Combined mutations in nonstructural protein 14, envelope, and membrane proteins mitigate the neuropathogenicity of SARS-CoV-2 Omicron BA.1 in K18-hACE2 mice
ABSTRACT We previously reported that mutations outside the spike protein play a role in the attenuation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.1 variant in human ACE2 transgenic mice (K18-hACE2). Here, we assessed the pathogenicity of SARS-CoV-2 (WA1/2020) con...
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American Society for Microbiology
2025-01-01
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| Series: | mSphere |
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| Online Access: | https://journals.asm.org/doi/10.1128/msphere.00726-24 |
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| author | Kotou Sangare Shufeng Liu Prabhuanand Selvaraj Charles B. Stauft Matthew F. Starost Tony T. Wang |
| author_facet | Kotou Sangare Shufeng Liu Prabhuanand Selvaraj Charles B. Stauft Matthew F. Starost Tony T. Wang |
| author_sort | Kotou Sangare |
| collection | DOAJ |
| description | ABSTRACT We previously reported that mutations outside the spike protein play a role in the attenuation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.1 variant in human ACE2 transgenic mice (K18-hACE2). Here, we assessed the pathogenicity of SARS-CoV-2 (WA1/2020) containing mutations from the Omicron BA.1 variant in K18-hACE2 mice. At an infection dose of 104 plaque-forming units (PFU), WA1 virus carrying Omicron BA.1 Nsp14(I42V), E(T9I), M(D3G/Q19E/A63T), but not Nsp6(Δ105–107, I189V), substitutions showed significant reduction in lethality. Interestingly, reduction of viral load is more pronounced in the brains than in the lungs. Subsequent analyses suggest that BA.1 E(T9I) and M(D3G/Q19E/A63T) substitutions result in less efficient packaging of virus-like particles. Given that Nsp14(I42V), E(T9I), M(Q19E/A63T) are well preserved in subsequent omicron subvariants, including currently circulating variants, our findings highlight the importance of understanding how non-spike mutations affect the pathogenicity of SARS-CoV-2 variants.IMPORTANCEInoculation of transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) with SARS-CoV-2 often leads to a fatal brain infection. Omicron BA.1 variant, however, was found to be non-lethal in this model. Here, we systematically assessed the effect of individual mutations of Omicron BA.1 on the pathogenicity of the virus in hACE2 transgenic mice and found that combination of 5 mutations of Nsp14, E, and M of BA.1 variant significantly lowered brain viral load and reduced lethality. These results provide new insights into how SARS-CoV-2 Omicron BA.1 is attenuated. |
| format | Article |
| id | doaj-art-a7f7019bb2f0409db3d574582dd3c6ca |
| institution | Kabale University |
| issn | 2379-5042 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSphere |
| spelling | doaj-art-a7f7019bb2f0409db3d574582dd3c6ca2025-01-28T14:00:57ZengAmerican Society for MicrobiologymSphere2379-50422025-01-0110110.1128/msphere.00726-24Combined mutations in nonstructural protein 14, envelope, and membrane proteins mitigate the neuropathogenicity of SARS-CoV-2 Omicron BA.1 in K18-hACE2 miceKotou Sangare0Shufeng Liu1Prabhuanand Selvaraj2Charles B. Stauft3Matthew F. Starost4Tony T. Wang5Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USADivision of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USADivision of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USADivision of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USADivision of Veterinary Resources, Diagnostic and Research Services Branch, National Institutes of Health, Bethesda, Maryland, USADivision of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USAABSTRACT We previously reported that mutations outside the spike protein play a role in the attenuation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.1 variant in human ACE2 transgenic mice (K18-hACE2). Here, we assessed the pathogenicity of SARS-CoV-2 (WA1/2020) containing mutations from the Omicron BA.1 variant in K18-hACE2 mice. At an infection dose of 104 plaque-forming units (PFU), WA1 virus carrying Omicron BA.1 Nsp14(I42V), E(T9I), M(D3G/Q19E/A63T), but not Nsp6(Δ105–107, I189V), substitutions showed significant reduction in lethality. Interestingly, reduction of viral load is more pronounced in the brains than in the lungs. Subsequent analyses suggest that BA.1 E(T9I) and M(D3G/Q19E/A63T) substitutions result in less efficient packaging of virus-like particles. Given that Nsp14(I42V), E(T9I), M(Q19E/A63T) are well preserved in subsequent omicron subvariants, including currently circulating variants, our findings highlight the importance of understanding how non-spike mutations affect the pathogenicity of SARS-CoV-2 variants.IMPORTANCEInoculation of transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) with SARS-CoV-2 often leads to a fatal brain infection. Omicron BA.1 variant, however, was found to be non-lethal in this model. Here, we systematically assessed the effect of individual mutations of Omicron BA.1 on the pathogenicity of the virus in hACE2 transgenic mice and found that combination of 5 mutations of Nsp14, E, and M of BA.1 variant significantly lowered brain viral load and reduced lethality. These results provide new insights into how SARS-CoV-2 Omicron BA.1 is attenuated.https://journals.asm.org/doi/10.1128/msphere.00726-24SARS-CoV-2 variantsCOVID-19Syrian hamstersspike proteinOmicron BA.1 |
| spellingShingle | Kotou Sangare Shufeng Liu Prabhuanand Selvaraj Charles B. Stauft Matthew F. Starost Tony T. Wang Combined mutations in nonstructural protein 14, envelope, and membrane proteins mitigate the neuropathogenicity of SARS-CoV-2 Omicron BA.1 in K18-hACE2 mice mSphere SARS-CoV-2 variants COVID-19 Syrian hamsters spike protein Omicron BA.1 |
| title | Combined mutations in nonstructural protein 14, envelope, and membrane proteins mitigate the neuropathogenicity of SARS-CoV-2 Omicron BA.1 in K18-hACE2 mice |
| title_full | Combined mutations in nonstructural protein 14, envelope, and membrane proteins mitigate the neuropathogenicity of SARS-CoV-2 Omicron BA.1 in K18-hACE2 mice |
| title_fullStr | Combined mutations in nonstructural protein 14, envelope, and membrane proteins mitigate the neuropathogenicity of SARS-CoV-2 Omicron BA.1 in K18-hACE2 mice |
| title_full_unstemmed | Combined mutations in nonstructural protein 14, envelope, and membrane proteins mitigate the neuropathogenicity of SARS-CoV-2 Omicron BA.1 in K18-hACE2 mice |
| title_short | Combined mutations in nonstructural protein 14, envelope, and membrane proteins mitigate the neuropathogenicity of SARS-CoV-2 Omicron BA.1 in K18-hACE2 mice |
| title_sort | combined mutations in nonstructural protein 14 envelope and membrane proteins mitigate the neuropathogenicity of sars cov 2 omicron ba 1 in k18 hace2 mice |
| topic | SARS-CoV-2 variants COVID-19 Syrian hamsters spike protein Omicron BA.1 |
| url | https://journals.asm.org/doi/10.1128/msphere.00726-24 |
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