LSU SVM Center for Lung Biology and Disease investigates lung and lung-related heart diseases during the COVID-19 pandem

BATON ROUGE—Last year, the LSU School of Veterinary Medicine (LSU SVM) launched the Center for Lung Biology and Disease (CLBD) with more than $11.5 million in funding over five years from the National Institutes of Health, or NIH. No one involved could have predicted then that just one year later, a deadly new coronavirus that attacks lungs and causes severe acute respiratory syndrome would spread throughout the world.

At the CLBD, scientists are conducting research that leads to a better understanding of COVID-19 and are contributing knowledge that helps address its deadly effects.

Deaths of those with SARS-CoV-2 or COVID-19 often involve comorbidities, the presence of one or more additional conditions often occurring with the primary condition. In an April 2020 study published in the Journal of the American Medical Association (JAMA), researchers studied New York City patients hospitalized with COVID-19 and learned that almost every patient had another underlying health issue.

"All research projects underway at the lung center tie into COVID-19 because we're researching how asthma, smoking, and pneumonia exacerbate the severity of COVID-19 in patients and contribute to secondary bacterial infections," said Principal Investigator and Center Director Samithamby "Jey" Jeyaseelan, DVM, Ph.D., the Dr. William L. Jenkins Endowed Professor in the Department of Pathobiological Sciences (PBS) at the LSU SVM.

Many of the CLBD investigators focus on multiple aspects of lung research related to the current COVID-19 pandemic Research findings of the CLBD investigators will improve the understanding of the human body's defenses in order to develop effective therapeutics and vaccines against devastating lung diseases that can cause acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), which is the primary complication in COVID-19 infection in humans.

What follows are insights into researchers' discoveries-in-progress and a view of COVID-19 through the prism of their research:

Weishan Huang, Ph.D. (Project Investigator), Assistant Professor in Pathobiological Sciences

Dr. Huang's lab uses mouse adapted H1N1 influenza viruses to study how flu infection can be blocked and inhibit viral entry, how immune responses to flu can be made specific (flu antigen-specific antibodies and T cells, induced by infections or vaccines), and how immunopathology, or immune responses associated with disease, caused by flu infection can be prevented and treated with molecular and cellular immunotherapies. Dr. Huang will continue these studies and start to investigate the similarities of viral pneumonia during flu and COVID-19.

Yogesh Saini, MVSc, Ph.D. (Project Investigator), Associate Professor in Comparative Biomedical Sciences

COVID-19 patients with preexisting lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) are more likely to develop a severe COVID-19 illness. These patients manifest obstruction of their airways due to excessive production of mucus, thus their lungs lack much ability to clear inhaled microbes and environmental insults. Dr. Saini's research is focused on asthma and the role of macrophages (virus fighting front-responder cells in the airways of lungs) in asthma outcomes. He is researching the macrophages function in the lungs of animal models that possess defects in clearing the inhaled viruses, bacteria, and inhaled pollutants. According to Dr. Saini, the defective clearance function of airways in these patients make them more susceptible to the COVID-19 illness because their lungs have compromised capabilities to remove viruses that made their ways into the lungs and lodged in the mucus. Patients with asthma develop pulmonary exacerbations due to heightened immune responses. Therefore, current line of treatment such as corticosteroids aim to suppress immune responses and thus put these patients in the immunocompromised category.

Sonika Patial, DVM, Ph.D. (Project Investigator), Assistant Professor in Comparative Biomedical Sciences

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are serious health concerns due to a high rate of mortality in those diagnosed with the conditions. Excessive accumulation of protein-rich fluid mixed with immune cells in the lung results in hypoxemia in ARDS that require aggressive clinical management, including mechanical ventilation. The novel coronavirus was named as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) due to the fact that it causes acute respiratory distress syndrome and high mortality. Dr. Patial's research focuses on understanding the mechanisms of ALI/ARDS, specifically the identification of key cellular and molecular players of host defense in the pathogenesis of ALI/ARDS. Immunological studies in SARS-CoV-2 patients have reported the presence of a cytokine storm with immune suppression in the later stages.

Alexandra Noel, Ph.D. (Project Investigator), Assistant Professor in Comparative Biomedical Sciences

Currently, more than 13 million Americans engage in using the electronic nicotine delivery system (ENDS) or vaping, including middle school and high school students, as well as adults. With COVID-19 now a pandemic, it is critical to conduct more research to investigate the mechanisms whereby vaping increases the risk of developing severe COVID-19 complications. Dr. Noel is researching the effect of vaping in health outcomes. SARS CoV-2 is a virus belonging to the beta-coronavirus family and causes the COVID-19 disease. Emerging evidence is showing that people with unhealthy lifestyle habits, including smoking and vaping, are among those more at risk of developing severe symptoms of COVID-19. Studies suggest that impaired pulmonary innate immune defense mechanisms induced by vaping aerosol exposures, may increase the susceptibility to invasive lung bacterial or viral infections.

Tirumalai Rangasamy, Ph.D. (Pilot Project Investigator), Assistant Professor in Pathobiological Sciences

Dr. Rangasamy's work focuses on understanding the role of inflammasome-associated proteins as well as the major antioxidative transcription factor, Nrf2, in bacterial pneumonia and cigarette smoke-induced pulmonary emphysema COPD-associated bacterial exacerbations. Prior studies in the laboratory have shown that chronic (six months) exposure to cigarette smoke causes pulmonary emphysema. In addition, Dr. Rangasamy's recent preliminary data shows that subacute (one and a half months) exposure to cigarette smoke enhances the bacterial burden in the lungs as well as in other organs of mice infected with S. pneumoniae. COVID-19 with the A2a mutation is highly efficient in entering human lung cells in large numbers, is efficient in transmission, and highly prevalent across all regions. While the virus can infect individuals of any age, to date, most of the severe cases have been described in those of over the age of 55 years and with significant comorbidities such as COPD. Interestingly, patients with COPD have increased expression of ACE-2 in bronchial epithelial cells in lower respiratory tract.

Xing Fu, Ph.D. (Pilot Project Investigator), Assistant Professor, LSU School of Animal Sciences

Even though the main target of COVID-19 is the respiratory system, increasing evidence suggests a connection between COVID-19 and cardiovascular diseases (CVD). It has been shown that CVD is one of the most common and fatal comorbidities in COVID-19 patients. A study found that COVID-19 patients with CVD had a 10.5% fatality rate while the fatality rate is 0.9% in COVID-19 patients without comorbidity. Even though the detailed mechanism remains to be explored, angiotensin-converting enzyme 2 (ACE2) seems to be involved in this correlation. It is now known that SARS-CoV-2, the causal agent of COVID-19, recognizes ACE2 on the host cell and enters the cell through internalization with ACE2. Therefore, ACE2 is deemed a candidate target for preventing and treating SARS-CoV-2 infection. However, ACE2 is highly expressed in the heart and has a protective effect on CVD. It converts angiotensin II (Ang II), a major inducer of CVD, to Ang-(1-7) which antagonizes the effects of Ang II (2). Ang II induces cardiac hypertrophy and fibrosis through its effects on cardiomyocytes and cardiac fibroblasts, which stiffens the myocardium and reduces cardiac function. The expression of ACE2 is significantly enhanced in patients with myocardial infarction. The enhanced ACE2 activity is also a major mode of action of renin-angiotensin-aldosterone system (RAAS) blocker, a common CVD medicine. Thus, the increased ACE2 level in CVD patients may contribute to their higher vulnerability to SARS-CoV-2 infection. In addition, reduced ACE2 activity has been observed in a murine model of SARS-CoV, possibly due to increased ACE2 internalization, which may increase the Ang II level in COVID-19 patients, putting them at a higher risk of developing CVD. This is on top of the increase risk of thrombosis in COVID-19 patients due to the chronic inflammation which may also lead to myocardial infarct and other CVD. Thus, the development of COVID-19 prevention and treatment strategies through targeting ACE2 should include a careful evaluation of their effect on CVD.

As principal investigator, Dr. Jeyaseelan has assembled a team of outstanding investigators with advanced knowledge and research expertise across basic science departments in the LSU SVM Departments of Pathobiological Sciences (PBS) and Comparative Biomedical Sciences (CBS) to address immunological mechanisms contributing to numerous infectious and non-infectious pulmonary diseases. In addition to co-investigator Dr. Rhonda Cardin, associate dean for research and advanced studies, key research personnel include Dr. Smriti Mehra, associate professor, Division of Microbiology at the Tulane National Primate Research Center, or TNPRC; Dr. Weishan Huang, assistant professor in the LSU Department of Pathobiological Sciences; and Dr. Yogesh Saini, associate professor, and Dr. Sonika Patial and Dr. Alexandra Noel, who are assistant professors in CBS. Additional key scientific core personnel are Dr. Tammy Dugas, professor and head in CBS and core lead for the Pulmonary Immunopathology (PIP) Core, Dr. Ingeborg Langohr, professor in PBS and Co-Investigator for the PIP Core and Dr. Rebecca Christofferson, assistant professor in PBS and Co-Investigator for the PIP Core. Regarding the Molecular Biology (MB) Core, Dr. Konstantin "Gus" Kousoulas, professor and head of PBS and core lead, Dr. Vladimir Chouljenko, associate professor (research) in PBS and Co-Investigator for the MB Core and Dr. Tirumalai Rangasamy, assistant professor (research) in PBS and Co-Investigator for the MB Core.

About the Center for Lung Biology and Disease

The LSU School of Veterinary Medicine (LSU SVM) was awarded more than $11.5 million in funding over five years from the National Institutes of Health, or NIH, to launch the Center for Lung Biology and Disease (CLBD) in January 2019. Samithamby "Jey" Jeyaseelan, DVM, Ph.D., the Dr. William L. Jenkins Endowed Professor in the PBS, serves as principal investigator, and Rhonda Cardin, Ph.D., associate dean for research and advanced studies, serves as co-investigator.

The CLBD augments research on campus in the molecular and cellular immunological mechanisms of pulmonary and pulmonary-related heart diseases. Lung diseases are an increasing problem, especially in babies, the immunocompromised and the elderly, and Louisiana is in the top five states most affected by pulmonary diseases. The over-arching goal of the CLBD is to gain new insights into the pathogenesis of devastating lung diseases that will guide improved strategies to treat and prevent lung diseases in human populations. Learn more at clbd.cobre.lsu.edu/.

The funding comes from the NIH Centers of Biomedical Research Excellence, or COBRE program, which seeks to promote the initiation and development or expansion of unique, innovative, state-of-the-art biomedical and behavioral research centers at institutions in states that historically have received low levels of support from NIH, including Louisiana.

According to the NIH, COBRE support comes in three sequential 5-year phases: Phase I focuses on developing research infrastructure and providing junior investigators with formal mentoring and research project funding to help them acquire preliminary data and successfully compete for independent research grant support. Phase II seeks to strengthen each center through further improvements in research infrastructure and continuing development and support of a critical mass of investigators with shared scientific interests. After 10 years of COBRE support, centers are expected to be able to compete successfully for other sources of research funding, such as program project or center grants from other NIH institutes and centers or other funding sources. Phase III transitional centers provide support for maintaining COBRE research cores developed during Phases I and II, and sustain a collaborative, multidisciplinary research environment with pilot project programs and mentoring and training components. Although this new grant garners more than $11.5 million in total costs for its initial five years, the grant is renewable for two additional five-year terms for a total of more than $32 million.

"This grant focuses on lung disease, which is an ongoing area of breakthrough research done by the investigators at the LSU School of Veterinary Medicine," Dr. Jeyaseelan said. "This is an outstanding opportunity for a group of new and early-stage investigators to get their research programs off the ground and to flourish. It sets essential milestones in research that they have to fulfill and includes the remarkable value of personalized mentoring. It is indeed an awesome program."

Research supported by this program spans the full spectrum of basic and clinical sciences and encompasses all areas of health-related investigation. In addition, COBRE projects augment the ability of investigators to compete for investigator-initiated NIH research grants or other external nationally peer-reviewed funding.

About the LSU School of Veterinary Medicine

The LSU School of Veterinary Medicine is one of only 30 veterinary schools in the U.S. and the only one in Louisiana. The LSU SVM is dedicated to improving the lives of people and animals through education, research and service. We teach. We heal. We discover. We protect.

Media Contact

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