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A Study Reveals What Triggers Lung Damage during COVID-19
A longitudinal study of macrophages from SARS-CoV-2 infected lungs offers new insights into dynamic immunological changes
A KAIST immunology research team found that a specific subtype of macrophages that originated from blood monocytes plays a key role in the hyper-inflammatory response in SARS-CoV-2 infected lungs, by performing single-cell RNA sequencing of bronchoalveolar lavage fluid cells. This study provides new insights for understanding dynamic changes in immune responses to COVID-19.
In the early phase of COVID-19, SARS-CoV-2 infected lung tissue and the immediate defense system is activated. This early and fast response is called ‘innate immunity,’ provided by immune cells residing in lungs. Macrophages are major cell types of the innate immune system of the lungs, and newly differentiated macrophages originating from the bloodstream also contribute to early defenses against viruses.
Professor Su-Hyung Park and his collaborators investigated the quantitative and qualitative evaluation of immune responses in the lungs of SARS-CoV-2 infected ferrets. To overcome the limitations of research using patient-originated specimens, the researchers used a ferret infection model to obtain SARS-CoV-2 infected lungs sequentially with a defined time interval.
The researchers analyzed the 10 subtypes of macrophages during the five-day course of SARS-CoV-2 infection, and found that infiltrating macrophages originating from activated monocytes in the blood were key players for viral clearance as well as damaged lung tissue. Moreover, they found that the differentiation process of these inflammatory macrophages resembled the immune responses in the lung tissue of severe COVID-19 patients.
Currently, the research team is conducting a follow-up study to identify the dynamic changes in immune responses during the use of immunosuppressive agents to control hyper-inflammatory response called ‘cytokine storm’ in patients with COVID-19.
Dr. Jeong Seok Lee, the chief medical officer at Genome Insight Inc., explained, “Our analysis will enhance the understanding of the early features of COVID-19 immunity and provide a scientific background for the more precise use of immunosuppressive agents targeting specific macrophage subtypes.”
“This study is the first longitudinal study using sequentially obtained immune cells originating from SARS-CoV-2 infected lungs. The research describes the innate immune response to COVID-19 using single cell transcriptome data and enhances our understanding of the two phases of inflammatory responses,” Professor Park said.
This work was supported by the Ministry of Health and Welfare and KAIST, and was published in Nature Communications on July 28.
-PublicationSu-Hyung Park, Jeong Seok Lee, Su-Hyung Park et al. “Single-cell transcriptome of bronchoalverolar lavage fluid reveals sequential change of macrophages during SARS-CoV-2 infection in ferrets” Nature Communications (https://doi.org/10.1038/s41467-021-24807-0)
-ProfileProfessor Su-Hyung ParkLaboratory of Translational Immunology and Vaccinologyhttps://ltiv.kaist.ac.kr/
Graduate School of Medical Science and EngineeringKAIST
2021.08.04 View 17448 -
Study of T Cells from COVID-19 Convalescents Guides Vaccine Strategies
Researchers confirm that most COVID-19 patients in their convalescent stage carry stem cell-like memory T cells for months
A KAIST immunology research team found that most convalescent patients of COVID-19 develop and maintain T cell memory for over 10 months regardless of the severity of their symptoms. In addition, memory T cells proliferate rapidly after encountering their cognate antigen and accomplish their multifunctional roles. This study provides new insights for effective vaccine strategies against COVID-19, considering the self-renewal capacity and multipotency of memory T cells.
COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. When patients recover from COVID-19, SARS-CoV-2-specific adaptive immune memory is developed. The adaptive immune system consists of two principal components: B cells that produce antibodies and T cells that eliminate infected cells. The current results suggest that the protective immune function of memory T cells will be implemented upon re-exposure to SARS-CoV-2.
Recently, the role of memory T cells against SARS-CoV-2 has been gaining attention as neutralizing antibodies wane after recovery. Although memory T cells cannot prevent the infection itself, they play a central role in preventing the severe progression of COVID-19. However, the longevity and functional maintenance of SARS-CoV-2-specific memory T cells remain unknown.
Professor Eui-Cheol Shin and his collaborators investigated the characteristics and functions of stem cell-like memory T cells, which are expected to play a crucial role in long-term immunity. Researchers analyzed the generation of stem cell-like memory T cells and multi-cytokine producing polyfunctional memory T cells, using cutting-edge immunological techniques.
This research is significant in that revealing the long-term immunity of COVID-19 convalescent patients provides an indicator regarding the long-term persistence of T cell immunity, one of the main goals of future vaccine development, as well as evaluating the long-term efficacy of currently available COVID-19 vaccines.
The research team is presently conducting a follow-up study to identify the memory T cell formation and functional characteristics of those who received COVID-19 vaccines, and to understand the immunological effect of COVID-19 vaccines by comparing the characteristics of memory T cells from vaccinated individuals with those of COVID-19 convalescent patients.
PhD candidate Jae Hyung Jung and Dr. Min-Seok Rha, a clinical fellow at Yonsei Severance Hospital, who led the study together explained, “Our analysis will enhance the understanding of COVID-19 immunity and establish an index for COVID-19 vaccine-induced memory T cells.”
“This study is the world’s longest longitudinal study on differentiation and functions of memory T cells among COVID-19 convalescent patients. The research on the temporal dynamics of immune responses has laid the groundwork for building a strategy for next-generation vaccine development,” Professor Shin added. This work was supported by the Samsung Science and Technology Foundation and KAIST, and was published in Nature Communications on June 30.
-Publication:
Jung, J.H., Rha, MS., Sa, M. et al. SARS-CoV-2-specific T cell memory is sustained in COVID-19 convalescent patients for 10 months with successful development of stem cell-like memory T cells. Nat Communications 12, 4043 (2021). https://doi.org/10.1038/s41467-021-24377-1
-Profile:
Professor Eui-Cheol Shin
Laboratory of Immunology & Infectious Diseases (http://liid.kaist.ac.kr/)
Graduate School of Medical Science and Engineering
KAIST
2021.07.05 View 19908 -
'Mini-Lungs' Reveal Early Stages of SARS-CoV-2 Infection
Researchers in Korea and the UK have successfully grown miniature models of critical lung structures called alveoli, and used them to study how the coronavirus that causes COVID-19 infects the lungs.
To date, there have been more than 40 million cases of COVID-19 and almost 1.13 million deaths worldwide. The main target tissues of SARS-CoV-2, the virus that causes COVID-19, especially in patients that develop pneumonia, appear to be alveoli – tiny air sacs in the lungs that take up the oxygen we breathe and exchange it with carbon dioxide to exhale.
To better understand how SARS-CoV-2 infects the lungs and causes disease, a team of Professor Young Seok Ju from the Graduate School of Medical Science and Engineering at KAIST in collaboration with the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge turned to organoids – ‘mini-organs’ grown in three dimensions to mimic the behaviour of tissue and organs.
The team used tissue donated to tissue banks at the Royal Papworth Hospital NHS Foundation Trust and Addenbrooke’s Hospital, Cambridge University NHS Foundations Trust, UK, and Seoul National University Hospital to extract a type of lung cell known as human lung alveolar type 2 cells. By reprogramming these cells back to their earlier ‘stem cell’ stage, they were able to grow self-organizing alveolar-like 3D structures that mimic the behaviour of key lung tissue.
“The research community now has a powerful new platform to study precisely how the virus infects the lungs, as well as explore possible treatments,” said Professor Ju, co-senior author of the research.
Dr. Joo-Hyeon Lee, another co-senior author at the Wellcome-MRC Cambridge Stem Cell Institute, said: “We still know surprisingly little about how SARS-CoV-2 infects the lungs and causes disease. Our approach has allowed us to grow 3D models of key lung tissue – in a sense, ‘mini-lungs’ – in the lab and study what happens when they become infected.”
The team infected the organoids with a strain of SARS-CoV-2 taken from a patient in Korea who was diagnosed with COVID-19 on January 26 after traveling to Wuhan, China. Using a combination of fluorescence imaging and single cell genetic analysis, they were able to study how the cells responded to the virus.
When the 3D models were exposed to SARS-CoV-2, the virus began to replicate rapidly, reaching full cellular infection just six hours after infection. Replication enables the virus to spread throughout the body, infecting other cells and tissue.
Around the same time, the cells began to produce interferons – proteins that act as warning signals to neighbouring cells, telling them to activate their antiviral defences. After 48 hours, the interferons triggered the innate immune response – its first line of defence – and the cells started fighting back against infection.
Sixty hours after infection, a subset of alveolar cells began to disintegrate, leading to cell death and damage to the lung tissue.
Although the researchers observed changes to the lung cells within three days of infection, clinical symptoms of COVID-19 rarely occur so quickly and can sometimes take more than ten days after exposure to appear. The team say there are several possible reasons for this. It may take several days from the virus first infiltrating the upper respiratory tract to it reaching the alveoli. It may also require a substantial proportion of alveolar cells to be infected or for further interactions with immune cells resulting in inflammation before a patient displays symptoms.
“Based on our model we can tackle many unanswered key questions, such as understanding genetic susceptibility to SARS-CoV-2, assessing relative infectivity of viral mutants, and revealing the damage processes of the virus in human alveolar cells,” said Professor Ju. “Most importantly, it provides the opportunity to develop and screen potential therapeutic agents against SARS-CoV-2 infection.”
“We hope to use our technique to grow these 3D models from cells of patients who are particularly vulnerable to infection, such as the elderly or people with diseased lungs, and find out what happens to their tissue,” added Dr. Lee.
The research was a collaboration involving scientists from KAIST, the University of Cambridge, Korea National Institute of Health, Institute for Basic Science (IBS), Seoul National University Hospital and Genome Insight in Korea.
- ProfileProfessor Young Seok JuLaboratory of Cancer Genomics https://julab.kaist.ac.kr the Graduate School of Medical Science and EngineeringKAIST
2020.10.26 View 16032 -
Biomarker Predicts Who Will Have Severe COVID-19
- Airway cell analyses showing an activated immune axis could pinpoint the COVID-19 patients who will most benefit from targeted therapies.-
KAIST researchers have identified key markers that could help pinpoint patients who are bound to get a severe reaction to COVID-19 infection. This would help doctors provide the right treatments at the right time, potentially saving lives. The findings were published in the journal Frontiers in Immunology on August 28.
People’s immune systems react differently to infection with SARS-CoV-2, the virus that causes COVID-19, ranging from mild to severe, life-threatening responses.
To understand the differences in responses, Professor Heung Kyu Lee and PhD candidate Jang Hyun Park from the Graduate School of Medical Science and Engineering at KAIST analysed ribonucleic acid (RNA) sequencing data extracted from individual airway cells of healthy controls and of mildly and severely ill patients with COVID-19. The data was available in a public database previously published by a group of Chinese researchers.
“Our analyses identified an association between immune cells called neutrophils and special cell receptors that bind to the steroid hormone glucocorticoid,” Professor Lee explained. “This finding could be used as a biomarker for predicting disease severity in patients and thus selecting a targeted therapy that can help treat them at an appropriate time,” he added.
Severe illness in COVID-19 is associated with an exaggerated immune response that leads to excessive airway-damaging inflammation. This condition, known as acute respiratory distress syndrome (ARDS), accounts for 70% of deaths in fatal COVID-19 infections.
Scientists already know that this excessive inflammation involves heightened neutrophil recruitment to the airways, but the detailed mechanisms of this reaction are still unclear.
Lee and Park’s analyses found that a group of immune cells called myeloid cells produced excess amounts of neutrophil-recruiting chemicals in severely ill patients, including a cytokine called tumour necrosis factor (TNF) and a chemokine called CXCL8.
Further RNA analyses of neutrophils in severely ill patients showed they were less able to recruit very important T cells needed for attacking the virus. At the same time, the neutrophils produced too many extracellular molecules that normally trap pathogens, but damage airway cells when produced in excess.
The researchers additionally found that the airway cells in severely ill patients were not expressing enough glucocorticoid receptors. This was correlated with increased CXCL8 expression and neutrophil recruitment.
Glucocorticoids, like the well-known drug dexamethasone, are anti-inflammatory agents that could play a role in treating COVID-19. However, using them in early or mild forms of the infection could suppress the necessary immune reactions to combat the virus. But if airway damage has already happened in more severe cases, glucocorticoid treatment would be ineffective.
Knowing who to give this treatment to and when is really important. COVID-19 patients showing reduced glucocorticoid receptor expression, increased CXCL8 expression, and excess neutrophil recruitment to the airways could benefit from treatment with glucocorticoids to prevent airway damage. Further research is needed, however, to confirm the relationship between glucocorticoids and neutrophil inflammation at the protein level.
“Our study could serve as a springboard towards more accurate and reliable COVID-19 treatments,” Professor Lee said.
This work was supported by the National Research Foundation of Korea, and Mobile Clinic Module Project funded by KAIST.
Figure. Low glucocorticoid receptor (GR) expression led to excessive inflammation and lung damage by neutrophils through enhancing the expression of CXCL8 and other cytokines.
Image credit: Professor Heung Kyu Lee, KAIST. Created with Biorender.com.
Image usage restrictions: News organizations may use or redistribute these figures and image, with proper attribution, as part of news coverage of this paper only.
-Publication:
Jang Hyun Park, and Heung Kyu Lee. (2020). Re-analysis of Single Cell Transcriptome Reveals That the NR3C1-CXCL8-Neutrophil Axis Determines the Severity of COVID-19. Frontiers in Immunology, Available online at https://doi.org/10.3389/fimmu.2020.02145
-Profile: Heung Kyu Lee
Associate Professor
heungkyu.lee@kaist.ac.kr
https://www.heungkyulee.kaist.ac.kr/
Laboratory of Host Defenses
Graduate School of Medical Science and Engineering (GSMSE)
The Center for Epidemic Preparedness at KAIST Institute
http://kaist.ac.kr
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon, Republic of Korea
Profile: Jang Hyun Park
PhD Candidate
janghyun.park@kaist.ac.kr
GSMSE, KAIST
2020.09.17 View 22970