# data[].attributes.title
Racial discrimination, Intergenerational Cultural Conflict and Asian American Mental Health

# data[].attributes.funder_divisions[]
National Institute of Mental Health (NIMH)

# data[].attributes.abstract
PROJECT SUMMARY: The high rates and upward trend of mental health (MH) problems among young Asian Americans (AAs) are disturbing. Despite mounting evidence of MH crisis, AAs are severely understudied, exacerbating health disparities. Spikes in sociopolitical tensions and racial hostility in recent years may explain the upsurge of the problems. Young AAs are under great acculturative as well as minority stress, including being the frequent victims of hate crimes, experiencing harmful objectification by the majority and other minority groups, and having their American identities questioned. This stressful environment has been aggravated by the COVID-19 pandemic, which has provoked an unprecedented surge in anti-Asian racism and bigotry. There is a particularly pressing need for young AAs to identify ways to navigate these multifold pressures. This proposed study will extend an existing, highly successful longitudinal study of young AAs. The Midwest Longitudinal Study of Asian American Families (MLSAAF) is an ongoing survey of Filipino American (FA) and Korean American (KA) families (786 youth and their parents; MAGE of youth = 15 at Wave 1 in 2014). Wave 4 in 2021 collected data from 615 young adults (YAs) (MAGE=21.5; 78% retention). The MLSAAF has substantiated a troubling upward trend in MH struggles from 2014 to 2021 as participants transitioned to early young adulthood (YAH). We also uncovered racial discrimination and intergenerational cultural conflict (ICC) in the family as the etiology of this upsurge of problems. Minority and acculturative stresses are expected to amplify as YAs build careers and families of their own. AA families remain interdependent during YAH, with unwavering expectations of familism, conceivably prolonging ICC among AA YAs. By adding 3 waves, the proposed study will leverage the rich and rare MLSAAF data to follow the original samples from adolescence (ADOL) into their twenties to disentangle the complex and dynamic effects of family process, minority stress, and acculturation across the critical stages of YAH, including such pivotal outcomes as education, employment, marriage, and parenthood. Biomarkers (cortisol, C-reactive protein, and sleep) are added to investigate physiological damage of chronic stress from racial/cultural minority status. The inclusion of biomarkers will significantly enhance our capacity to more accurately assess biological, physical, and psychological harms of chronic stress that individuals may be unaware of. This study will (1) determine the trajectory and etiology of MH and physical health among young AAs as they transition from early ADOL to YAH. We will test (a) how AA family process (e.g., harmful vs. beneficial practices) is concurrently and longitudinally associated with ICC and the MH/health outcomes and (b) how racial discriminations are concurrently and longitudinally associated with poor outcomes, (2) investigate how bicultural competence mitigates the negativity of chronic psychosocial stressors (i.e., ICC and discrimination) and (3) to examine the associations in Aims 1 and 2 with biomarkers as outcome measures and to identify harms of chronic stress that self-report measures may not capture.

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National Institute of Child Health and Human Development

# data[].attributes.title
What Precursors Become Lung-Resident CD4 Memory that Protect Against Respiratory Infections or Cause Lung Pathology?

# data[].attributes.funder_divisions[]
National Institute of Allergy and Infectious Diseases (NIAID)

# data[].attributes.abstract
What Precursors Become Lung-Resident CD4 Memory that Protect Against Respiratory Infections or Cause Lung Pathology? Respiratory viruses such as SARS-CoV1, Influenza and recently SARS-CoV2 (COVID-19) have caused the major pandemics in the 21st century and influenza causes high levels of death from yearly circulating outbreaks. T cells can target internal viral proteins, that mutate less frequently. Thus, T cell memory induced by previous vaccination or infection can still be effective against emerging mutant viral strains. Tissue resident memory (TRM) cells, that develop in the lung are at the first line of defense of our adaptive immune response against respiratory infections because of their location. However, lung CD8 TRM, which are most- studied, are short- lived. The few studies that have examined lung CD4 TRM suggest that they may decay less rapidly. We know relatively little about lung CD4 TRM longevity and mechanisms of function, though they are known to protect against many respiratory infections such Influenza, Sendai, B.pertussis, pneumococcal pneumonia and tuberculosis infections. Moreover, we know little about the CD4 effectors that are precursors to the lung CD4 TRM. If CD4 lung TRM are longer-lived, they might compensate over the long-term for the rapid decline in CD8 lung TRM, thus making them good vaccine targets to provide strong more durable immunity. A majority of the CD4 and CD8 T cells in human lung express TRM features, so it is vital to understand their impact when they are reactivated during an immune response, both their positive effect on protection against pathogens and negative effects on lung function and tissue damage. In many respiratory infections such as influenza and COVID-19 there is also potential for severe lung damage leading to poor prognosis. We show that cytotoxic CD4 T cells, that are resident effectors in the lung and that contribute to damage, can be precursors oflung CD4 TRM. Thus, it is vital that we learn how CD4 TRM can both protect and cause lung pathology on reactivation, especially if they are maintained long-term. Here, we propose to identify the precursors of CD4 lung TRM from CD4 lung effectors, and better define their protective and pathogenic potentials. We will phenotypically and molecularly characterize the CD4 TRM formed from subsets of lung CD4 effectors. We will study their longevity and their maintenance via mechanisms such as homeostatic proliferation and recruitment from circulation. Finally, we will study in detail their functional mechanisms of eliciting protection vs those causing lung immunopathology by direct cytolysis, inflammation and helper function. Understanding mechanisms/conditions driving protection and pathology by CD4 TRM will enable design of interventions like vaccines and immunotherapies, that favor the development of protection while minimizing pathology. Identifying precursor CD4 effectors that give rise to protective CD4 TRM will also allow us to finetune vaccine approaches that drive generation of those CD4 effector subsets. In future studies, we will use the knowledge gained here, to identify transcriptional networks that regulate the development of CD4 TRM from CD4 effectors and naïve CD4.

# data[].attributes.title
What Precursors Become Lung-Resident CD4 Memory that Protect Against Respiratory Infections or Cause Lung Pathology?

# data[].attributes.funder_divisions[]
National Institute of Allergy and Infectious Diseases (NIAID)

# data[].attributes.abstract
What Precursors Become Lung-Resident CD4 Memory that Protect Against Respiratory Infections or Cause Lung Pathology? Respiratory viruses such as SARS-CoV1, Influenza and recently SARS-CoV2 (COVID-19) have caused the major pandemics in the 21st century and influenza causes high levels of death from yearly circulating outbreaks. T cells can target internal viral proteins, that mutate less frequently. Thus, T cell memory induced by previous vaccination or infection can still be effective against emerging mutant viral strains. Tissue resident memory (TRM) cells, that develop in the lung are at the first line of defense of our adaptive immune response against respiratory infections because of their location. However, lung CD8 TRM, which are most- studied, are short- lived. The few studies that have examined lung CD4 TRM suggest that they may decay less rapidly. Relatively little is known about lung CD4 TRM longevity and mechanisms of function, though they are known to protect against many respiratory infections such Influenza, Sendai, B.pertussis, pneumococcal pneumonia and tuberculosis infections. Moreover, it is unclear which CD4 effectors precursors become lung CD4 TRM. If CD4 lung TRM are longer-lived, they might compensate over the long-term for the rapid decline in CD8 lung TRM, thus making them good vaccine targets to provide strong more durable immunity. A majority of the CD4 and CD8 T cells in human lung express TRM features, so it is vital to understand their impact when they are reactivated during an immune response, both their positive effect on protection against pathogens and negative effects on lung function and tissue damage. In many respiratory infections such as influenza and COVID-19 there is also potential for severe lung damage leading to poor prognosis. We show that cytotoxic CD4 T cells, that are resident effectors in the lung and that contribute to damage, can be precursors of lung CD4 TRM. Thus, an understanding of how CD4 TRM can both protect and cause lung pathology on reactivation, especially if they are maintained long-term, is vital. Here, the research proposed will identify the precursors of CD4 lung TRM from CD4 lung effectors, and better define their protective and pathogenic potentials. It will phenotypically and molecularly characterize the CD4 TRM formed from subsets of lung CD4 effectors. It will study their longevity and their maintenance via mechanisms such as homeostatic proliferation and recruitment from circulation. Finally, it will study in detail their functional mechanisms of eliciting protection vs those causing lung immunopathology by direct cytolysis, inflammation andhelper function. Understanding mechanisms/conditions driving protection and pathology by CD4 TRM will enable design of interventions like vaccines and immunotherapies, that favor the development of protection while minimizing pathology. Identifying precursor CD4 effectors that give rise to protective CD4 TRM will also allow to finetune vaccine approaches that drive generation of those CD4 effector subsets. In future studies, the knowledge gained here, will allow identification of transcriptional networks that regulate the development of CD4 TRM from CD4 effectors and naïve CD4.

# data[].attributes.title
Dissecting mechanisms of antibody-Fc interactions that shape innate immune antiviral responses.

# data[].attributes.funder_divisions[]
National Institute of Allergy and Infectious Diseases (NIAID)

# data[].attributes.abstract
Antibodies are critical mediators of immune protection against pathogens, simultaneously acting to neutralize entry and activate innate immune cells through interaction between the antibody Fc domain and Fc-receptors (FcRs) on innate immune cells. Leveraging Fc-mediated activation in monoclonal antibody-based therapies is increasingly being investigated for the treatment of infectious diseases but the precise mechanisms and breadth of functions that can be induced by range of FcR-bearing immune cells is still unclear. However, these efforts are limited by the fact that we do not fully understand the spectrum of effector functions and effector programs that are induced via different FcRs, which could greatly impact efficacy and safety of mAb-based therapeutics. Moreover, as some innate immune cells such as monocytes express multiple FcRs, understanding how these pathways interact will help in the development of rational antibody design strategies to effectively harness innate immune cells against a variety of pathogens.  There are four activating FcRs that bind IgG and are expressed on innate immune cells (FcγR1, FcγR2A, FcγR3A, and FcγR3B) and one inhibitory receptor (FcγR2B). The interplay between these receptors can impact Fc-effector functions, especially in monocytes that express multiple FcRs. Moreover, antibody-mediated activation of non-classical monocytes that express 3 activating FcγRs must balance protection and pathology, as antibody-dependent enhancement of infection/disease has been observed in some contexts. Thus, defining the transcriptional profiles of FcR-mediated activation of will be critical to better predict in vivo activity of immunotherapies and antibodies induced by vaccination or infection. To that end, we propose to begin to generate an ‘FcR Effector Atlas’ that defines the anti-pathogen pathways that are induced in distinct innate immune cell types mediated by different FcRs. The Atlas can be used to map the pathways induced across all innate immune cells to help guide development of optimally efficacious and safe antibody therapeutics against infectious diseases.  By combining Fc-engineered antibodies that facilitate individual or combinatorial activation of specific FcRs and nascent transcriptomics, the goal of this proposal is pioneer an approach to generate the Atlas in nonclassical monocytes. We will use SARS-CoV-2-specfic Fc-engineered monoclonal antibodies as a model system to specifically engage different FcRs on monocytes to define the FcR-mediated transcriptional network using capped small RNA-sequencing (csRNA-seq) that enables transcriptional profiling of nascent RNA transcriptional start sites. Further, we will functionally link induction of specific pathways to restriction of SARS- CoV-2 infection. Together, the approaches and results generated from this proposal will contribute to our fundamental understanding of how antibodies leverage innate immunity and can be used to guide development of highly effective and safe immunotherapeutics for infectious diseases and beyond.

# data[].attributes.title
Characterization of the SARS-CoV-2-mediated piracy of p38ß

# data[].attributes.funder_divisions[]
National Institute of Allergy and Infectious Diseases (NIAID)

# data[].attributes.abstract
COVID-19 has resulted in a significant burden on the human population following the emergence of SARS- CoV-2. Since the discovery of SARS-CoV-2 in 2019, millions have succumbed to infection due to an imbalanced host response orchestrated by the biology of the virus. Characterization of the interactions between SARS-CoV- 2 and the infected host have revealed that the virus manipulates a small subset of signaling pathways culminating in an overproduction of proinflammatory cytokines and chemokines juxtaposed to an underproduction of type I interferons, the central antiviral defense of vertebrates. An effort to identify kinase drug targets for the treatment of COVID-19, as kinases represent ideal druggable targets, found that the p38 family of mitogen-activated protein kinases (MAPKs) are among the most highly active kinases during SARS-CoV-2 infection. Moreover, perturbation of p38 kinases inhibited both virus replication and cytokine production. Thus, p38 kinases are promising drug targets to block both virus replication and the excessive inflammation that is a hallmark of severe COVID-19.  In a subsequent study, a genetic perturbation approach was used to explore the p38/MAPK-SARS-CoV-2 interface and it was determined that the β isoform of the p38 kinase is an essential host factor for virus replication. Additionally, inhibition of p38β reduces the abundance of SARS-CoV-2 nucleocapsid protein (N), but not viral mRNA during infection. Contrary to the assumed pro-inflammatory activity of p38 kinases, findings suggested p38β negatively regulates the expression of inflammatory cytokines. Lastly, p38-dependent phosphosites on SARS-CoV-2 N were identified and mutation of these sites resulted in attenuated virus replication. Based on these data, the overarching goal of the research proposed here is to test the hypothesize that p38β phosphorylates both viral and host proteins to cumulatively promote SARS-CoV-2 replication and modulate the host response.  To further characterize the SARS-CoV-2-p38β interface, Aim 1 will explore the mechanism(s) responsible for p38β's proviral activity and ascertain the contribution of this biology to the inflammatory response observed in the context of COVID-19. To this end, viral protein stability will be assessed with translation inhibitors and affinity-purification mass spectrometry to establish how p38β promotes the steady-state level of viral protein during infection. In parallel, different immune agonists and genetic perturbations will be tested in Aim 2 to assess the specificity of p38β-mediated downregulation of inflammatory cytokines and determine if altered expression of these cytokines contributes to the proviral activity of p38β.  By characterizing these p38β-SARS-CoV-2 interactions, the research proposed here will enhance the understanding of SARS-CoV-2 biology, virus-host interactions, and p38β biology in order to inform the development of novel drug therapies critically needed for the treatment of COVID-19.

# data[].attributes.title
Functional Viromics of Betacoronavirus Entry

# data[].attributes.funder_divisions[]
National Institute of Allergy and Infectious Diseases (NIAID)

# data[].attributes.abstract
After the severe acute respiratory coronavirus (SARS-CoV) emerged in China in 2002, the virus was traced back to animal markets and several genetically related viruses were identified in bats. This early work into coronavirus zoonosis and the concomitant rise of next generation sequencing technologies in the early 2000’s helped initiate global research efforts to identify viruses circulating in wildlife. The genomes for tens of thousands of novel animal viruses have now been sequenced and deposited in online repositories. Coronaviruses are abundant in mammals and birds and comprise approximately 25% of all bat viruses discovered to date. The highly pathogenic human coronaviruses, SARS-CoV, and middle east respiratory syndrome coronavirus (MERS-CoV) are only representative members of their respective sarbeco- and merbeco- subgenera, which encompass hundreds of related viruses found in bats and other wildlife, worldwide. Unfortunately, because there are few tools available for researchers to study uncharacterized animal viruses, virus discovery studies rarely isolate viruses under laboratory conditions or perform experiments beyond genetic sequencing, leaving some of the most essential questions about these viruses – including if they have the potential to infect humans – unanswered. An improved understanding for what species these viruses can infect and how they invade the cells of their hosts is essential for future pandemic preparedness.  The most significant species barrier for the coronaviruses that have transmitted to humans is at the level of cell entry and studies have shown that overcoming this barrier allows for coronaviruses to replicate in cells from diverse species. To invade cells, the “spike” glycoprotein on the surface of viral particles binds to host cell receptor molecules. The receptor binding domain (RBD) is a small region on the distal tip of the spike protein, capable of folding independently of spike and contains all amino acids that contact the host receptor. We previously developed “SarbecoType” – a BSL2-compatible, viral pseudotype-based platform to functionally screen the cell entry properties of the RBD from any sarbecovirus. This approach is highly cost- efficient and scalable, requiring synthesis of only a small portion of the spike gene, and has allowed us to characterize the cell entry phenotypes of approximately 95% of all published sarbecoviruses. This dataset identified multiple clades of sarbecovirus RBDs that vary in their zoonotic properties for humans, and has formed a foundational basis for ongoing universal sarbecovirus design. Therefore, we hypothesize uncharacterized coronaviruses pose a threat to humans. Here we propose to functionally screen the much larger and diverse group of merbecoviruses with similar methods (I.e., “MerbecoType”) and use this entry data to predict the entry capabilities of novel sarbeco- and merbeco-virus sequences.

# data[].attributes.keywords[]
Middle East Respiratory Syndrome Coronavirus

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Utilizing alternative dietary interventions to alter gut microbiome and improve T cell responses to viral infection in obesity

# data[].attributes.funder_divisions[]
National Institute of Allergy and Infectious Diseases (NIAID)

# data[].attributes.abstract
Obesity is associated with chronic inflammation and an impaired immune response to infection from select viruses, including influenza and SARS-CoV-2, leading to increased morbidity and mortality. Many studies have demonstrated a critical role for T cells in this setting, with primary and memory T cell responses to viral infection impaired in mice and humans with obesity. Given the high prevalence of obesity and viral infections with influenza and coronavirus worldwide, it is critically important to understand T cell dysfunction in obesity and identify novel strategies to improve immune response to infection in this high-risk population. T cell function and metabolism are closely linked, and many studies have demonstrated that changes to T cell metabolism influence T cell fate and function. We have found that activated T cells from obese animals have an altered metabolic profile characterized by increased glucose uptake, increased conversion of glucose to pyruvate, and increased mitochondrial oxidation. This represents a unique cellular metabolic phenotype of glucose oxidation that is not utilized by naive, memory, or activated T cells from lean animals and may mechanistically explain obesity- associated T cell dysfunction. Interestingly, we found that weight loss achieved by continuous low-fat diet was unable to improve obesity-associated inflammation, normalize T cell metabolism, or improve survival to influenza infection in obese mice. Thus, alternative approaches to decrease obesity-associated inflammation and/or restore T cell metabolism may be needed to improve T cell responses to viral infection in individuals with obesity. Alternative dietary approaches using variations of time-restricted feeding such as intermittent calorie restriction, intermittent fasting, or alternate day fasting have been shown to be beneficial to both weight loss and multiple indices of health, including metabolic disease, inflammation, and immune response to bacterial infection. Recent publications suggest that the immunomodulation seen following time-restricted feeding is at least partially mediated by changes in the gut microbiome. Indeed, it is now well established that the gut microbiome of mice and humans with obesity is different than the gut microbiome of lean animals, and it is the prevailing view that these changes in gut microbiome in obesity drive adipose and system inflammation and thereby influence immune cell responses. Therefore, the overall objective of this R21 proposal is to determine the effects of time- restricted feeding on gut microbiome diversity, T cell function and metabolism, and survival to influenza infection. We hypothesize that weight loss achieved through time-restricted feeding will alter the gut microbiome and reduce obesity-induced inflammation, thereby restoring T cell metabolism and function, resulting in decreased morbidity and increased survival to influenza infection. Successful completion of these studies will identify metabolic and microbiome-related mechanisms underlying T cell dysfunction in obesity and test the impact of alternative dietary approaches on T cell response to viral infection.

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Innate immune pathways underlying sexual dimorphism in obesity pathogenesis

# data[].attributes.funder_divisions[]
National Institute of Allergy and Infectious Diseases (NIAID)

# data[].attributes.abstract
Obesity incidence is increasing worldwide with the urgent need to identify new therapeutics. Increased adiposity is associated with chronic inflammation, which can exacerbate a number of obesity-associated diseases, including COVID-19 infection and allergic disease. There are profound sex differences in immune cell activation driving obesity-mediated pathologies. However, there remain critical gaps in knowledge on the immune mechanisms underlying obesity, and whether they are sexually dimorphic. Preliminary data generated from transgenic mice, adoptive immune cell transfer, and adipose single cell sequencing uncovered a new RELMα-eosinophil-macrophage axis that is female-specific and protective in obesity and associated inflammation. Transcriptomic profiling of the adipose macrophages identified novel sex-specific and RELMα-dependent genes such as chemokines, hemoglobins and a long non- coding RNA (lncRNA) as new molecular candidates to treat obesity. Based on these findings, the overarching goal of this study is to investigate sexual dimorphism in innate immune cell crosstalk in obesity, from how gonadal hormones direct macrophage-eosinophil interaction (Aim 1) to determining downstream effectors in macrophages, such as hemoglobins and lncRNA, and their mechanisms of action associated with oxidative stress in the obese adipose tissues (Aim 2). Strengths of the proposed study include the multidisciplinary nature of the experimental design, which combines the co-PIs expertise in reproductive endocrinology and innate immunity, and the public health impact of investigating the understudied area of sex differences and how they may guide more specific treatments for obesity and associated risks for infection and allergic disease.

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Modifying Adiposity Through Behavioral Strategies to Improve COVID-19 Rehabilitation

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Findings of post-acute sequelae of Post-COVID Conditions (PCC) manifestations of fatigue, pain, dyspnea, and muscle weakness, provide a strong rationale for rehabilitation; yet few formal studies exist and the effects of severe acute respiratory syndrome coronavirus-2 infection on function are not well described. Notably, two- thirds of Veterans are overweight and obese, rendering excess adiposity a significant risk factor and a high- priority area related to PCC prevention and care. Obesity increases the risk of severe illness in Veterans recovering from PCC, but how it does so is not fully understood.  Recent research suggests that excess adipose tissue is associated with adverse changes in adipose cellular function, and that these variations may be involved in the biology of aging and the etiology of aging- related diseases. Adipose tissue contains cells that have undergone cellular senescence, which induces inflammation, cytotoxicity, and metabolic dysfunction in other cells and tissues. However, the precise role of adipose tissue cellular composition on PCC recovery is limited.  Thus, we propose to evaluate the role of obesity and PCC on physical functioning, health-related quality of life (HRQOL), and systemic and adipose tissue inflammatory and cellular senescence profiles in ethnically diverse older Veterans from the Audie Murphy (San Antonio) and Baltimore VA Medical Centers. Further, we propose a randomized controlled trial to determine whether a reduction in body weight and increased physical function by a weight loss intervention (WL), including dietary modification and exercise, in obese Veterans with PCC will reduce systemic and adipose tissue inflammation and senescence, which will have important implications for PCC recovery. We will pursue the following aims: Aim 1: To compare physical function, body composition, HRQOL, PCC symptoms, and adipose tissue molecular profiling in four cohorts of Veterans at baseline: lean PCC naïve, lean with PCC, obese PCC naïve, and obese with PCC (N=150). Aim 2: To compare in Veterans with obesity: a) a 12-week randomized WL vs. weight stability (WS) intervention (30/group) on physical function, body composition, HRQOL, and PCC symptoms together with changes in the global molecular profile in adipose tissue in Veterans with PCC and b) the WL intervention in PCC naïve vs. with PCC (N=30/group) on these outcomes.  Older (55-80 years) men and women Veterans will be recruited. We will perform a standard functional battery (maximal aerobic capacity [VO2max; primary outcome], usual gait speed, six min walk distance, timed up and go, and handgrip strength), body composition (dual energy x-ray absorptiometry and computed tomography scans), HRQOL (NIH PROMIS-57), and PCC symptoms (COVID-19 Yorkshire Rehabilitation Scale [C19-YRS]) and adipose tissue will be collected. Further, we will test, in a randomized controlled trial, the hypothesis that a WL intervention, compared to weight stability (WS), improves physical function, body composition, and HRQOL and reduces inflammation and senescent cell burden and to a similar extent as the PCC naïve group with obesity.  A deeper understanding of the relationship between adipose tissue and PCC will likely reveal factors that predispose to or protect against aging-related functional declines. Moreover, a better understanding of the effects of a lifestyle intervention on the molecular profile of adipose tissue will help to determine how changes in adipose tissue contribute to PCC and PCC recovery. Lastly, this research will provide important mechanistic insights into how cellular senescence influences the pathophysiology of physical, mental, and social dysfunction in older Veterans. Our findings could provide evidence-based recommendations to promote this type of intervention in Veterans recovering from PCC.

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Post-Acute Sequelae of SARS-CoV-2 Infection

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United States National Institutes of Health

# data[].attributes.title
Prevalence of Coronaviruses in Wild Rodents

# data[].attributes.funder_divisions[]
National Institute of Allergy and Infectious Diseases (NIAID)

# data[].attributes.abstract
/ Abstract COVID-19 is caused by a bat-borne coronavirus, SARS-CoV-2, that has resulted in more than 1 million deaths in the USA. Experimental and bioinformatic analyses suggest cricetid rodents, but not murid rodents, may be susceptible to the virus. We determined that two such cricetid rodents, the North American deer mouse (Peromyscus maniculatus) and California deer mouse (P. californicus) are susceptible, with some of the latter species developing severe disease that required euthanasia. This raises the concern that spillback from humans or susceptible domesticated animals, such as mins (Neogale vison), to North American cricetid rodents could occur and lead to establishment of SARS-CoV-2 in secondary reservoir hosts in the New World. Several rodent species in Europe and Asia have been found to harbor coronaviruses but, surprisingly, there are no reports wild rodents in the New World have been examined for coronaviruses, even though they are found in several bat species. Moreover, because of disease that occurred in California deer mice, it is possible that it or other North American rodents could serve as new pathogenesis models for COVID-19. To examine these possibilities, we will survey cricetid rodents in Colorado for the presence of coronaviruses, which we have detected at a site in Utah, and generate genome sequences of these viruses for phylogenetic analysis and important domains (e.g., protease cleavage sites). We will also determine the T cell response of deer mice vaccinated against SARS-CoV-2 using single-cell RNA seq analysis and compared to unvaccinated deer mice. This will lay the foundation of using deer mice as a long-lived small animal model (8 years), which cannot be replicated with Syrian hamsters or human ACE2 laboratory mice (2 years). Together this work will determine coronavirus diversity in North American rodents, and whether the deer mouse can serve as a durable immunity model for SARS-CoV-2.