infection with SARS-CoV-2. A quantitative analysis revealed an increase in the non-aerated lung volume in these hamsters. (2021), Journal of NeuroVirology Collaborative Cross mice were previously used with mouse-adapted SARS-CoV to identify mechanisms of pathogenesis and genetic loci that determine susceptibility28. 217, e20201241 (2020). Pascal, K. E. et al. 81, 1162–1173 (2007). Although cats may represent a suitable model for asymptomatic-to-moderate COVID-19, before they are used as such we should be sure that the benefits outweigh the concerns of using companion animals for research; furthermore, cats are difficult to handle in biosafety level-3 containment, and are not a standard animal model. (2021), Cellular & Molecular Immunology The … volume 586, pages509–515(2020)Cite this article. CAS  USA 117, 22311–22322 (2020). Many readers grew nostalgic this week, sharing memories of watching movies such as “Grease,” “Titanic” and “Young Frankenstein” at Bethlehem’s Boyd Theatre. Menachery, V. D. et al. As discussed in this Review, a number of studies have been conducted—many of them by members of the WHO-COM—that indicate that some of the animal models support viral replication. Genome wide identification of SARS-CoV susceptibility loci using the collaborative cross. The predominant histopathology findings in SARS-CoV-2-infected ferrets euthanized at the peak of virus replication include inflammation within alveolar spaces and perivascular mononuclear inflammation. Continued refinement and development of animal models for COVID-19 will contribute to the development of vaccines, therapeutic agents and other countermeasures. Zhao, J. et al. COVID-19 is also characterized by damage to additional organ systems, associated with coagulopathy and characterized by elevated fibrinogen and D-dimer levels that indicate increased thrombus generation and fibrinolysis4. Ferrets also are able to transmit virus efficiently to uninfected ferrets in experimental settings. Viruses 10, 727 (2018). & Paessler, S. 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Front. However, over the past decade, advances in engineering, cell biology and microfabrication have come together to enable the development of new human-cell-based alternatives to animal models. Both experimentally infected and contact cats seroconverted. J. Exp. Therefore, owing to their importance as livestock and the enormous global number of pigs, it may be important for future studies to address the putative susceptibility of additional pig breeds to infection with SARS-CoV-2. ISSN 1476-4687 (online). Respiratory disease in rhesus macaques inoculated with SARS-CoV-2. Richard, M. et al. Lung disease was also demonstrated by computed tomography. Comparison of severe acute respiratory syndrome coronavirus 2 spike protein binding to ACE2 receptors from human, pets, farm animals, and putative intermediate hosts. This method thus allows quantitative monitoring of disease without the need to euthanize the animals. Additional ongoing efforts to develop mouse models for studying SARS-CoV-2 infection involve mice humanized with human ACE2 and human haematopoiesis, or Collaborative Cross mice. Han, Y. et al. J. Med. These mutations could thus result in a monoclonal antibody that neutralizes the wild-type virus being falsely considered as non-neutralizing. Euro Surveill. and JavaScript. 88, 2205–2218 (2014). Both studies showed that aged macaques shed virus from nose and throat for longer periods of time that do young adult macaques. Cockrell, A. S. et al. Menachery, V. D. et al. Yahoo ist Teil von Verizon Media. A limitation with these mice—as well as in some of the transgenic mice expressing human ACE2—is that human ACE2 is expressed ectopically, which may change the tissue or cellular tropism of the virus. 133, 74–87 (2008). Human organs-on-chips as tools for repurposing approved drugs as potential influenza and COVID19 therapeutics in viral pandemics. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. The content of this Review represents the opinions of the authors, and does not reflect the views or policies of any of their corresponding institutions. This analysis noted that many predicted affinities of the spike protein for the ACE2 receptor (especially those of dog and pig) did not match the relative natural resistance of the corresponding species to SARS-CoV-2. The imperfect cytokine storm: severe COVID-19 with ARDS in a patient on durable LVAD support. You are using a browser version with limited support for CSS. Recent studies have reported the immunogenicity and protective efficacy of several candidates for a COVID-19 vaccine in the rhesus macaque model57,58,59,60,61. Among the non-respiratory-tract tissues, only the intestine demonstrated expression of viral antigen in association with severe epithelial-cell necrosis, damaged and deformed intestinal villi, and increased infiltration of the lamina propria by mononuclear cells. The induction of innate, humoral and cellular immune responses as well as robust protection against rechallenge has also been reported, which demonstrates the induction of natural protective immunity in this model54. Overall, these mice will probably be very useful models of human disease—especially if combined with viral adaptation that increases the virulence of SARS-CoV-2 in mice. 25, 737 (2020). Standardized and sequenced challenge stocks and protocols will be needed to compare vaccine efficacy in non-human primates. Damas, J. et al. Therefore, pigs do not appear to represent a suitable animal model for COVID-19. The comparative pathogenesis of SARS-CoV-2 and other highly pathogenic coronaviruses in the non-human primate model. As with Syrian hamsters, virus replication is detected in the upper respiratory tract very early after infection (day 2) and is detectable during two weeks of infection. This study provides evidence that natural infection protects against SARS-CoV-2 rechallenge in non-human primates. Zheng, J. et al. 383, 334–346 (2020). Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model. Stories of resilience and connection for families during Covid-19 Jun 18, 2020 at 12:51 pm Non-human primates inoculated via multiroute mucosal, intrabronchial and aerosol exposure showed radiographic abnormalities (by chest X-ray, computed tomography scan or fluorodeoxyglucose positron emission tomography scan) within 2 days, which tended to resolve by 11–15 days after infection. 10, 914–916 (2004). Clin. This map shows the risk level of attending an event, given the event size and location. Gao, Q. et al. PubMed  Future studies will need to standardize challenge stocks, assays and protocols to allow comparisons of different candidate interventions. Note: Community Celebration Series performances are at Flagler Auditorium, 5500 East Hwy. Upon infection with SARS-CoV-2, mice transduced with Ad5-hACE2 develop a widespread infection of the lungs and histopathological changes that are consistent with viral pneumonia. J. Virol. Pathogenesis and transmission of SARS-CoV-2 in golden hamsters. However, more severe disease is expected to occur in human ACE2 knock-in mice if virus is passaged serially through mouse lungs. Studies from several laboratories have shown high levels of viral replication for 7–14 days (including both viral RNA and infectious virus) in both the upper and lower respiratory tract, pathological features of viral pneumonia and the variable induction of mild clinical disease52,53,54,55. STAT2 signaling as double-edged sword restricting viral dissemination but driving severe pneumonia in SARS-CoV-2 infected hamsters. The outcomes of these clinical-efficacy trials will allow an unprecedented opportunity for the back-validation and refinement of these animal models. MathSciNet  Nature https://doi.org/10.1038/s41586-020-2708-8 (2020). Dr. Pierre Kory on having COVID-19 research censored by Big Tech March 3, 2021, 3:40 AM President of the FLCCC Alliance responds to coronavirus cancel culture on 'Fox & Friends First.' Nature 585, 268–272 (2020). Barr, I. G., Rynehart, C., Whitney, P. & Druce, J. SARS-CoV-2 does not replicate in embryonated hen’s eggs or in MDCK cell lines. Rapid generation of a mouse model for Middle East respiratory syndrome. Sci. Natl Acad. Development of an inactivated vaccine candidate for SARS-CoV-2. Natl Acad. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. Verity, R. et al. Mercado, N. B. et al. 11, 446–448 (2005). It is thus not surprising that the ferret model has been investigated for studies of the pathogenesis of COVID-19 and SARS-CoV-2 transmission. Ji, H.-L., Zhao, R., Matalon, S. & Matthay, M. A. Elevated plasmin(ogen) as a common risk factor for COVID-19 susceptibility. The mink (Neovison vison), which is a member of the Mustelidae, has previously been shown to be susceptible to infection with SARS-CoV62; mink lung epithelial cells and lung-derived cells could also be infected with SARS-CoV63. J. Med. https://doi.org/10.1056/NEJMoa2024671 (2020). Microbiol. Discovery of novel human and animal cells infected by the severe acute respiratory syndrome coronavirus by replication-specific multiplex reverse transcription-PCR. 10, 179–184 (2004). Furthermore, SARS-CoV-2 can be transmitted between hamsters via close contact and non-contact routes35,39. Infect. These types of syndrome have been linked to vaccines that induced substantial levels of non-neutralizing antibodies or responses biased toward type-2 helper CD4 T cells. Chau, V. Q. et al. J. Virol. REUTERS/Ivan Pierre A YF17D-vectored SARS-CoV-2 vaccine candidate conferred efficient protection against SARS-CoV-2 challenge in hamsters42. Transmission via fomites was possible, but not efficient39. Virology 479–480, 259–270 (2015). Here we summarize the findings to date and provides relevant information for preclinical testing of vaccine candidates and therapeutic agents for COVID-19. The main impediment to the infection of mouse (Mus musculus) cells with SARS-CoV-2 is the lack of appropriate receptors to initiate viral infection. Age-dependent progression of SARS-CoV-2 infection in Syrian hamsters. Although most individuals subsequently resolve the infection, the disease may also progress to severe pneumonia. Senate begins marathon COVID-19 relief push as debate opens with reading bill aloud By Angelo Fichera, FactCheck.org. Following mucosal exposure to SARS-CoV-2, clinical alterations in ferrets are undetectable or mild and may include lethargy, nasal discharge, wheezing, oropharyngeal build-up of mucus, sneezing and loose stools46. SARS-CoV-2-induced lung pathology in hamsters appears to be driven by immune pathology, as lung injury at four days after infection is markedly reduced in STAT2-knockout hamsters whereas viral loads are massively increased and viral RNA is disseminated in several peripheral tissues36. Tseng, C.-T. K. et al. FILE - In this Feb. 23, 2014, file photo Jason Ravnsborg speaks in Sioux Falls, S.D. 20, 669–677 (2020). 94, 1199 (2020). Susceptibility of pigs and chickens to SARS coronavirus. Science 346, 987–991 (2014). USA 117, 16587–16595 (2020). Andersen, K. G., Rambaut, A., Lipkin, W. I., Holmes, E. C. & Garry, R. F. The proximal origin of SARS-CoV-2. Bauer, D. C. et al. The susceptibility of both cats and dogs to natural and experimental infection with SARS-CoV-2 strongly suggests that antibody testing in these species could be a useful tool for epidemiological studies, in particular in areas with high density of cases of COVID-19 in humans. In part, these symptoms are caused by the capacity of SARS-CoV-2 to replicate efficiently in the upper respiratory tract. Für nähere Informationen zur Nutzung Ihrer Daten lesen Sie bitte unsere Datenschutzerklärung und Cookie-Richtlinie. Chen, W. et al. Dis. PubMed Central  There are currently three transgenic mouse models, in which human ACE2 is under the expression of a tissue-specific promoter (for example, the Krt18 promoter for epithelial cells10; K18-hACE2 mice), a universal promoter (cytomegalovirus enhancer followed by the chicken β-actin promoter11) or the endogenous mouse Ace2 promoter12.
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