SARS-CoV-2 Omicron (B.1.1.529) shows minimal neurotropism in a double-humanized mouse model

Alves, Rúbens Prince dos Santos; Wang, Ying-Ting; Mikulski, Zbigniew; McArdle, Sara; Shafee, Norazizah; Valentine, Kristen M.; Miller, Robyn; Verma, Shailendra Kumar; Batiz, Fernanda  Ana Sosa; Maule, Erin; Nguyen, Michael N.; Timis, Julia; Mann, Colin; Zandonatti, Michelle; Alarcon, Suzie; Rowe, Jenny; Kronenberg, Mitchell; Weiskopf, Daniela; Sette, Alessandro; Hastie, Kathryn M.; Saphire, Erica Ollmann; Festin, Stephen; Kim, Kenneth; Shresta, Sujan

doi:10.1016/j.antiviral.2023.105580

Cited by 2 publications

(2 citation statements)

References 84 publications

(93 reference statements)

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“…Our analysis of the brain of mice infected with the Omicron variant shows reduced viral RNA levels as compared to the brain of mice infected with Wild-type or Delta at 3dpi and humane endpoint/8dpi. These results were also observed in a double humanized mouse model infected with these viruses 43 . The brain of mice infected with Omicron shows downregulation of inflammatory markers at 8dpi suggesting that infection by this variant results in attenuated neurological consequences as compared with mice infected with either Wild-type or Delta.…”

Section: Discussionsupporting

confidence: 64%

Differential outcomes of infection by wild-type SARS-CoV-2 and the B.1.617.2 and B.1.1.529 variants of concern in K18-hACE2 transgenic mice

He,

Henley,

Sell

et al. 2023

Preprint

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BackgroundSARS-CoV-2 is a respiratory virus with neurological complications including loss of smell and taste, headache, and confusion that can persist for months or longer. Severe neuronal cell damage has also been reported in some cases. The objective of this study was to compare the infectivity of Wild-type, Delta, and Omicron variants in transgenic mice that express the human angiotensin-converting enzyme 2 (hACE2) receptor under the control of the keratin 18 promoter (K18) and characterize the progression of infection and inflammatory response in the lung and brain of these animals.MethodsK18-hACE2 female mice were intranasally infected with Wild-type, Delta, or Omicron variants and euthanized either at 3 days post-infection (dpi) or at the humane endpoint. None of the animals infected with the Omicron variant reached the humane endpoint and were euthanized at day 8 dpi. Virological and immunological analyses were performed in the lungs, olfactory bulbs, medulla oblongata, and brains.ResultsWe established that Wild-type, Delta, and Omicron infect the lung and brain of K18-hACE2 mice. At 3 dpi, mice infected with the Omicron variant show lower levels of viral RNA than those infected with Wild-type or Delta in the lung and brain. However, they still demonstrate upregulation of cytokines and chemokines, indicating that the Omicron variant can induce pulmonary and neuronal inflammation despite reduced viral proliferation after infection. At the humane endpoint/8dpi, there is a significant increase in viral RNA in mice infected with the Wild-type or Delta variant brains. However, viral RNA levels in Omicron-infected mice did not increase significantly as compared to 3dpi, and the expression of cytokines and chemokines in the brain, olfactory bulb, and medulla oblongata was downregulated, suggesting that infection by the Omicron variant results in attenuated neuroinflammation as compared with Wild-type and Delta.

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Section: Discussionsupporting

confidence: 64%

Differential outcomes of infection by wild-type SARS-CoV-2 and the B.1.617.2 and B.1.1.529 variants of concern in K18-hACE2 transgenic mice

He,

Henley,

Sell

et al. 2023

Preprint

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“…Because current predominant circulating SARS-CoV-2 are Omicron variants ( 60 ), we examined 11d in K18-hACE2 mice infected with SARS-CoV-2 Omicron XBB.1.16. It has been shown that SARS-CoV-2 Omicron variants are known to cause less severe diseases in the mouse model ( 45 , 61 , 62 ). Because infections of Omicron subvariant XBB.1.16 in K18-hACE2 mice can lead to fatal outcome, we used this combination to evaluate in vivo efficacy of 11d in this study.…”

Section: Discussionmentioning

confidence: 99%

Potent 3CLpro inhibitors effective against SARS-CoV-2 and MERS-CoV in animal models by therapeutic treatment

Li,

Kim,

Dampalla

et al. 2024

mBio

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) are zoonotic betacoronaviruses that continue to have a significant impact on public health. Timely development and introduction of vaccines and antivirals against SARS-CoV-2 into the clinic have substantially mitigated the burden of COVID-19. However, a limited or lacking therapeutic arsenal for SARS-CoV-2 and MERS-CoV infections, respectively, calls for an expanded and diversified portfolio of antivirals against these coronavirus infections. In this report, we examined the efficacy of two potent 3CLpro inhibitors, 5d and 11d , in fatal animal models of SARS-CoV-2 and MERS-CoV to demonstrate their broad-spectrum activity against both viral infections. These compounds significantly increased the survival of mice in both models when treatment started 1 day post infection compared to no treatment which led to 100% fatality. Especially, the treatment with compound 11d resulted in 80% and 90% survival in SARS-CoV-2 and MERS-CoV-infected mice, respectively. Amelioration of lung viral load and histopathological changes in treated mice correlated well with improved survival in both infection models. Furthermore, compound 11d exhibited significant antiviral activities in K18-hACE2 mice infected with SARS-CoV-2 Omicron subvariant XBB.1.16. The results suggest that these are promising candidates for further development as broad-spectrum direct-acting antivirals against highly virulent human coronaviruses. IMPORTANCE Human coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) continue to have a significant impact on public health. A limited or lacking therapeutic arsenal for SARS-CoV-2 and MERS-CoV infections calls for an expanded and diversified portfolio of antivirals against these coronavirus infections. We have previously reported a series of small-molecule 3C-like protease (3CLpro) inhibitors against human coronaviruses. In this report, we demonstrated the in vivo efficacy of 3CLpro inhibitors for their broad-spectrum activity against both SARS-CoV-2 and MERS-CoV infections using the fatal animal models. The results suggest that these are promising candidates for further development as broad-spectrum direct-acting antivirals against highly virulent human coronaviruses.

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SARS-CoV-2 Omicron (B.1.1.529) shows minimal neurotropism in a double-humanized mouse model

Cited by 2 publications

References 84 publications

Differential outcomes of infection by wild-type SARS-CoV-2 and the B.1.617.2 and B.1.1.529 variants of concern in K18-hACE2 transgenic mice

Differential outcomes of infection by wild-type SARS-CoV-2 and the B.1.617.2 and B.1.1.529 variants of concern in K18-hACE2 transgenic mice

Potent 3CLpro inhibitors effective against SARS-CoV-2 and MERS-CoV in animal models by therapeutic treatment

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