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 h post infection.

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 h 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.

A hybrid discrete-continuum model of immune responses to SARS-CoV-2 infection in the lung alveolar region, with a focus on interferon induced innate response.

We develop a lattice-based, hybrid discrete-continuum modeling framework for SARS-CoV-2 exposure and infection in the human lung alveolar region, or parenchyma, the massive surface area for gas exchange. COVID-19 pneumonia is alveolar infection by the SARS-CoV-2 virus significant enough to compromise gas exchange. The modeling framework orchestrates the onset and progression of alveolar infection, spatially and temporally, beginning with a pre-immunity baseline, upon which we superimpose multiple mechanisms of immune protection conveyed by interferons and antibodies. The modeling framework is tunable to individual profiles, focusing here on degrees of innate immunity, and to the evolving infection-replication properties of SARS-CoV-2 variant strains. The model employs partial differential equations for virion, interferon, and antibody concentrations governed by diffusion in the thin fluid coating of alveolar cells, species and lattice interactions corresponding to sources and sinks for each species, and multiple immune protections signaled by interferons. The spatial domain is a two-dimensional, rectangular lattice of alveolar type I (non-infectable) and type II (infectable) cells with a stochastic, species-concentration-governed, switching dynamics of type II lattice sites from healthy to infected. Once infected, type II cells evolve through three phases: an eclipse phase during which RNA copies (virions) are assembled; a shedding phase during which virions and interferons are released; and then cell death. Model simulations yield the dynamic spread of, and immune protection against, alveolar infection and viral load from initial sites of exposure. We focus in this paper on model illustrations of the diversity of outcomes possible from alveolar infection, first absent of immune protection, and then with varying degrees of four known mechanisms of interferon-induced innate immune protection. We defer model illustrations of antibody protection to future studies. Results presented reinforce previous recognition that interferons produced solely by infected cells are insufficient to maintain a high efficacy level of immune protection, compelling additional mechanisms to clear alveolar infection, such as interferon production by immune cells and adaptive immunity (e.g., T cells). This manuscript was submitted as part of a theme issue on "Modelling COVID-19 and Preparedness for Future Pandemics".

A hybrid discrete-continuum model of immune responses to SARS-CoV-2 infection in the lung alveolar region, with a focus on interferon induced innate response

We develop a lattice-based, hybrid discrete-continuum modeling framework for SARS-CoV-2 exposure and infection in the human lung alveolar region, or parenchyma, the massive surface area for gas exchange. COVID-19 pneumonia is alveolar infection by the SARS-CoV-2 virus significant enough to compromise gas exchange. The modeling framework orchestrates the onset and progression of alveolar infection, spatially and temporally, beginning with a pre-immunity baseline, upon which we superimpose multiple mechanisms of immune protection conveyed by interferons and antibodies. The modeling framework is tunable to individual profiles, focusing here on degrees of innate immunity, and to the evolving infection-replication properties of SARS-CoV-2 variant strains. The model employs partial differential equations for virion, interferon, and antibody concentrations governed by diffusion in the thin fluid coating of alveolar cells, species and lattice interactions corresponding to sources and sinks for each species, and multiple immune protections signaled by interferons. The spatial domain is a two-dimensional, rectangular lattice of alveolar type I (non-infectable) and type II (infectable) cells with a stochastic, species-concentration-governed, switching dynamics of type II lattice sites from healthy to infected. Once infected, type II cells evolve through three phases: an eclipse phase during which RNA copies (virions) are assembled;a shedding phase during which virions and interferons are released;and then cell death. Model simulations yield the dynamic spread of, and immune protection against, alveolar infection and viral load from initial sites of exposure. We focus in this paper on model illustrations of the diversity of outcomes possible from alveolar infection, first absent of immune protection, and then with varying degrees of four known mechanisms of interferon-induced innate immune protection. We defer model illustrations of antibody protection to future studies. Results presented reinforce previous recognition that interferons produced solely by infected cells are insufficient to maintain a high efficacy level of immune protection, compelling additional mechanisms to clear alveolar infection, such as interferon production by immune cells and adaptive immunity (e.g., T cells). This manuscript was submitted as part of a theme issue on “Modelling COVID-19 and Preparedness for Future Pandemics”.

Aerosol Transport Modeling: The Key Link Between Lung Infections of Individuals and Populations.

The recent COVID-19 pandemic has propelled the field of aerosol science to the forefront, particularly the central role of virus-laden respiratory droplets and aerosols. The pandemic has also highlighted the critical need, and value for, an information bridge between epidemiological models (that inform policymakers to develop public health responses) and within-host models (that inform the public and health care providers how individuals develop respiratory infections). Here, we review existing data and models of generation of respiratory droplets and aerosols, their exhalation and inhalation, and the fate of infectious droplet transport and deposition throughout the respiratory tract. We then articulate how aerosol transport modeling can serve as a bridge between and guide calibration of within-host and epidemiological models, forming a comprehensive tool to formulate and test hypotheses about respiratory tract exposure and infection within and between individuals.

Modeling insights into SARS-CoV-2 respiratory tract infections prior to immune protection.

Mechanistic insights into human respiratory tract (RT) infections from SARS-CoV-2 can inform public awareness as well as guide medical prevention and treatment for COVID-19 disease. Yet the complexity of the RT and the inability to access diverse regions pose fundamental roadblocks to evaluation of potential mechanisms for the onset and progression of infection (and transmission). We present a model that incorporates detailed RT anatomy and physiology, including airway geometry, physical dimensions, thicknesses of airway surface liquids (ASLs), and mucus layer transport by cilia. The model further incorporates SARS-CoV-2 diffusivity in ASLs and best-known data for epithelial cell infection probabilities, and, once infected, duration of eclipse and replication phases, and replication rate of infectious virions. We apply this baseline model in the absence of immune protection to explore immediate, short-term outcomes from novel SARS-CoV-2 depositions onto the air-ASL interface. For each RT location, we compute probability to clear versus infect; per infected cell, we compute dynamics of viral load and cell infection. Results reveal that nasal infections are highly likely within 1-2 days from minimal exposure, and alveolar pneumonia occurs only if infectious virions are deposited directly into alveolar ducts and sacs, not via retrograde propagation to the deep lung. Furthermore, to infect just 1% of the 140 m2 of alveolar surface area within 1 week, either 103 boluses each with 106 infectious virions or 106 aerosols with one infectious virion, all physically separated, must be directly deposited. These results strongly suggest that COVID-19 disease occurs in stages: a nasal/upper RT infection, followed by self-transmission of infection to the deep lung. Two mechanisms of self-transmission are persistent aspiration of infected nasal boluses that drain to the deep lung and repeated rupture of nasal aerosols from infected mucosal membranes by speaking, singing, or cheering that are partially inhaled, exhaled, and re-inhaled, to the deep lung.