A joint research team has revealed the characteristics and origins of the specific immune cells that cause damage in Covid-19 patients’ lungs, the Korea Advanced Institute of Science and Technology (KAIST) said on Wednesday.

The research results will be able to control pulmonary damages caused by excessive immunological reactions in Covid-19 patients, KAIST said.

It has become possible by researching quantitative and qualitative immunological changes that occur at the peak of Covid-19 virus propagation and during the convalescent stage, it added.

The joint research was led by Professor Park Su-hyung of Graduate School of Medical Science and Engineering at KAIST, Professor Choi Young-ki of College of Medicine and Medical Research Institute at Chungbuk National University, and Doctor Lee Jeong-seok of Genome Insight Inc., the institute said in a news release.

Within the lung tissue infected by the influx of virus, immune cells are immediately vitalized. Most of these cells are “macrophages.” As a primary defense reaction of SARS-CoV-2 infection, the vitalized mononuclear cells enter the lung tissue through blood flow. These mononuclear cells differentiate into additional macrophages. In due process, the cells of infected parts of the lung tissues are removed.

It is impossible to study immune cells extracted from human lungs infected by Covid-19 at different stages of infection. Therefore, respiratory infected animal models like ferrets, the carnivorous mustelidae mammals, had an important role in finding the precise aspects of immune response after the virus infection, according to the news release. Professor Choi’s team was the first to report that experimental animals like ferrets have SARS-CoV-2 virus susceptibility.

With the Covid-19 infected animal model, the joint-research team made a precise analysis of the changes in the immune cells of the lung tissues at different stages of Covid-19 infection using single-cell sequencing. The macrophages that take up most of the immune cells of the lungs were classified into 10 distinct subpopulations. Of these, an analysis was made to find the ones with the highest contribution to lung damage.

The research team found that the quantity of macrophages rapidly increases after two days of Covid-19 virus infection. This is due to many activated mononuclear cells in the blood flow that permeate the lung tissue, which goes through macrophage differentiation. Especially, these macrophages that permeate from blood flow have strong qualities of inflammatory macrophages. Therefore, it contributes to the eradication of the virus but also can be the main culprit of tissue damage. Also, conditions of macrophage differentiation were very similar to the changes found in lung tissue of severe Covid-19 patients.

The research, supported by the Ministry of Health and Welfare and KAIST, was published in the journal ‘Nature Communications’ on July 28  with the title, “Single-cell transcriptome of bronchoalveolar lavage fluid reveals a sequential change of macrophages during SARS-CoV-2 infection in ferrets.”

The joint research team is preparing for a follow-up research protocol on defining the immunological effects of drugs and appropriate control of the excessive immune reaction. Fatal immune responses of severe Covid-19 patients include cytokine storm. Currently, the team is secondarily tracking the immunological changes on Covid-19 patients that had immunosuppressive drugs administered.

“The research result is an important reference in understanding the duality of immune reaction of macrophages in Covid-19 infection. Using single-cell transcriptome omics data, multilateral analysis was made on an innate immune reaction that the lungs of Covid-19 patients experience,” said Drs. Koh June-young of KAIST and Lee of Genome Insight, the lead authors of the research.

Professor Choi said, “The research material that contains the proliferation changes and pathological analysis of different stages of SARS-CoV-2 virus infection is an important tool in understanding pathogenesis related to the overall infection and recovery.” 

Professor Park also said, “The most significant point of the study is the precise definition of consecutive changes before and after the Covid-19 infection. Also, the study identified specific inflammatory macrophages as the cause of lung damage after infection. This gives a basis for planning precise immunosuppressive treatment strategies for severe Covid-19 patients.”