Mucosal Associated Invariant T (MAIT) Cell Responses Differ by Sex in COVID-19.
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Sexual dimorphisms in immune responses contribute to coronavirus disease 2019 (COVID-19) outcomes, yet the mechanisms governing this disparity remain incompletely understood. We carried out sex-balanced sampling of peripheral blood mononuclear cells from confirmed COVID-19 inpatients and outpatients, uninfected close contacts, and healthy controls for 36-color flow cytometry and single cell RNA-sequencing. Our results revealed a pronounced reduction of circulating mucosal associated invariant T (MAIT) cells in infected females. Integration of published COVID-19 airway tissue datasets implicate that this reduction represented a major wave of MAIT cell extravasation during early infection in females. Moreover, female MAIT cells possessed an immunologically active gene signature, whereas male counterparts were pro-apoptotic. Collectively, our findings uncover a female-specific protective MAIT profile, potentially shedding light on reduced COVID-19 susceptibility in females.
Published Version (Please cite this version)
Yu, Chen, Sejiro Littleton, Nicholas S Giroux, Rose Mathew, Shengli Ding, Joan Kalnitsky, Yuchen Yang, Elizabeth Petzold, et al. (2021). Mucosal Associated Invariant T (MAIT) Cell Responses Differ by Sex in COVID-19. Med (New York, N.Y.). 10.1016/j.medj.2021.04.008 Retrieved from https://hdl.handle.net/10161/22841.
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Clinical and translational research, COVID-19 therapeutics, clinical biomarkers for infectious disease.
My research at Duke has focused on understanding the dynamic between host and pathogen so as to discover and develop host-response markers that can diagnose and predict health and disease. This new and evolving approach to diagnosing illness has the potential to significantly impact individual as well as public health considering the rise of antibiotic resistance.
With any potential infectious disease diagnosis, it is difficult, if not impossible, to determine at the time of presentation what the underlying cause of illness is. For example, acute respiratory illness is among the most frequent reasons for patients to seek care. These symptoms, such as cough, sore throat, and fever may be due to a bacterial infection, viral infection, both, or a non-infectious condition such as asthma or allergies. Given the difficulties in making the diagnosis, most patients are inappropriately given antibacterials. However, each of these etiologies (bacteria, virus, or something else entirely) leaves a fingerprint embedded in the host’s response. We are very interested in finding those fingerprints and exploiting them to generate new approaches to understand, diagnose, and manage disease.
These principles also apply to sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Just as with acute respiratory illness, it is often difficult to identify whether infection is responsible for a patient’s critical illness. We have embarked on a number of research programs that aim to better identify sepsis; define sepsis subtypes that can be used to guide future clinical research; and to better predict sepsis outcomes. These efforts have focused on many systems biology modalities including transcriptomics, miRNA, metabolomics, and proteomics. Consequently, our Data Science team has utilized these highly complex data to develop new statistical methods, furthering both the clinical and statistical research communities.
These examples are just a small sampling of the breadth of research Dr. Tsalik and his colleagues have conducted.
In April 2022, Dr. Tsalik has joined Danaher Diagnostics as the VP and Chief Scientific Officer for Infectious Disease, where he is applying this experience in biomarkers and diagnostics to shape the future of diagnostics in ID.
Dr. Sempowski earned his PhD in Immunology from the University of Rochester and was specifically trained in the areas of inflammation, wound healing, and host response (innate and adaptive). Dr. Sempowski contributed substantially to the field of lung inflammation and fibrosis defining the roles of pulmonary fibroblast heterogeneity and CD40/CD40L signaling in regulating normal and pathogenic lung inflammation. During his postdoctoral training with Dr. Barton F. Haynes at Duke University, Dr. Sempowski focused on human immunology and more specifically immune reconstitution in settings of immune deficiency. This resulted in publication of seminal findings regarding the cellular and molecular mechanisms that drive attenuation of immune function in the elderly.
Since joining the Duke School of Medicine faculty in 2000, Dr. Sempowski has developed an independent research program studying immune deficiency associated with aging and radiation exposure. Dr. Sempowski is highly collaborative and works closely with investigators across the US, Europe, Australia and Japan and is internationally recognized as a thought leader in thymic aging, immunosenescence and multiplex biomarker analysis.
In 2017 Dr. Sempowski assumed Directorship of the Duke Global Health Research Building, a division of the Duke Human Vaccine Institute. This state-of-the-art Regional Biocontainment Laboratory (RBL) was built with funding from the NIH to support basic research to develop drugs, diagnostics and vaccines for emerging/reemerging infections and biodefense. The Duke RBL has a comprehensive safety and operations program to provide the Duke and RTP communities biocontainment facilities for BSL2, BSL3, and Select Agent research. The facility is home to a portfolio of sponsored research programs focused on biosafety and biopreparedness, vaccine and therapeutic development, host response and immune monitoring and assay proficiency and quality assurance.
Thomas N. Denny, MSc, M.Phil, is the Chief Operating Officer of the Duke Human Vaccine Institute (DHVI), Associate Dean for Duke Research and Discovery @RTP, and a Professor of Medicine in the Department of Medicine at Duke University Medical Center. He is also an Affiliate Member of the Duke Global Health Institute. Previously, he served on the Health Sector Advisory Council of the Duke University Fuquay School of Business. Prior to joining Duke, he was an Associate Professor of Pathology, Laboratory Medicine and Pediatrics, Associate Professor of Preventive Medicine and Community Health and Assistant Dean for Research in Health Policy at the New Jersey Medical School, Newark, New Jersey. He has served on numerous committees for the NIH over the last two decades and currently is the principal investigator of an NIH portfolio in excess of 65 million dollars. Mr. Denny was a 2002-2003 Robert Wood Johnson Foundation Health Policy Fellow at the Institute of Medicine of the National Academies (IOM). As a fellow, he served on the US Senate Health, Education, Labor and Pensions Committee with legislation/policy responsibilities in global AIDS, bioterrorism, clinical trials/human subject protection and vaccine related-issues.
As the Chief Operating Officer of the DHVI, Mr. Denny has senior oversight of the DHVI research portfolio and the units/teams that support the DHVI mission. He has extensive international experience and previously was a consultant to the U.S. Centers for Disease Control and Prevention (CDC) for the President’s Emergency Plan for AIDS Relief (PEPFAR) project to oversee the development of an HIV and Public Health Center of Excellence laboratory network in Guyana. In September 2004, the IOM appointed him as a consultant to their Board on Global Health Committee studying the options for overseas placement of U.S. health professionals and the development of an assessment plan for activities related to the 2003 PEPFAR legislative act. In the 1980s, Mr. Denny helped establish a small laboratory in the Republic of Kalmykia (former Soviet Union) to improve the care of children with HIV/AIDS and served as a Board Member of the Children of Chernobyl Relief Fund Foundation. In 2005, Mr. Denny was named a consulting medical/scientific officer to the WHO Global AIDS Program in Geneva. He has also served as program reviewers for the governments of the Netherlands and South Africa as well as an advisor to several U.S. biotech companies. He currently serves as the Chair of the Scientific Advisory Board for Grid Biosciences.
Mr. Denny has authored and co-authored more than 200 peer-reviewed papers and serves on the editorial board of Communications in Cytometry and Journal of Clinical Virology. He holds an M.Sc in Molecular and Biomedical Immunology from the University of East London and a degree in Medical Law (M.Phil) from the Institute of Law and Ethics in Medicine, School of Law, University of Glasgow. In 1991, he completed a course of study in Strategic Management at The Wharton School, University of Pennsylvania. In 1993, he completed the Program for Advanced Training in Biomedical Research Management at Harvard School of Public Health. In December 2005, he was inducted as a Fellow into the College of Physicians of Philadelphia, the oldest medical society in the US.
While living in New Jersey, Mr. Denny was active in his community, gaining additional experience from two publicly elected positions. In 2000, Mr. Denny was selected by the New Jersey League of Municipalities to Chair the New Jersey Community Mental Health Citizens’ Advisory Board and Mental Health Planning Council as a gubernatorial appointment.
1. Emerging Infections
2. Global Health
3. Epidemiology of infectious diseases
4. Clinical microbiology and diagnostics
5. Bioterrorism Preparedness
6. Surveillance for communicable diseases
7. Antimicrobial resistance
Dr. Shen’s research interests lie at precision medicine and systems biology. His lab integrates engineering, computational and biological techniques to study cancer, stem cells, microbiota and the nervous system in the gut. This multidisciplinary work has been instrumental in initiating several translational clinical trials in precision therapy. He is the director of the Woo Center for Big Data and Precision Health (DAP) and a core member of the Center for Genomics and Computational Biology (GCB).
My broad research interests are the cellular and molecular mechanisms that contribute to pathogenic immunity in ophthalmic disease and vision loss. My studies are currently focused on dendritic cells (DC), a unique leukocyte population of antigen presenting cells required for both initiating and determining the type of immune response generated. These cells contribute to the maintenance of health versus immunity in ocular disease.
I am currently investigating the role of DCs in allergic immune responses in the eye. We have developed a robust experimental mouse model that allows us to engraft ex vivo manipulated DCs into the ocular surface tissues prior to allergen challenge. This has allowed us to address very precise mechanistic pathways regarding DC function in allergy, such as identifying the pathogenic subset(s) of DCs required to trigger allergic immunity, and the factors drive the recruitment versus homing of these cells to the lymphoid organs.
I am also interested in examining the role of antigen presenting cells in other clinically relevant models of immune-associated ophthalmic disease. It is now widely appreciated that immunity and inflammation contributes to the pathogenesis of very prevalent conditions, including dry eye disease, glaucoma, and age-related macular degeneration. Elucidating a possible role(s) for antigen presenting cells such as DCs in these conditions may be an important step in furthering our understanding and possibly in identifying novel targets for treatments.
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