tetano
Editor, Senior Moderator
J Theor Biol
. 2023 Mar 23;111470.
doi: 10.1016/j.jtbi.2023.111470. Online ahead of print.
Modeling identifies variability in SARS-CoV-2 uptake and eclipse phase by infected cells as principal drivers of extreme variability in nasal viral load in the 48 hours post infection
Jason Pearson[SUP] 1 [/SUP], Timothy Wessler[SUP] 1 [/SUP], Alex Chen[SUP] 2 [/SUP], Richard C Boucher[SUP] 3 [/SUP], Ronit Freeman[SUP] 4 [/SUP], Samuel K Lai[SUP] 5 [/SUP], Raymond Pickles[SUP] 6 [/SUP], M Gregory Forest[SUP] 7 [/SUP]
Affiliations
Abstract
The SARS-CoV-2 coronavirus continues to evolve with scores of mutations of the spike, membrane, envelope, and nucleocapsid structural proteins that impact pathogenesis. Infection data from nasal swabs, nasal PCR assays, upper respiratory samples, ex vivo cell cultures and nasal epithelial organoids reveal extreme variabilities in SARS-CoV-2 RNA titers within and between the variants. Some variabilities are naturally prone to clinical testing protocols and experimental controls. Here we focus on nasal viral load sensitivity arising from the timing of sample collection relative to onset of infection and from heterogeneity in the kinetics of cellular infection, uptake, replication, and shedding of viral RNA copies. The sources of between-variant variability are likely due to SARS-CoV-2 structural protein mutations, whereas within-variant population variability is likely due to heterogeneity in cellular response to that particular variant. With the physiologically faithful, agent-based mechanistic model of inhaled exposure and infection from (Chen et al., 2022), we perform statistical sensitivity analyses of the progression of nasal viral titers in the first 0-48 hours post infection, focusing on three kinetic mechanisms. Model simulations reveal shorter latency times of infected cells (including cellular uptake, viral RNA replication, until the onset of viral RNA shedding) exponentially accelerate nasal viral load. Further, the rate of infectious RNA copies shed per day has a proportional influence on nasal viral load. Finally, there is a very weak, negative correlation of viral load with the probability of infection per virus-cell encounter, the model proxy for spike-receptor binding affinity.
Keywords: SARS-CoV-2; mechanistic modeling; nasal infection; viral load.
. 2023 Mar 23;111470.
doi: 10.1016/j.jtbi.2023.111470. Online ahead of print.
Modeling identifies variability in SARS-CoV-2 uptake and eclipse phase by infected cells as principal drivers of extreme variability in nasal viral load in the 48 hours post infection
Jason Pearson[SUP] 1 [/SUP], Timothy Wessler[SUP] 1 [/SUP], Alex Chen[SUP] 2 [/SUP], Richard C Boucher[SUP] 3 [/SUP], Ronit Freeman[SUP] 4 [/SUP], Samuel K Lai[SUP] 5 [/SUP], Raymond Pickles[SUP] 6 [/SUP], M Gregory Forest[SUP] 7 [/SUP]
Affiliations
- PMID: 36965846
- PMCID: PMC10033495
- DOI: 10.1016/j.jtbi.2023.111470
Abstract
The SARS-CoV-2 coronavirus continues to evolve with scores of mutations of the spike, membrane, envelope, and nucleocapsid structural proteins that impact pathogenesis. Infection data from nasal swabs, nasal PCR assays, upper respiratory samples, ex vivo cell cultures and nasal epithelial organoids reveal extreme variabilities in SARS-CoV-2 RNA titers within and between the variants. Some variabilities are naturally prone to clinical testing protocols and experimental controls. Here we focus on nasal viral load sensitivity arising from the timing of sample collection relative to onset of infection and from heterogeneity in the kinetics of cellular infection, uptake, replication, and shedding of viral RNA copies. The sources of between-variant variability are likely due to SARS-CoV-2 structural protein mutations, whereas within-variant population variability is likely due to heterogeneity in cellular response to that particular variant. With the physiologically faithful, agent-based mechanistic model of inhaled exposure and infection from (Chen et al., 2022), we perform statistical sensitivity analyses of the progression of nasal viral titers in the first 0-48 hours post infection, focusing on three kinetic mechanisms. Model simulations reveal shorter latency times of infected cells (including cellular uptake, viral RNA replication, until the onset of viral RNA shedding) exponentially accelerate nasal viral load. Further, the rate of infectious RNA copies shed per day has a proportional influence on nasal viral load. Finally, there is a very weak, negative correlation of viral load with the probability of infection per virus-cell encounter, the model proxy for spike-receptor binding affinity.
Keywords: SARS-CoV-2; mechanistic modeling; nasal infection; viral load.