Project Team

Akiko Iwasaki, PhD, Sterling Professor of Immunobiology and Professor of Dermatology and of Molecular, Cellular, and Developmental Biology and of Epidemiology (Microbial Diseases), Yale School of Medicine, Investigator of the Howard Hughes Medical Institute.

Harlan M. Krumholz, MD,  Harold H. Hines, Jr. Professor of Medicine (Cardiology), and the School of Public Health (Health Policy), Yale School of Medicine.

David Putrino, PhD, Director of Rehabilitation Innovation for the Mt Sinai Health System, Associate Professor of Rehabilitation Medicine at the Icahn School of Medicine at Mt Sinai.

Aaron Ring, MD, PhD, Associate Professor of Immunobiology, Yale School of Medicine.

David van Dijk, PhD, Assistant Professor at Yale Dept. of Computer Science and Yale Dept. of Internal Medicine, Yale School of Medicine.

Project Summary:

Project co-lead Dr. Akiko Iwasaki

This study is probing the relationship among human endogenous retrovirus (HERV) activity, viral and bacterial pathogen reactivation, the human immune response, and Long COVID disease pathogenesis. The team is using advanced technologies to determine if pathologic antibodies to 1) HERVs 2) herpesviruses 3) tick-borne pathogens such as Borrelia burgdorferi are elevated in Long COVID individuals compared to controls. Cytokine, chemokine, and hormone levels are also being measured, and multivariate immune profiling used to define leukocyte subsets and activation status. Leukocytes are cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. Machine learning methods are being used to identify immune parameters that may associate with HERV, herpesvirus, and tickborne pathogen reactivities. The study is being performed in two well-characterized cohorts of Long COVID individuals: 1) the Yale LISTEN study 2) the MY-LC cohort.  

Project background:

The project team recently posted an important study demonstrating biological changes in individuals with Long COVID. These included the finding that Long COVID study participants had elevated levels of antibody reactivity to glycoproteins of Epstein-Barr virus and varicella-zoster virus (suggestive of recent reactivation). The data suggest a link between recent reactivation of latent herpesviruses in Long COVID disease pathogenesis.

The current study is expanding on these findings to additionally test the possibility that pathologic antibodies to tick-borne pathogen proteins or human endogenous retrovirus (HERV) antigens may be elevated in Long COVID. HERVs are inherited genetic germline elements derived from exogenous retroviral infections that occupy 8% of our genomes. While they are not active in replication, they encode viral proteins including envelope and capsid antigens that can drive inflammatory processes. The project team has experience studying the role of HERV activity in chronic disease processes. They recently published a study showing that lupus patients demonstrated elevated HERV expression as well as inflammatory antibodies to HERV envelope proteins that can engage immune cells.

The project team’s studies are done in partnership with participants, with a commitment to channel their wisdom, integrate their perspectives, acknowledge their expertise, honor their contributions, and share with them the results.

Image courtesy of Klein et al., 2022. Shows Three-dimensional mapping of LC-enriched linear peptide sequence PVXF[ND]K (magenta) onto Epstein Barr Vrisu gp42 (purple) in complex with gH (light grey) and gL (dark grey).