COVID infection in 4 steps: Thermodynamic considerations reveal how viral mucosal diffusion, target receptor affinity and furin cleavage act in concert to drive the nature and degree of infection in human COVID-19 disease
We have developed a mechanistic model of SARS-CoV-2 and SARS-CoV infection, exploring the relationship between the viral diffusion in the mucosa and viral affinity for the angiotensin converting enzyme 2 (ACE2) target. Utilising the structural similarity of SARS-CoV and SARS-CoV-2 and a shared viral...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844023043827 |
| _version_ | 1827926540543852544 |
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| author | Marko Popovic Jennifer H. Martin Richard J. Head |
| author_facet | Marko Popovic Jennifer H. Martin Richard J. Head |
| author_sort | Marko Popovic |
| collection | DOAJ |
| description | We have developed a mechanistic model of SARS-CoV-2 and SARS-CoV infection, exploring the relationship between the viral diffusion in the mucosa and viral affinity for the angiotensin converting enzyme 2 (ACE2) target. Utilising the structural similarity of SARS-CoV and SARS-CoV-2 and a shared viral target receptor (ACE2), but a dramatic difference in upper or lower respiratory tract infectivity, we were able to generate insights into the linkage of mucosal diffusion and target receptor affinity in determining the pathophysiological pathways of these two viruses.Our analysis reveals that for SARS-CoV-2 the higher affinity of ACE2 binding, the faster and more complete the mucosal diffusion in its transport from the upper airway to the region of the ACE2 target on the epithelium. This diffusional process is essential for the presentation of this virus to the furin catalysed highly efficient entry and infection process in the upper respiratory tract epithelial cells. A failure of SARS-CoV to follow this path is associated with lower respiratory tract infection and decreased infectivity. Thus, our analysis supports the view that through tropism SARS-CoV-2 has evolved a highly efficient membrane entry process that can act in concert with a high binding affinity of this virus and its variants for its ACE2 which in turn promotes enhanced movement of the virus from airway to epithelium. In this way ongoing mutations yielding higher affinities of SARS-CoV-2 for the ACE2 target becomes the basis for higher upper respiratory tract infectivity and greater viral spread. It is concluded that SARS-CoV-2 is constrained in the extent of its activities by the fundamental laws of physics and thermodynamics. Laws that describe diffusion and molecular binding. Moreover it can be speculated that the very earliest contact of this virus with the human mucosa defines the pathogenesis of this infection. |
| first_indexed | 2024-03-13T05:40:04Z |
| format | Article |
| id | doaj.art-ecf6cb3975ca4b7e9c67c49e488f3821 |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-03-13T05:40:04Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj.art-ecf6cb3975ca4b7e9c67c49e488f38212023-06-14T04:33:55ZengElsevierHeliyon2405-84402023-06-0196e17174COVID infection in 4 steps: Thermodynamic considerations reveal how viral mucosal diffusion, target receptor affinity and furin cleavage act in concert to drive the nature and degree of infection in human COVID-19 diseaseMarko Popovic0Jennifer H. Martin1Richard J. Head2Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia; Corresponding author.Centre for Drug Repurposing and Medicines Research, University of Newcastle and Hunter Medical Research Institute, Newcastle 2305, AustraliaDrug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, AustraliaWe have developed a mechanistic model of SARS-CoV-2 and SARS-CoV infection, exploring the relationship between the viral diffusion in the mucosa and viral affinity for the angiotensin converting enzyme 2 (ACE2) target. Utilising the structural similarity of SARS-CoV and SARS-CoV-2 and a shared viral target receptor (ACE2), but a dramatic difference in upper or lower respiratory tract infectivity, we were able to generate insights into the linkage of mucosal diffusion and target receptor affinity in determining the pathophysiological pathways of these two viruses.Our analysis reveals that for SARS-CoV-2 the higher affinity of ACE2 binding, the faster and more complete the mucosal diffusion in its transport from the upper airway to the region of the ACE2 target on the epithelium. This diffusional process is essential for the presentation of this virus to the furin catalysed highly efficient entry and infection process in the upper respiratory tract epithelial cells. A failure of SARS-CoV to follow this path is associated with lower respiratory tract infection and decreased infectivity. Thus, our analysis supports the view that through tropism SARS-CoV-2 has evolved a highly efficient membrane entry process that can act in concert with a high binding affinity of this virus and its variants for its ACE2 which in turn promotes enhanced movement of the virus from airway to epithelium. In this way ongoing mutations yielding higher affinities of SARS-CoV-2 for the ACE2 target becomes the basis for higher upper respiratory tract infectivity and greater viral spread. It is concluded that SARS-CoV-2 is constrained in the extent of its activities by the fundamental laws of physics and thermodynamics. Laws that describe diffusion and molecular binding. Moreover it can be speculated that the very earliest contact of this virus with the human mucosa defines the pathogenesis of this infection.http://www.sciencedirect.com/science/article/pii/S2405844023043827Viral diffusionPharmacologyAffinity constantThermodynamicsHuman diseaseSARS-CoV2 |
| spellingShingle | Marko Popovic Jennifer H. Martin Richard J. Head COVID infection in 4 steps: Thermodynamic considerations reveal how viral mucosal diffusion, target receptor affinity and furin cleavage act in concert to drive the nature and degree of infection in human COVID-19 disease Heliyon Viral diffusion Pharmacology Affinity constant Thermodynamics Human disease SARS-CoV2 |
| title | COVID infection in 4 steps: Thermodynamic considerations reveal how viral mucosal diffusion, target receptor affinity and furin cleavage act in concert to drive the nature and degree of infection in human COVID-19 disease |
| title_full | COVID infection in 4 steps: Thermodynamic considerations reveal how viral mucosal diffusion, target receptor affinity and furin cleavage act in concert to drive the nature and degree of infection in human COVID-19 disease |
| title_fullStr | COVID infection in 4 steps: Thermodynamic considerations reveal how viral mucosal diffusion, target receptor affinity and furin cleavage act in concert to drive the nature and degree of infection in human COVID-19 disease |
| title_full_unstemmed | COVID infection in 4 steps: Thermodynamic considerations reveal how viral mucosal diffusion, target receptor affinity and furin cleavage act in concert to drive the nature and degree of infection in human COVID-19 disease |
| title_short | COVID infection in 4 steps: Thermodynamic considerations reveal how viral mucosal diffusion, target receptor affinity and furin cleavage act in concert to drive the nature and degree of infection in human COVID-19 disease |
| title_sort | covid infection in 4 steps thermodynamic considerations reveal how viral mucosal diffusion target receptor affinity and furin cleavage act in concert to drive the nature and degree of infection in human covid 19 disease |
| topic | Viral diffusion Pharmacology Affinity constant Thermodynamics Human disease SARS-CoV2 |
| url | http://www.sciencedirect.com/science/article/pii/S2405844023043827 |
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