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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
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
Universal Virus Detection Platform to Expedite Viral Diagnosis
Reactive polymer-based tester pre-screens dsRNAs of a wide range of viruses without their genome sequences The prompt, precise, and massive detection of a virus is the key to combat infectious diseases such as Covid-19. A new viral diagnostic strategy using reactive polymer-grafted, double-stranded RNAs will serve as a pre-screening tester for a wide range of viruses with enhanced sensitivity. Currently, the most widely using viral detection methodology is polymerase chain reaction (PCR) diagnosis, which amplifies and detects a piece of the viral genome. Prior knowledge of the relevant primer nucleic acids of the virus is quintessential for this test. The detection platform developed by KAIST researchers identifies viral activities without amplifying specific nucleic acid targets. The research team, co-led by Professor Sheng Li and Professor Yoosik Kim from the Department of Chemical and Biomolecular Engineering, constructed a universal virus detection platform by utilizing the distinct features of the PPFPA-grafted surface and double-stranded RNAs. The key principle of this platform is utilizing the distinct feature of reactive polymer-grafted surfaces, which serve as a versatile platform for the immobilization of functional molecules. These activated surfaces can be used in a wide range of applications including separation, delivery, and detection. As long double-stranded RNAs are common byproducts of viral transcription and replication, these PPFPA-grafted surfaces can detect the presence of different kinds of viruses without prior knowledge of their genomic sequences. “We employed the PPFPA-grafted silicon surface to develop a universal virus detection platform by immobilizing antibodies that recognize double-stranded RNAs,” said Professor Kim. To increase detection sensitivity, the research team devised two-step detection process analogues to sandwich enzyme-linked immunosorbent assay where the bound double-stranded RNAs are then visualized using fluorophore-tagged antibodies that also recognize the RNAs’ double-stranded secondary structure. By utilizing the developed platform, long double-stranded RNAs can be detected and visualized from an RNA mixture as well as from total cell lysates, which contain a mixture of various abundant contaminants such as DNAs and proteins. The research team successfully detected elevated levels of hepatitis C and A viruses with this tool. “This new technology allows us to take on virus detection from a new perspective. By targeting a common biomarker, viral double-stranded RNAs, we can develop a pre-screening platform that can quickly differentiate infected populations from non-infected ones,” said Professor Li. “This detection platform provides new perspectives for diagnosing infectious diseases. This will provide fast and accurate diagnoses for an infected population and prevent the influx of massive outbreaks,” said Professor Kim. This work is featured in Biomacromolecules. This work was supported by the Agency for Defense Development (Grant UD170039ID), the Ministry of Science and ICT (NRF-2017R1D1A1B03034660, NRF-2019R1C1C1006672), and the KAIST Future Systems Healthcare Project from the Ministry of Science and ICT (KAISTHEALTHCARE42). Profile:-Professor Yoosik KimDepartment of Chemical and Biomolecular Engineeringhttps://qcbio.kaist.ac.kr KAIST-Professor Sheng LiDepartment of Chemical and Biomolecular Engineeringhttps://bcpolymer.kaist.ac.kr KAIST Publication:Ku et al., 2020. Reactive Polymer Targeting dsRNA as Universal Virus Detection Platform with Enhanced Sensitivity. Biomacromolecules (https://doi.org/10.1021/acs.biomac.0c00379).
Long Economic Depressions and Disparities Loom in the Wake of the COVID-19
"Global Cooperation for Managing Data Key to Mitigating the Impacts Around the World" <Full recorded video of the GSI-IF2020> The COVID-19 pandemic will lead to long economic depressions around the entire world. Experts predicted that the prevalent inequities among the countries, regions, and individuals will aggravate the economic crisis. However, crises always come with new opportunities and international cooperation and solidarity will help creating a new normal in the post-coronavirus era. In a very basic but urgent step, global cooperation for managing data is the key to respond to COVID-19 since medicine and healthcare are intertwined with data science, said experts during an online international forum hosted by the Global Strategy Institute at KAIST on April 22. KAIST launched its think-tank, the Global Strategy Institute (GSI), in February. The GSI aims to identify global issues proactively and help make breakthroughs well aligned with solid science-based policies. The inaugural forum of the GSI focused on how the COVID-19 pandemic would impact socio-economic, scientific, and political landscapes, under the theme “Global Cooperation in the Coronavirus Era.” In his opening remarks, KAIST President Sung-Chul Shin stressed that future global governance will be dominated by the power of science and technology. “If we can implement efficient policies together with troubleshooting technology for responding to future crises, we will emerge stronger than before,” he said. President Shin said ‘the Korean model’, which is being recognized as a shining example for dealing with the pandemic, is the result of collaborations combining the creativity of the private sector, the public sector’s strong infrastructure, and the full support of the citizens. He added, “Without the technological prowess coming from the competent R&D power of Korea, we could not achieve these impressive results.” “Creative collaboration among the private and public sectors, along with research universities from around the world, will help shore up global resilience against the epidemic. We should work together to build a world of growing prosperity,” President Shin said. Prime Minister Sye-Kyun Chung, who is in charge of the Central Disaster and Safety Countermeasures Headquarters in Korea, stressed global solidarity in his welcoming remarks, saying that “We need to share information and rely on the strength of our connections, rather than retreating into nationalistic isolation.” Peter Lee, Vice President of the Microsoft Healthcare, pointed out in his welcoming remarks three critical sectors for global cooperation: medicine and healthcare, public health and prevention, and life and the economy. He emphasized the rule of thumb for managing data, saying that data in these fields should be open, standardized, and shared among countries to combat this global pandemic. During a keynote session, Director General of the International Vaccine Institute (IVI) Jerome Kim described the challenges that go along with developing a vaccine. Dr. Kim said that only 7% of vaccine candidates go through the clinical trial stages, and it will take five to 10 years to completely prove a new vaccine’s safety after completing three stages of clinical tests. “It’s very challenging to develop the vaccine for COVID-19 within 12 to 15 months,” said Dr. Kim. He added that 78 out of 115 candidates are currently undergoing clinical trials around the world. There are five groups, including Moderna, Inovio, Jenner Institute, CanSino, and the Beijing Institute of Biological Products, who are doing clinical trials in phases 1 and 2. “Given the fact that COVID-19 is a totally new type of virus, various stakeholders’ participation, such as the National Immunization Technical Advisory Groups, the WHO, and UNICEF, is needed to work together to benefit the entire world,” he pointed out. Professor Edward Yoonjae Choi from the Graduate School of AI at KAIST shared how AI and data sciences are being utilized to interpret the major trends of the epidemic. His group mainly focuses on deep learning to model electronic health records (EHR) for disease predictions. Professor Choi said AI and machine learning would be crucial solutions and collaborative research projects will surely accelerate how quickly we can overcome the pandemic. In addition, Dr. Kijung Shin’s group is interpreting the SIR (Susceptible, Infected, and Recovered) model in Korea to predict the number of infections and when people were infected. However, researchers noticed that they could not see the typical modeling in Korea for predicting the number of infections since the model disregarded the new variable of humans’ efforts to stop the spread the virus. According to research by Professor Steven Whang’s group on social distancing and face mask distribution among vulnerable age groups, people in their 20s, 60s, and 70s followed the social distancing guidelines the most strictly. The research team analyzed the data provided by SK Telecom in the Gangnam district of Seoul. The data provided on people in their 70s, a group that accounted for half of all fatalities, showed that masks were generally well distributed nationwide. Dr. Alexandros Papaspyrids, Tertiary Education Industry Director of the Asia region of Microsoft, said that despite all the disadvantages and problems related to remote education, we shouldn’t expect to return to the days before the COVID-19 any time soon. “We should accept the new normal and explore new opportunities in the new educational environment,” he said. Hongtaek Yong, Deputy Minister at the Office of R&D Policy at the Ministry of Science and ICT presented the Korean government’s disease prevention and response policy and how they tried to mitigate the economic and social impact. He stressed the government’s fast testing, tracing, and openness for successfully flattening the curve, adding that the government used an ICT-based approach in all aspects of their response. From early this year when the first patient was reported, the government aggressively encouraged the biotech industry to develop diagnostic kits and novel therapeutic medications. As a result, five companies were able to produce genetic diagnostic reagents through the emergency approval. More notably, four of them are conducting massive R&D projects sponsored by the government and this is the result of the government’s continuous investment in R&D. Korea is the leader in R&D investment among the OECD countries. According to Yong, the government’s big data project that was launched in 2017 continuously traces the trends of epidemics in Korea. The epidemiological studies based on the paths taken by suspected patients using credit card transaction made the difference in predicting the spread of the coronavirus and implementing countermeasures. The data has been provided to the Korea’s Center for Disease Control (CDC). “In addition to the epidemics, we have so many other pending issues arising from digital and social equities, un-contact services, and job security. We are very open to collaborate and cooperate with other countries to deal with this global crisis,” Yong said. During the subsequent panel discussions, David Dollar, a senior fellow at the Brookings Institution, said, “The global economy in the coronavirus era will not have a rapid V-shaped recovery, but rather will fall into a long depression for at least two years.” He pointed out that if countries practice protectionism like they did during the Great Depression, the recession will be even worse. Hence, he urged the international community, especially developed nations, to avoid protectionism, consider the economic difficulties of developing countries, and provide them with financial support. Co-Director of the Center for Universal Education at the Brookings Institution Rebecca Winthrop raised concerns over the recent shift to online teaching and learning, claiming that insufficient infrastructures in low-income families in developing nations are already causing added educational disparities and provoking the inequity issue around the world. “The ways to provide quality education equally through faster and more effective means should be studied,” she said. Professor Joungho Kim, the director of the KAIST GSI and the forum’s organizer, concluded the event by saying that this forum will be a valuable resource for everyone who is providing assistance to those in need, both during and after the COVID-19 pandemic. (END)
KAIST Vaccine for Tick-Borne Disease ‘SFTS’ Protects Against Lethal Infection
A KAIST research team reported the development of a DNA vaccine for Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV) which completely protects against lethal infection in ferrets. The team confirmed that ferrets immunized with DNA vaccines encoding all SFTSV proteins showed 100% survival rate without detectable viremia and did not develop any clinical symptoms. This study was published in Nature Communications on August 23. Severe Fever with Thrombocytopenia Syndrome (SFTS) is a newly emerging tick-borne infectious disease. The disease causes fever, severe thrombocytopenia, leukocytopenia as well as vomiting and diarrhea. Severe cases end up with organ system failure often accompanied by hemorrhages, and its mortality rate stands at 10–20%. The viral disease has been endemic to East Asia but the spread of the tick vector to North America increases the likelihood of potential outbreak beyond the Far East Asia. The World Health Organization (WHO) has also put SFTSV into the priority pathogen requiring urgent attention category. Currently, no vaccine has been available to prevent SFTS. The research team led by Professor Su-Hyung Park noted that DNA vaccines induce broader immunity to multiple antigens than traditional ones. Moreover, DNA vaccines stimulate both T cell and antibody immunity, which make them suitable for vaccine development. They constructed DNA vaccines that encode full-length Gn, Gc, N, NS, and RNA polymerase genes based on common sequences of 31 SFTSV strains isolated from patients. Their vaccine candidates induced both neutralizing antibody response and multifunctional SFTSV-specific T cell response in mice and ferrets. To investigate the vaccine’s efficacy in vivo, the research team applied a recently developed ferret model that recapitulates fatal clinical symptoms in SFTSV infection in humans. Vaccinated ferrets were completely protected from lethal SFTSV challenge without SFTSV detection in their blood, whereas all control ferrets died within 10 days’ post-infection. The KAIST team found that anti-envelope antibodies play an important role in protective immunity, suggesting that envelope glycoproteins of SFTSV may be the most effective antigens for inducing protective immunity. Moreover, the study revealed that T cell responses specific to non-envelope proteins of SFTSV also can contribute to protection against SFTSV infection. Professor Park said, “This is the first study demonstrating complete protection against lethal SFTSV challenge using an immunocompetent, middle-sized animal model with clinical manifestations of SFTSV infection. We believe this study provides valuable insights into designing preventive vaccines for SFTSV.”
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