Dysregulated transcriptional responses to SARS-CoV-2 in the periphery.
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2021-02-17
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SARS-CoV-2 infection has been shown to trigger a wide spectrum of immune responses and clinical manifestations in human hosts. Here, we sought to elucidate novel aspects of the host response to SARS-CoV-2 infection through RNA sequencing of peripheral blood samples from 46 subjects with COVID-19 and directly comparing them to subjects with seasonal coronavirus, influenza, bacterial pneumonia, and healthy controls. Early SARS-CoV-2 infection triggers a powerful transcriptomic response in peripheral blood with conserved components that are heavily interferon-driven but also marked by indicators of early B-cell activation and antibody production. Interferon responses during SARS-CoV-2 infection demonstrate unique patterns of dysregulated expression compared to other infectious and healthy states. Heterogeneous activation of coagulation and fibrinolytic pathways are present in early COVID-19, as are IL1 and JAK/STAT signaling pathways, which persist into late disease. Classifiers based on differentially expressed genes accurately distinguished SARS-CoV-2 infection from other acute illnesses (auROC 0.95 [95% CI 0.92-0.98]). The transcriptome in peripheral blood reveals both diverse and conserved components of the immune response in COVID-19 and provides for potential biomarker-based approaches to diagnosis.
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McClain, Micah T, Florica J Constantine, Ricardo Henao, Yiling Liu, Ephraim L Tsalik, Thomas W Burke, Julie M Steinbrink, Elizabeth Petzold, et al. (2021). Dysregulated transcriptional responses to SARS-CoV-2 in the periphery. Nature communications, 12(1). p. 1079. 10.1038/s41467-021-21289-y Retrieved from https://hdl.handle.net/10161/22409.
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Scholars@Duke
Micah Thomas McClain
Ricardo Henao
Ephraim Tsalik
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.
Thomas Burke
Julie Steinbrink
I am a transplant infectious diseases physician. My clinical care focuses on the management of infections in immunocompromised patients, including solid organ and bone marrow transplant recipients, as well as cancer patients. My research focuses on developing noninvasive biomarker diagnostics and severity prognostic tools for infectious diseases in immunocompromised patients.
Bryan David Kraft
Dr. Kraft has a wide variety of clinical and research interests, including sepsis, pneumonia, and acute respiratory distress syndrome (ARDS), and has special expertise in rare lung diseases such as pulmonary fibrosis and pulmonary alveolar proteinosis (PAP). PAP can be congenital, hereditary, autoimmune, or due to occupational exposures (e.g. dusts, fibers, silica).
Dr. Kraft performs whole lung lavage (WLL) at Duke in a state-of-the art hyperbaric chamber within the Duke Center for Hyperbaric Medicine and Environmental Physiology. Performing WLL with hyperbaric oxygen (when necessary) augments oxygen delivery during the procedure, meaning both lungs can be lavaged on the same day, during a single episode of anesthesia.
Dr. Kraft’s research laboratory is devoted to understanding mechanisms of acute lung injury resolution, and uses translational models and clinical patient samples to identify novel pathways of recovery. Dr. Kraft is also an active investigator in clinical trials to develop new therapies for patients with lung diseases.
Matthew Kelly
My research is broadly focused on elucidating the complex interactions that exist between the host microbiome and exogenous pathogens that cause infections in children. We have several ongoing projects evaluating: 1) the impact of the upper respiratory microbiome on the risk of colonization and invasion by bacterial respiratory pathogens among infants in Botswana; 2) associations between the gut microbiome of pediatric stem cell transplant recipients and the risk of infections (bloodstream infection, C. difficile infection) and graft-versus-host disease; and 3) the role of the gut and respiratory microbiomes in mediating COVID-19 infection susceptibility and disease severity in children. Ultimately, I aim to develop strategies that use targeted modification of the microbiome for the prevention of infections in children.
Daniel Raphael Saban
The human immune system and nervous system, two complex networks, are intricately linked. The Saban Lab is dedicated to understanding how this partnership shapes our health and well-being. We believe that uncovering the secrets of this neuroimmune connection holds the key to preventing and treating a wide range of diseases.
To explore this complex relationship, we use the eye as a powerful model system. It's like a window into the brain, as well as the periphery, allowing us to observe and manipulate immune cells and neurons in real-time. By studying how these cells interact in the eye, we gain valuable insights into how they function throughout the body.
Our research workflow starts with a deep dive into genomic data, searching for hidden clues about how the immune and nervous systems communicate. Once we identify a promising target, we carefully investigate its role in health and disease. This knowledge empowers us to develop innovative therapies that can restore balance and prevent disease progression.
A prime example of our work is our focus on microglia, specialized immune cells in the brain. We use the retina as a window into the central nervous system, allowing us to study microglia in vivo. We've made significant strides in understanding how these cells contribute to both healthy vision and blinding eye diseases. Our research has led to the development of a promising drug that targets microglia to potentially save sight in patients with inherited and age-related retinal degenerative disease.
Another area of our research focuses on the cornea, the clear front part of the eye. This remarkable tissue is packed with nerves and is constantly interacting with the immune system. By studying the cornea, we're unraveling the complex interplay between nerves and immune cells, which has implications for understanding pain, wound healing, and other conditions.
The eye also offers a unique perspective on mucosal immunity. The conjunctiva, a thin tissue lining the eyelid and white part of the eye, is a readily accessible model of mucosal surfaces found throughout the body, such as the lungs and gut. By studying the conjunctiva, we can gain insights into how the immune system responds to infections and inflammation in these vital tissues.
We are actively seeking collaborations with researchers in immunology, neuroscience, ophthalmology, bioinformatics and related fields to advance our understanding of neuroimmunology. We invite talented and motivated individuals to join our team as postdoctoral fellows, graduate students, or research technicians. Together, we can make a significant impact on human health.
Xiling Shen
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).
Geoffrey Steven Ginsburg
Dr. Geoffrey S. Ginsburg's research interests are in the development of novel paradigms for developing and translating genomic information into medical practice and the integration of personalized medicine into health care.
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