Effect of SARS-CoV-2 on host metabolism and its influence on innate and adaptive immunity

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Pulmonary infections represent 5 of the 30 most common causes of death around the world, with lower respiratory infections resulting on average of 4 million deaths each year and the leading cause of death among children under the age of 5. We are currently in the midst of a pandemic caused by the pulmonary pathogen SARS-CoV-2. To date, the number of infections and deaths have surpassed other more typical respiratory infections with over 200 million cases and 4.25 million deaths. Since this is a new virus, there is very little we understand about all facets of the disease (COVID-19) it causes. The IPP section has over a decade of experience dissecting the innate and adaptive immune responses to pulmonary pathogens. Thus, in this project we leverage that experience to define unique features of both innate and adaptive immune responses to this virus with a special emphasis on the metabolic and lipidomic perturbations occurring during sub-lethal and lethal disease. Specific Aim 1: Identify the lipid signatures associated with mild, moderate and severe disease in humans. Lipids and lipid mediators are important molecules for initiating and maintaining inflammatory responses as well as resolving inflammation post-infection. Fortunately, many of these mediators are either targetable with established therapeutics and with drugs that are undergoing early clinical trials. Thus, identification of lipid mediators that are correlated with progression or resolution of SARS-CoV-2 infection provides new therapeutic targets. In FY2021 we identified that obesity was a strong comorbidity for SARS-CoV-2 infection. Moreover we identified that severe infections in the obese host was correlated with lack of production of key lipid mediators. We have extended these studies using a diet induced obesity mouse model in k18-hACE2 mice to more thoroughly interrogate the role of lipid mediators and obesity in infection. Specific Aim 2: Characterize the metabolic shifts in the host that are associated with sub-lethal and lethal SARS-CoV-2 infections in mice Specific shifts in metabolism are critical for mounting effective innate and adaptive immune responses. Using other models of infection we have found that pathogens can influence the ability of the host to properly regulate these shifts. Further, different tissues have differing abilities to mobilize metabolic pathways which also impacts disease progression and resolution. Using a variety of in vivo and in vitro techniques including but not limited to live animal imaging, assessment of metabolites and lipids from target and peripheral tissues, flow cytometry and assessment of metabolic flux in vitro we will determine how SARS-CoV-2 infection alters host metabolism to cause disease. Additionally, we will determine which pathways and mediators are required to resolve infection. By overlaying these results with those we obtain from human samples we will identify new targets for therapeutic intervention for SARS-CoV-2. Specific Aim 3: Identify the role of resident versus circulating T cells in protection against SARS-CoV-2 infection in mice. Generation and retention of T cells in the lung following sub-lethal infection or vaccination is essential for development of effective, long lasting immunity. Currently, there is no data concerning the presence or absence of resident T cells directed against SARS-CoV-2 among hosts that have either resolved infection or received a vaccine. We have determined that sublethal infection results in development of a population of resident T cells in the lung, but that these cells are not sufficient to confer immunity in the nave host. We will also characterize the phenotype and function of these cells to determine why T cells generated following a natural infection cannot provide protective immune responses on their own. Specific Aim 4: Long COVID is an increasing problem for people recovering from SARS-CoV-2 infection. Little is understood about this multi symptom condition. We are developing a model of Long COVID with specific emphasis on the lung and lung function following resolution of a sub-lethal SARS-CoV-2 infection in the mouse model. We will gain insight into how this virus compromises the lung environment long after clearance of infectious virions. We have initiated development of model of long COVID in the k18-hACE2 mouse model and are utilizing our expertise in other infectious diseases and models of pulmonary insult to determine how prior SARS-CoV-2 infection compromises lung function. Telemetry will also be employed to gain real time measurements of pulmonary function following infection.