Immortal Cells and Mathematics Reveal Mechanism behind Coronavirus Infection

A mathematical model has helped describe the course of infection caused by two variants of coronavirus: Omicron and Delta, and explain the differences between them. It appears that the cell entry rate is lower for Omicron, allowing infected cells ample time to alert neighbouring cells of the threat and trigger the activation of their innate immune response. In the future, the developed model could be employed to investigate any other variant of COVID-19, potentially leading to effective strategies for combating new hazardous strains, such as Pirola and JN.1. The findings from the study conducted with the participation of HSE researchers have been published in PeerJ.

While the World Health Organization (WHO) lifted the pandemic status for COVID-19 in May 2023, this does not mean that the coronavirus is no longer a global threat. The virus has remained in the population and continues to spread and mutate. The most active variants of COVID-19 today are derivatives of the Omicron variant. Omicron differs significantly from previous variants of SARS-CoV-2 in that it is much more contagious but causes less severe illness and fewer complications.

COVID-19 enters host cells using a spike protein which binds to target receptors on the cell's surface. The Delta variant employs a mechanism whereby its proteins are cleaved, facilitating rapid injection of the virus' genetic material into the cell. Due to mutations, the Omicron strain has lost this capability and therefore enters cells much more slowly using specialised membrane vesicles.

A team of Russian researchers with the participation of scientists at the HSE Faculty of Biology and Biotechnology modelled the process of cell entry for both the Omicron and Delta strains, describing through mathematical methods the subsequent viral spread in body tissues.

Mathematics plays an active role in biology. On one hand, mathematics can accurately describe complex biological processes, and on the other hand, mathematical modelling enables researchers to examine individual components of these processes, revealing insights not observable through experimentation alone, eg how a cell consumes lipids and proteins during a viral process. In a previous paper, we employed mathematics to investigate the characteristics of the initial variant of coronavirus and the Delta variant within the intestinal epithelium model. This time, we have adapted our mathematical model to incorporate the behaviour of the Omicron variant within both intestinal and lung epithelia.

Evgeny Knyazev
Co-author of the study, Head of the Laboratory of Molecular Physiology, HSE University

The proposed model is based on real experimental data. The researchers infected intestinal and lung cells with both Delta and Omicron strains, observing the rate at which the virus enters the cells, the extent of cell infection, and the speed at which it leads to cell death.

The experiment was conducted using cell material from the intestines and lungs, as these organs have the highest concentration of receptors to which the virus binds. However, while lung infection typically manifests with clinical symptoms such as cough and fever, intestinal infection can act as a concealed reservoir of the virus, often presenting with no obvious symptoms.

When the virus enters the human body, two levels of immunity are activated: innate, which is evolutionarily older and involves the release of special molecules—cytokines, and acquired, which is associated with the activity of cells such as lymphocytes and the production of antibodies targeting the virus. The scientists were particularly interested in the innate immune response and the local reaction to foreign proteins from the virus. To eliminate the influence of acquired immunity, immortal cell lines from the lungs and intestines were used in the experiment.

In biological research, immortal cell lines are often used in place of healthy human cells. These are human cancerous cells capable of endless division and therefore referred to as immortal. In laboratories, they are employed as a model due to their stability, predictability, and close resemblance to the epithelium of the respective organs.

Evgeny Knyazev
Co-author of the study, Head of the Laboratory of Molecular Physiology, HSE University

The findings from the laboratory experiment were subsequently presented as a mathematical model, revealing an additional factor contributing to the mild nature of Omicron infections. It appears that the mild course of Omicron can be attributed not only to its slower cell entry compared to Delta but also to the robust activation of innate immunity.

Upon contact with both variants, infected cells release signalling molecules called cytokines, which notify neighbouring cells of the danger and prompt them to activate protection. However, the strength of the produced effect varies. While even alerted cells can become infected with Delta, the situation is different with Omicron, as the resistance of cells alerted by cytokines becomes nearly absolute.

Mathematical modelling enables us to anticipate how the virus will behave during mutations and, consequently, identify strategies to respond to new challenges. For instance, since 2023, a new variant of the coronavirus, Pirola, has emerged, which has regained the ability to utilise a cellular enzyme that cleaves the virus's spike protein upon entry. The JN.1 variant of SARS-CoV-2, derivative of Pirola, is now the dominant variant globally. To mitigate the threat posed by new strains, we must devise means to impede the virus's cell entry and give the innate immune system an opportunity to mount a response.

Evgeny Knyazev
Co-author of the study, Head of the Laboratory of Molecular Physiology, HSE University

IQ

April 18