Exercise and COVID-19 Viral T-cell Immunity

Acute upper and lower respiratory tract infections (RTI) due to respiratory viruses, such as, respiratory syncytial virus (RSV), influenza, parainfluenza virus (PIV) and human metapneumovirus (hMPV) are a major public health problem. During the 2019-2020 influenza season, the Center for Disease Control (CDC) determined that influenza accounted for 38 million illnesses, 18 million medical visits, 405,000 hospitalizations, and 22,00 deaths, and annual costs of approximately 87.1 billion in disease management in the United States. Simultaneously, the COVID 19 pandemic is currently a major health crisis across of the United States and worldwide with the number of cases surpassing 50 million and deaths totaling more than 1.3 million. Latent herpesviruses (cytomegalovirus (CMV), Epstein Barr virus (EBV), and Varicella Zoster virus (VZV)) are other types of viral infections that are easily controlled in healthy people but in immunocompromised people, such as elderly or cancer patients, these latent viruses can become deadly. People receiving allogenic hematopoietic cell transplantation (allo-HCT) are at high risk of CMV infection and can lead to significant morbidity in transplant patients. Due to these populations. An acute bout of exercise, as well as, chronic exercise training, have been shown to enhance anti-viral immunity against many of these respiratory viruses and latent herpesviruses. However, the immune response to viral infections is usually limited to the detection of humoral responses and the ability to produce antibodies titers is the gold standard for determining the effectiveness of the immune system in response to vaccination. However, monitoring the cellular immune response following natural or vaccine induced immunization less standardized. Numerous laboratory techniques have been developed to test the cellular immune response including, phenotyping antigen specific T-cells, intracellular staining of cytokines, ELISPOT or ELISA for antigen derived cytokine production, and antigen specific cytotoxicity assays. However, theses assays are laborious and typically require highly specialized lab equipment and techniques. Interferon-gamma (IFN-γ) release assays have been developed to focus on cellular immunity and could complement or replace these other laborious procedures. Thus we propose that a single bout of exercise in humans will enhance the total antiviral immunity to numerous respiratory viruses and latent herpesviruses, using a whole blood IFN-γ assay. Secondly, there is a critical need to develop new therapeutics that can be used both prophylactically and in the treatment of SARS CoV-2 infections. Adoptive cell therapy with viral specific T-cells (VST) has been used effectively to treat viral infections in immunocompromised patients, particularly in recipients of hematopoietic stem cell transplantation. This procedure has been used for \>25 years with evidence of safety and efficacy. No group to our knowledge has attempted to manufacture SARS CoV-2 VSTs as a potential therapeutic to prevent and/or treat refractory SARS Co-V-2 infections during the current COVID-19 pandemic. Having a personalized or 'third-party' T-cell product that is 'banked' and readily available could offer a life-saving intervention for many 'at-risk' individuals (e.g. the elderly, cancer patients, diabetics, transplant recipients) should they develop COVID-19. Current COVID-19 vaccination strategies are focused on inducing neutralizing antibodies. This strain-specific approach is limited because immunity against drifted strains that emerge from one season to the next, or even during a single season, is often lost. Given that T-cells offer protection against multiple viral strains, there is strong rationale to develop a vaccine that targets T-cells capable of providing coronavirus heterotypic immunity. Dendritic Cell (DC) vaccines pulsed with viral antigen peptides have been used successfully to elicit immune responses against influenza, hepatitis C and HIV and could, therefore, serve as a personalized vaccine solution to the COVID-19 pandemic. In the present study, we plan to demonstrate preclinical proof of concept for a DC based vaccine by attempting to immunize "humanized" mice in vivo. Our proposed NOD-scid-IL2Rγnull (NSG) mouse model has been used successfully to generate preclinical data for human DC and VST based vaccines.