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Genetic predictors, pathophysiological mechanisms, and functional consequences of post-acute sequelae of SARS-CoV-2: Exercise challenge of gut microbiome and neuroinflammation in PASC

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The long-term goals of this research are to determine the mechanisms that underlie Post-Acute Sequelae of SARSCoV-2 (PASC)-related symptoms in Veterans and to develop targeted and personalized treatments. PASC is a condition of long-term symptom burden following coronavirus disease 2019 (COVID-19) that is having serious adverse effects among Veteran populations. Known colloquially as Long-COVID, symptoms of pain, fatigue, irritable bowel, and cognitive impairment overlap considerably with chronic multisymptom illnesses (CMIs) such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Gulf War illness (GWI). Critically, all three conditions report that physical activity worsens their illness, a characteristic of CMIs known as post-exertional malaise (PEM). As with CMIs, PEM is a promising model for studying Long-COVID in Veterans because, as we have shown in ME/CFS and GWI, PEM reveals pathophysiology not apparent at rest by challenging multiple physiological systems. The causes of PEM/CMIs are currently unknown, but converging evidence suggests that gut-microbiome perturbations and neuroinflammation act to sustain/worsen symptoms. Our central hypothesis is that neuroinflammation and gut-microbiome perturbations act to produce and maintain symptoms, and that dysfunction among these systems is best studied using an exercise challenge model. Our pilot data indicate that those with CMI: 1) report moderate-to-large symptom changes and worsened cognitive performance following a standardized exercise challenge; 2) show disturbed gut microbiome at rest and differential responses to exercise compared to controls, and 3) that peripheral inflammation (interleukin-6) is associated with augmented brain activity during fatiguing cognition in ME/CFS compared to controls. We intend to extend our exercise challenge research in CMI to PASC with the following specific aims: Aim 1: To determine the effects of a standardized exercise challenge on PEM (symptoms and cognition). Aim 2: To determine the effects of a standardized exercise challenge on gut microbiome structure and function. Aim 3: To determine the effects of a standardized exercise challenge on neuroinflammation. This study will significantly enhance our understanding of PASC and will begin to determine the pathophysiological mechanisms that underlie symptoms at rest and symptom worsening with physical effort. The COVID-19 pandemic offers a unique window of opportunity to evaluate pathophysiology early in disease development and with known proximity to the initiating event – i.e., COVID-19 infection. This is a rare occurrence in CMI research, and one that can provide critical mechanistic insight to aid in the development of targeted and personalized therapies.

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Post-Acute Sequelae of SARS-CoV-2 Infection

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United States Department of Veterans Affairs

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EDITH NOURSE  ROGERS MEMORIAL VETERANS HOSPITAL

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A. Rani Elwy, PhD, is a 20-year VA health services researcher and implementation scientist, based at the Center for Healthcare Organization and Implementation Research, a VA HSR&D Center of Innovation at the VA Bedford Healthcare System. Her work exemplifies HSR&D’s embedded research goals: products and deliverables from her work are now part of VHA national policy and practice. Dr. Elwy has served as Principal Investigator on three HSR&D grants (IAC 07-087, IIR 07-199, and SDR 11-440), and as PI or MPI on four QUERI projects, partnered evaluation initiatives and programs (RRP 13-436; PEC 16-354; QUE 20-017; EBP 22-104). She has also served as PI or subaward PI on an additional 16 grants, and co-investigator on 22 further grants, funded by HSR&D, QUERI, CSR&D, NIH, CDC and PCORI. She has published 106 peer- reviewed articles, and has delivered 69 invited and 54 peer-reviewed international, national and regional presentations. She has received the HSR&D Best Research Paper Award, four Excellence in Teaching Awards, and is a Fellow of the Society of Behavioral Medicine. Dr. Elwy’s work has been cited in national and international media such as CBS News, The Washington Post, U.S. News and World Report, and the UK’s Daily Mail. She serves on COVID-19 workgroups of the World Health Organization and the White House Office of Science and Technology Policy, and attended, by invitation, the White House Summit on the Future of COVID-19 Vaccines. Dr. Elwy is a former fellow of the Implementation Research Institute, and is a Professor of Psychiatry and Human Behavior and Professor of Behavioral and Social Sciences at Brown University.  Through HSR&D and QUERI funding, Dr. Elwy has created evidence to answer research questions important to VA leaders, developed deliverables and tested these through implementation projects, and generated sustainment for this evidence-base through changes in national policy and practice within the Veterans Health Administration. This evidence to implementation to sustainment roadmap has been possible through extensive training in implementation science, received through Dr. Elwy’s roles as QUERI implementation research coordinator, NIH-VA implementation science trainee, and VA health services researcher and implementation science principal investigator. Dr. Elwy continuously gives back to the implementation science field, serving as invited faculty on NIH-funded implementation science training courses since 2016, participating in national organizations and committees seeking to use implementation science to improve health and health care, and serving as a committed mentor to 53 graduate students, postdoctoral fellows and early career faculty over the course of her 20-year career. Dr. Elwy’s career goals are to improve Veterans’ health and health care, through building VA implementation science capacity, and training and mentoring the next generation of VA researchers. Her strategies for providing support and caring through mentorship, developed through years of navigating her own health services and implementation science career, are the focus of her “Behind the Scenes CV”, a behind the scenes look at success that is not always understood and recognized by mentees, and what is needed for building and retaining the VA health services research and implementation science workforce. A Research Career Scientist Award will allow Dr. Elwy to devote even more of her time to ensuring that HSR&D does not lose highly regarded, talented, and skilled scientists as a result of misplaced perceptions of what it takes to succeed as a VA health services researcher. Additionally, a Research Career Scientist Award will provide the time needed for Dr. Elwy to develop expertise in policy implementation, a necessary step in her continued goal of building capacity in implementation science throughout VA. Developing policy implementation skills will allow her to focus on increasing further evidence- based policy implementation, building on her newly-funded QUERI Evidence, Policy and Implementation Center (EBP-22-104) and sharing this knowledge and skills to ensure a broad base of experts in this area.

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United States National Institutes of Health

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RR&D Research Career Scientist Award Application

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A primary goal of my research program is to identify and test new therapeutic approaches to improve and accelerate fracture healing and overall patient outcomes. This includes improving weightbearing, locomotion, and activity, while decreasing the associated pain and inflammation. In my current VA funded studies, we are seeking to determine how Sirtuin-1 (Sirt1, an NAD+ class III histone deacetylase) activators alter fracture healing outcomes. We began examining Sirt1 as a target as our preliminary data showed that mRNA levels of Sirt1 are robustly elevated during fracture healing. We knew that fracture healing is impaired with age, bone loss, inflammation, and with neurodegeneration, and realized that Sirt1 improves all of these conditions.  Our ultimate goal is to improve fracture outcomes for Veterans and civilians. Thus, an important objective of our studies is to translate our findings to the clinic. With this in mind, we have successfully obtained one patent (16/392,246, April 23, 2019) and have applied for a second patent (63/153,297, February 24, 2021). The second patent application includes Drs. Philip Low and Jeffery Nielsen as co-Inventors (also collaborators on our current VA Merit award) who are medicinal chemists. With their assistance, we developed a new fracture targeted SRT1720 drug, which we are investigating in our VA Merit studies. Notably, 15 drugs stemming from Dr. Low’s research have entered human clinical trials. Importantly, we have also developed an important collaboration with VA investigator, Dr. Fletcher White, a neuroscientist with expertise in locomotion, pain, and inflammation analyses. Together, our team will investigate whether pharmacological activation of Sirt1 by fracture targeting SRT1720 allows for improved fracture healing, while reducing pain behaviors.  Additional studies funded by 3 PI/mPI NIH R01s and internal, foundation and training awards focus on the bone marrow microenvironment and its regulation of fracture healing, bone mass, and hematopoiesis. The goal of NIH R01 AG060621 is to understand the mechanisms by which angiogeneic therapies can improve aged fracture healing. The goal of NIH R01 DK118782 is to understand the mechanisms by which osteomacs and megakaryocytes regulate hematopoiesis. The goal of NIH R01 DK108342 is to examine how CD166 regulates hematopoietic stem cell function and the hematopoietic niche. Pilot funds and an NIH F31 AG077931 PhD fellowship fund investigations on the bone loss following infection with SARS-CoV-2. These studies have significant implications to aiding in rehabilitation of Veterans and improving their quality of life.  My lab has been very productive with 52 data driven manuscripts and 17 review articles/chapters published since 2018. During this time, I have given 21 lectures at national/international venues, including an invitation as an Esteemed Speaker for the Australian and New Zealand Bone and Mineral Society meeting in 2019. Continuous extramural funding for the past 15 years has enabled us to achieve our research goals.  I have also been extensively involved with mentoring junior faculty, post-doctoral fellows, clinical residents, graduate students, medical students, undergraduate students, and high school students for more than 20 years (>100 mentees). I have served on numerous grant review committees at national and international levels including as a permanent member of the NIH, Skeletal Biology Development and Disease (SBDD) Study Section and will begin reviewing VA Merit Awards in 2023. I have served/am serving on the Editorial Review Board for the Journal of Orthopaedic Research and JBMR Plus; as a Guest Editor for Frontiers in Endocrinology; section editor for Current Osteoporosis Reports; and am Editor-in-Chief for Current Osteoporosis Reports. I have also been nominated and elected into leadership roles within several institutions/societies. Currently, I am the Vice Chair for Research for the Department of Orthopaedic Surgery at IUSM and am an elected member of the Council for the American Society for Bone and Mineral Research. These research, mentoring, leadership, and service activities highlight the significance and recognition of my research activities to the musculoskeletal field.

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United States National Institutes of Health

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My research focuses on understanding and improving chronic pain management for Veterans by leveraging my expertise in health communication, patient engagement, and relationship-centered care. Over the past 14 years, my work has developed from observational to interventional, steadily increasing the impact of my scholarship on Veterans’ care. My research has helped to advance our understanding of how communication shapes healthcare experiences and Veterans’ pain management. Early observational work led to insights into the role of the patient-provider relationship and social support in pain self-management, treatment decision- making, and opioid management, including opioid tapering. I have successfully built upon these findings with each new project, which has led to the design and testing of interventions to improve pain management for Veterans. These interventions have included developing and testing a peer-supported pain self-management program, a coaching program designed to increase patient activation for Black Veterans with chronic pain to help address racialized disparities in pain management, and a shared decision-making intervention to overcome patient-level barriers to use of and adherence to evidence-based nonpharmacologic pain treatments. Beyond developing and testing interventions, I am also moving toward implementation in an effort to broaden my impact and improve care for Veterans. My health equity study, COOPERATE, significantly increased patient activation and communication self-efficacy, while producing other positive outcomes for Black Veterans. In light of these positive results I will be exploring avenues for implementation through our operational partners as well as likely submitting a proposal for a Hybrid Type 2 multi-site effectiveness/implementation study, to further test COOPERATE and prepare for system-wide implementation. COOPERATE represents an important path to achieving health equity for Black Veterans with chronic pain and as such, also represents the increasing impact of my research. My newly-funded study, OPTIONS, also has direct relevance for Veteran care and impact. OPTIONS reflects VA’s priorities of reducing reliance on opioids and increasing use of multimodal care, including evidence-based complementary and integrative therapies and other nonpharmacologic approaches to chronic pain. As such, I have partnered with the VA National Pain Management, Opioid Safety, and Prescription Drug Monitoring Program Office and the Office of Patient- Centered Care and Cultural Transformation, and, assuming positive results, these partnerships will help increase the project’s impact by facilitating VA-wide dissemination and, ultimately, implementation. These examples reflect the evolution of my work from early observational studies to intervention studies, which will ultimately lead to system-wide implementation and greater impact on Veterans’ pain care. The other study I am currently leading as co-PI, CIPHER, is focused on understanding effects of COVID-19-related disruptions in pain care on Veterans with chronic low-back pain, with particular emphasis on disruptions to nonpharmacologic care, which can be more difficult to deliver via telehealth. Using a mixed-methods design with VA administrative data and qualitative interviews with clinicians and Veterans purposefully sampled from the administrative data, we are partnering with the VA National Pain Management Office to understand changes in care and, ultimately, apply these lessons to improving pain care for Veterans.

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United States National Institutes of Health

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SARS-CoV-2 and Innate Immunity: Mechanisms of Resistance to Human Interferons

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SARS-CoV-2 emerged in late 2019, with much evidence tracing the initial human spillover to a market with extensive human-animal contact. As the coronavirus spread in its new host species, multiple variants of concern representing distinct genetic lineages appeared and propagated globally. Ongoing viral evolution has increased transmission, and also evasion of neutralizing antibodies (adaptive arm of the immune system). Hence, many important studies have deservedly focused on dissecting consequences of Spike protein mutations in different emerged variants. However, mutations have also been detected in viral genes other than Spike, and several of these genes are linked to antagonism of innate immune responses. We provide detailed evidence that compared to ancestral or early SARS-CoV-2 isolates, the five major variants of concern so far (alpha, beta, gamma, delta and omicron) have become more resistant to multiple human interferons that included the 12 IFNα subtypes, IFNβ, IFNω and 3 IFNλ subtypes1. The underlying mechanisms for these IFN resistance phenotypes are unclear and, paralleling the four decades it has taken to understand innate immune evasions mediated by the proteins encoded by the nine genes of HIV-1, a full picture for SARS-CoV-2 will require sustained investigation over time. However, in both the short and long terms, the scientific and medical impacts of characterizing resistance of this newly emerged coronavirus mechanistically can be highly significant, for not only the current pandemic but potentially also for future sarbecovirus spillover events. We thus propose to build on our ample published1 and unpublished preliminary data and accumulated experience to track the evolution of SARS-CoV-2 IFN resistance during the course of the COVID-19 pandemic and to determine virus mutations and effector mechanisms involved. As interferon responses can regulate virus levels during the critical acute phase of infection, these studies will have implications for understanding SARS-CoV-2 transmission and pathogenesis that may inform therapeutic strategies not only against SARS- CoV-2 but also future emerging viruses.

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Calcium release-activated calcium (CRAC) channels in experimental traumatic brain injury

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This project will explore calcium-release-activated calcium channels (CRAC) as a potential therapeutic target in a laboratory model of traumatic brain injury (TBI). TBI is a common problem in the Veteran and civilian populations but definitive treatments are few. Microglia are the brain’s resident immune cell, and many studies have now shown that when activated, they contribute negatively to neurological outcome. Thus, strategies to inhibit microglial functions could prove therapeutic. Recent work has focused on the role of CRAC channels in inflammatory cells such as T cells, mast cells and neutrophils, and other inflammatory conditions such as autoimmune disease and acute pancreatitis; however, very little work has been published on CRAC channels as they pertain to microglia or inflammation in the brain. Past work has focused on calcineurin inhibitors such as cyclosporine A and FK 506 which act downstream of the CRAC channel, but have many off target effects and clinical toxicities which limit their use. These CRAC channel inhibitors are already being studied at the clinical level for other indications, and do not appear to have the same toxicities as the CNIs. In fact, a similar inhibitor produced by the same company was recently shown to improve outcome from severe COVID-19 pneumonia following infection with the SARS-CoV-2 virus, and was well tolerated in this patient population. Prior work in our lab showed that these specific CRAC channel inhibitors block microglial activation and that at least one of these inhibitors protects the brain from experimental TBI. This project will study CRAC channel inhibitors in a model of TBI to further define the conditions where neuroprotection may be observed. The first Aim will determine the more protective of two such novel CRAC channel inhibitors, and determine the optimal dosing required for maximum neurological benefit. This aim will also validate the specificity of the inhibitors and the expected mechanism of action of downstream calcium and inflammatory signaling. The second aim will then determine whether treatment can be delayed by hours and still show improvement in neurological outcomes. The third aim will then use the optimal dose and dosing regimen determined from the first two aims to see if any benefit is long lasting. In vivo experiments will include studies in female animals as well as comparing these novel, specific inhibitors to currently available, but less specific inhibitors.

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A Translational Research Approach to Healthy Technology Usage in Language-Minority Families with Young Children

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Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

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Technology use among young children in the U.S. has become increasingly prevalent over the past decade, and the transition to online learning during the COVID-19 pandemic has renewed concerns among parents and educators about screen time. Recommendations for choosing high-quality apps and setting boundaries around device use are often conveyed through position statements, white papers, and blog posts, but the information is rarely presented in an engaging, family-friendly manner that can be readily adopted and sustained in young children’s everyday routines. As a matter of health equity, this challenge is felt even more acutely among language-minority households, who additionally face language barriers when attempting to access relevant resources. This project delivers an interactive, bilingual, hybrid virtual-and-physical world approach to address these translational gaps. It presents recommendations from the academic and medical spheres through bilingual storytelling and a suite of interactive, co-play activities in an online virtual world, then transitions the gameplay to caretaker-child interactions in the physical world, empowering users to first practice healthy technology through interactive online games and then implement those rehearsed practices in their day-to-day lives. The effectiveness of the online platform and interactive content will be evaluated through a randomized controlled study. Improvements in knowledge, attitudes, and confidence related to healthy technology use will be assessed among children and their caretakers. The platform will also be evaluated for its ability to facilitate bilingual interactions between child and caretaker that support learning and language development. Overall, our product will serve not only as a means to inform families of best technology use practices, but as a catalyst to broaden and reimagine joint play with digital devices especially among linguistic minority families.

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National Institute of Child Health and Human Development

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Small Business Innovation Research Grant

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Evaluation of a Next Generation SchistoShield Vaccine

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National Institute of Allergy and Infectious Diseases (NIAID)

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Schistosomiasis is a major parasitic disease which could impact one billion people with 252 million currently infected and 779 million at risk to acquire the infection in 74 countries. Current control strategies have relied on repeated treatments with the drug praziquantel alone – however, this strategy has proven inadequate due to minimal reduction of disease transmission, reinfection, and the inherent threat of drug resistance. Over the course of 20 years, we have developed a potent schistosomiasis vaccine, termed SchistoShield®, targeting a functionally important antigen, Sm-p80, formulated in the TLR4-targeted adjuvant, GLA-SE. SchistoShield® has been exhaustively tested in numerous animal models and has consistently exhibited protection at all parasite life stages. We are near completion of a Phase 1 safety and dose-ranging human clinical trial with SchistoShield® in the US – with no serious safety signals reported – and will begin Phase 1B trials in Q3 of 2023 with a Phase 2 trial currently funded as well by the Bill and Melinda Gates Foundation. Despite the promise of SchistoShield®, it is important to ready a next-generation follow-on candidate that builds a pipeline and serves as an alternative should we encounter problems down the road in terms of e.g. scalability, cost, or field efficacy. To address these concerns, we are proposing to evaluate two new variations on the current SchistoShield® vaccine: the first being a redesigned Sm-p80 protein antigen, while the second being a novel RNA delivery platform version of the Sm- p80 antigen. For the redesign, we removed the hydrophobic and other irrelevant (outside of the catalytic triad domain) regions of the ~85 kDa Sm-p80 antigen resulting in a smaller, and more antigenically focused, ~44 kDa antigen which we have termed Catalysis-Targeted Constructs (CaTaCo™). CaTaCo™ is similar to Sm-p80 in that domains required for enzymatic activity are maintained while soluble production yields are improved. Compared to Sm- p80, CaTaCo™ exhibits minimal aggregation and less degradation -- a potential problem with the current antigen that was flagged by the FDA for potential improvement. In mice, CaTaCo™ elicits comparatively high titers in mice, binds to anti-Sm-p80 monoclonal antibodies (mAbs), and is detected by sera from mice and baboons immunized with SchistoShield®. With the increased use of RNA vaccines, we will also produce and evaluate both CaTaCo™ and Sm-p80 as RNA vaccines using a proprietary technology invented by our partners at HDT Bio. HDT recently used this technology for their COVID-19 vaccine HDT-301, which is similar to the COVID-19 vaccines from Moderna and Pfizer/BioNTech. The HDT-301 platform consists of a self-replicating RNA (repRNA) adsorbed and stabilized on a Lipid InOrganic Nanoparticle (LION™) carrier. This vaccine received emergency use approval in India – the only self-amplifying platform to be approved in humans. Introduction of the repRNA into cells results in ongoing biosynthesis of antigen-encoding RNA resulting in markedly higher protein concentrations in vivo leading to enhanced humoral and cellular immune responses and - perhaps most importantly - a dose sparing effect. The HDT-301 vaccine has been evaluated in both Phase 1 and Phase 2 human clinical trials trial in Brazil and the US and has been shown to be safe while eliciting high anti-COVID-19 titers. In this SBIR, we propose to produce both CaTaCo™ and Sm-p80 as repRNA/LION™ vaccines as well as the CaTaCo™ antigen, immunize them into mice, and challenge with S. mansoni directly comparing each to the existing SchistoShield® vaccine. Successful completion of this grant will address two key questions: 1) is an RNA vaccine for SchistoShield® feasible or superior to the existing vaccine, and 2) whether the redesigned CaTaCo™ antigen is an improvement for the next generation SchistoShield®.

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Small Business Innovation Research Grant

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Multi-component INTERLUNG intervention to protect lung health in Nepal

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National Institute of Environmental Health Sciences (NIEHS)

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Chronic respiratory diseases (CRDs) remain the third leading cause of death worldwide and their incidence is increasing. In 2019, it was estimated that 455 million people worldwide live with a CRD such as asthma, COPD, and chronic bronchitis. CRDs are responsible for 4 million deaths and 103.5 million disability-adjusted life years lost each year. The development and severity of CRDs is attributed to both environmental exposures and infectious causes. Individuals who live in densely populated cities in low- and middle-income countries (LMICs) are disproportionately affected by high levels of ambient particulate matter, indoor exposure to allergens, dust and tobacco smoke, and a high incidence of viral and bacterial infections. Therefore, to have a meaningful impact on the incidence and severity of CRDs, and prevent further lung function decline, a multi- component evidence-based intervention targeting multiple risk factors is needed. We seek to test the implementation and effectiveness of a tailored multi-component evidence-based intervention following a community health worker (CHW)-driven chronic care delivery model to protect lung health over a 40-month period using a Type I hybrid implementation-effectiveness randomized controlled trial in Bhaktapur, Nepal. The multi-component intervention will consist of: reducing environmental risk factors by targeting tobacco smoking through CHW-delivered messaging and education on smoking prevention and smoking cessation, and targeting indoor and ambient air pollution exposures by providing households with HEPA-indoor air purifiers and vacuum cleaners and encourage masking outdoors with N95 respirators when e-notified about days with high ambient air pollution; reducing infectious risks through an CHW-led vaccine campaign for annual influenza, COVID and pneumococcal vaccine in all eligible participants and household members; encouraging use of surgical masks in indoor public spaces during the peak winter season or at home when there are sick household contacts; and, improving physiologic health by encouraging physical activity through CHW- monitored pedometer goals. Aligned with the Consolidated Framework for Implementation Research, we will first conduct human-centered design workshops with community members and healthcare practitioners to tailor the multi-component intervention. We will then screen and identify 800 index participants aged ≥ 9 years (with a pre-bronchodilator FEV1/FVC Z-score ≤ 10th percentile and chronic cough or wheeze (i.e., at-risk participants). We will enroll index participants and household members and assign half of the households to the adapted intervention. Controls will be asked to continue usual care practices. We will evaluate the effect of the intervention on pre-bronchodilator FEV1 Z-score (primary outcome), respiratory symptoms, and evaluate implementation outcomes. We seek to facilitate scale-up of a multi-component intervention that responds to the real-world implementation context to protect lung health in Nepal and other LMICs.

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Pulmonary Function Test/Forced Expiratory Volume 1

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Role of respiratory viral infections and inflammation in promoting metastatic outgrowth in the lung

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The leading cause of breast cancer deaths is metastasis. Metastatic relapse can occur months to years after the initial diagnosis and treatment of the primary tumor. Cancer cells can disseminate from the primary tumor into different tissues including lungs and remain in a dormant state for years to decades. Awakening of these dormant disseminated cancer cells (DCC) leads to metastasis. Finding factors that trigger the awakening of dormant DCC and developing strategies to reduce the risk of awakening is therefore an unmet need. While it is known that inflammation is a key contributing factor to the awakening of dormant DCC, no studies have investigated whether inflammation triggered by viral respiratory infections (a very common infection worldwide) in the lung can promote the expansion of DCC and lead to the development of metastases. Our recent studies using a mouse model of breast cancer DCC dormancy in the lung have revealed a dramatic increase in DCC awakening and expansion in the lungs following influenza virus infection. Our data support the hypothesis that respiratory viral infections can promote DCC awakening and expansion through two phases: first, through IL-6 dependent DCC awakening and expansion, and second, CD4 T-cell mediated protection from elimination (in part by CD8 cells). We further show that infection with a mouse-adapted SARS-CoV-2 promotes a similar awakening and expansion of DCC in mice. Finally, epidemiological studies reveal how prior infection with SARS-CoV-2 infection increases metastatic progression in lungs and cancer- related deaths for cancer survivors. We propose to determine mechanisms by which acute respiratory viral infections induce the awakening of dormant DCC leading to metastatic disease, whether and how such infections can prime DCC for activation by subsequent exposures, and how CD4 and CD8 cells differentially control the persistence of expanded DCC during influenza virus infection. Impact: Proposed studies to understand how different pulmonary viral infections alter DCC dormancy and host immune responses, to determine the consequences for progression to metastatic disease, and to explore underlying mechanisms, should yield valuable and actionable insight into the key cell types and molecular mediators, informing early detection and prevention strategies for at-risk individuals.