Coronavirus SARS-CoV-2 replicates better in the upper respiratory tract

Coronavirus SARS-CoV-2 replicates best in the upper respiratory tract. Researchers: Silvio Steiner (bottom left), Jenna Kelly (top left), Mitra Gultom (top right), Philip V’kovski (top right) and corresponding author Ronald Dijkman (bottom right), Institute of Diseases Infectious, University of Bern. Photo: © UniBE

A team of researchers from the Institute of Infectious Diseases at the University of Bern and the Federal Institute of Virology and Immunology evaluated the growth of the coronavirus SARS-CoV-2 and the activation of cellular defense mechanisms in the respiratory tract.

The researchers showed that the temperature differences that exist in the upper and lower respiratory tract are natural and that this has a profound influence on the replication of SARS-CoV-2 and subsequent innate immune activation in human cells. The findings may help to develop antiviral drugs and preventive measures.

“SARS-CoV-2 like SARS-CoV are very similar genetically, generate a homologous repertoire of viral proteins and use the same receptor to infect human cells. However, despite these similarities, there are also important differences between the two viruses, ”said Ronald Dijkman, from the Institute of Infectious Diseases at the University of Bern.

SARS-CoV infection is characterized by severe disease and inflammation in the lower respiratory tract and infected individuals are only contagious after the onset of symptoms, making it easier to identify and break the chains of infection.

In the case of SARS-CoV-2, it replicates preferentially in the upper airways (nasal cavity, pharynx, trachea) and can be transmitted efficiently from one individual to another before the onset of symptoms of the disease. In addition, the result of SARS-CoV-2 infection varies widely from person to person and can manifest as an asymptomatic, mild or severe disease.

Elderly people, as well as individuals with certain underlying medical conditions (heart problems, diabetes, cancer), are at increased risk of developing serious illness, which are usually associated with infection of the lower respiratory tissues, high levels of inflammation and lung failure.

Temperature is the key

To better understand why infections with SARS-CoV and SARS-CoV-2 result in such different clinical results, researchers at the University of Bern used specialized cell cultures from human airways to investigate the impact of respiratory tract temperatures on replication of the SARS-CoV and SARS-CoV -2.

The cells originate from human samples and mimic the complexity of the cells found in the respiratory tract. Growing in special containers, they are nourished at the bottom and exposed to air at the top, just like the cells of the human trachea.

The crops also produce juice and have lashes that flap very quickly. “As the organization of these cells is very similar to the cells found in human tissues, they are a relevant system that can be used in the laboratory to study respiratory viruses,” explained Ronald Dijkman.

The researchers used this model for the first time to study the effects of respiratory temperatures on the replication of SARS-CoV and SARS-CoV-2. They found that temperature plays an important role, as SARS-CoV-2 prefers to replicate at temperatures normally found in the upper airways, around 33 ° C.

Cooler incubation temperatures allowed the virus to replicate faster and to a greater extent than when infections were performed at 37 ° C to mimic the lower lung environment. Unlike SARS-CoV-2, SARS-CoV replication was not affected by different incubation temperatures. The experiments were carried out in the high security laboratory of the Federal Institute of Virology in Mittelhäusern and in the biosafety laboratory of the Institute of Infectious Diseases at the University of Bern.

Temperature influences the response of the epithelium

The team also looked at which genes are activated and deactivated after infection with SARS-CoV and SARS-CoV-2 to understand how cells in the human respiratory tract respond to infection and which innate immune programs are activated.

The innate immune system is our body’s “first line of defense” against invading pathogens and is crucial not only to contain the invader, but also to teach other branches of the immune system how to react appropriately.

By mimicking the conditions found in the upper airways, where the temperature is around 33 ° C, the team found that infection with SARS-CoV-2 did not stimulate the innate immune response within these cells as strongly as it did when mimicking the conditions found in the lower respiratory tract, with 37 ° C.

“Since the strength of the innate immune response can directly influence the degree of viral replication, this may help explain why SARS-CoV-2 replicated more efficiently at lower temperatures,” said Ronald Dijkman. Although building a strong innate immune response against the virus is generally beneficial, it is important to note that, in some cases, the innate immune response can become overactivated. This, in turn, can be harmful to the infected individual,

“Detailed analysis of SARS-CoV-2 replication and temperature-induced changes in the host’s innate immune defense mechanisms help explain why SARS-CoV-2 replicates so well in the upper respiratory tract, and perhaps it is because this is why SARS-CoV-2 exhibits greater transmissibility between humans than SARS-CoV “, explains Ronald Dijkman.

Knowledge to fight coronavirus infections

The use of this cell culture model in a controlled laboratory environment has proven to accurately reflect the different behavior of two similar viruses in the context of a pandemic. “This unique system provides insight into the molecular battle that occurs between the virus and the host during an infection and highlights the importance of subtle changes in the virus-host microenvironment that can impact the replication and spread of the virus,” said Ronald Dijkman.

Understanding which key actors are involved in this process, and whether they favor the host or the virus, opens up new opportunities for the establishment of highly targeted intervention strategies and the development of new pharmaceutical compounds that will help to fight coronavirus infections.

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