The emergence of SARS-CoV-2 has resulted in a worldwide pandemic. Infection with SARS-CoV-2 causes a spectrum of disease symptoms ranging from asymptomatic and mild/self-limited disease, to severe disease associated with significant lung damage and high levels of morbidity and mortality. As all individuals are immunologically nave to this virus and there are currently no targeted treatments or vaccines against SARS- CoV-2, protection and recovery depend on our own immune responses and supportive clinical care. Initially, children experienced largely asymptomatic or mild disease with severe disease resulting in significant lung injury a rare occurrence. However, a new multisystem inflammatory disorder in children (MIS-C) related to SARS-CoV-2 has emerged as a late complication of infection. Children with MIS-C commonly present with cardiac dysfunction and shock, most closely resembling Kawasaki disease and toxic shock syndrome. Importantly, some children presenting with MIS-C have been reported to develop coronary artery aneurysms, a finding common to Kawasaki disease. The significant amount of mild/self-limited disease in children contrasted with the excessive inflammation associated with SARS-CoV-2 suggests distinct immune responses. Additionally, the long-term implications, particularly to the cardiovascular system, of early life infection with SARS-CoV-2 remain unknown. We hypothesize that these distinct clinical manifestations in children, including lack of symptomatic respiratory infection to SARS-Cov-2 is due to a robust and enhanced T cell response.
The aims of this proposal are to 1) Establish pediatric patient cohorts for comparing outcomes and immune responses across the spectrum of pediatric COVID-19 disease, 2) Define the pediatric immune response to SARS-CoV-2 and how it differs across the clinical spectrum of disease, and 3) Define the incidence of and patient characteristics associated with sustained adverse cardiac outcomes for children with MIS-C and pediatric COVID-19. This project proposes to provide new insights into the pediatric immune and long-term complications of SARS-CoV-2 infection by employing a multi-disciplinary approach utilizing a team of investigators including immunologists, pediatricians, and pediatric subspecialists (cardiology/critical care medicine). These studies will provide invaluable insight that will help guide future decision making for treatment and preventative strategies for children.
The pediatric manifestations of infection with SARS-CoV-2 are distinct from adults, with children mainly experiencing asymptomatic acute illness with some later developing a multisystem inflammatory syndrome (MIS-C) associated with cardiogenic shock. The proposed research will build on findings suggesting reduced quantitative and functional antibody responses in children with MIS-C while defining the long term health implications of infection during early life. We will test the hypothesis that self-limited disease experienced in early life is associated with enhanced effector T cell responses while children who experience MIS-C display aberrant adaptive immune responses with increased risk for future cardiac complications.
|Kumar, Brahma V; Connors, Thomas J; Farber, Donna L (2018) Human T Cell Development, Localization, and Function throughout Life. Immunity 48:202-213|
|Carpenter, D J; Granot, T; Matsuoka, N et al. (2018) Human immunology studies using organ donors: Impact of clinical variations on immune parameters in tissues and circulation. Am J Transplant 18:74-88|
|Senda, Takashi; Dogra, Pranay; Granot, Tomer et al. (2018) Microanatomical dissection of human intestinal T-cell immunity reveals site-specific changes in gut-associated lymphoid tissues over life. Mucosal Immunol :|
|Connors, Thomas J; Baird, J Scott; Yopes, Margot C et al. (2018) Developmental Regulation of Effector and Resident Memory T Cell Generation during Pediatric Viral Respiratory Tract Infection. J Immunol 201:432-439|
|Granot, Tomer; Senda, Takashi; Carpenter, Dustin J et al. (2017) Dendritic Cells Display Subset and Tissue-Specific Maturation Dynamics over Human Life. Immunity 46:504-515|
|Murray, Alexandra J; Kwon, Kyungyoon J; Farber, Donna L et al. (2016) The Latent Reservoir for HIV-1: How Immunologic Memory and Clonal Expansion Contribute to HIV-1 Persistence. J Immunol 197:407-17|
|Thome, Joseph J C; Grinshpun, Boris; Kumar, Brahma V et al. (2016) Longterm maintenance of human naive T cells throughin situhomeostasis in lymphoid tissue sites. Sci Immunol 1:|