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Developmental Biology - COVID-19 Uniqueness

Why Are There So Many Unique COVID-19 Cases?

Scientists in the US and UK publish first in-depth look at how CD4+ T cells fight SARS-CoV-2...

As scientists around the world develop life-saving COVID-19 vaccines and therapies, many are still wondering exactly why the disease proves deadly in some people yet is mild in others. To solve this puzzle, scientists need an in-depth understanding of how our body's many types of immune cells respond to SARS-CoV-2, the virus causing COVID-19.

A new international study led by scientists at La Jolla Institute for Immunology (LJI), The University of Liverpool and the University of Southampton, United Kingdom (UK), is the first to give a detailed snapshot of how the body's CD4+ T cells respond to the SARS-CoV-2 virus.
Their findings suggest early in the illness, patients hospitalized with severe COVID-19, develop a novel subset of T cells that can potentially kill B cells, reducing antibody production.

The study was published October 6, 2020, in Cell, and provides crucial foundation showing the power of a cutting-edge technique called single-cell RNA sequencing (RNA-seq).

Zooming in on individual cells

"This study employs single-cell RNA-seq to analyze RNA molecules expressed by CD4+ T cells — which specifically recognize SARS-CoV-2," according to Pandurangan Vijayanand MD PhD and La Jolla Institute (LJI) Associate Professor leading the study, along with long-time collaborator Christian H Ottensmeier MD PhD FRCP, professor at the University of Liverpool and adjunct professor at LJI.

Says Ottensmeier, a physician scientist who co-led the study: "This is the beginning. We needed to have a reference to look back at for further studies, and this work is novel, timely, detailed, innovative--and open."
Vijayanand and his colleagues at LJI have pioneered the use of single-cell RNA-seq in immunology. RNA-seq gives researchers a new window into the gene expression patterns that can make each person's immune response to a virus different. For the new study, the researchers focused on CD4+ T cells, which play many critical roles in fighting infection.

"CD4+ T cells play a central role in orchestrating the immune response," explains study co-first author Benjamin Meckiff PhD, postdoctoral fellow at LJI. "These are a heterogeneous population of immune cells carrying out a wide range of functions, and we have been able to specifically analyze their response to SARS-CoV-2."

Vijayanand and Ottensmeier had planned to use single-cell RNA-seq to analyze CD4+ T cells from patients hospitalized for influenza this year. When the pandemic hit, they applied in early March for approval to use samples from COVID-19 patients as well. "We were collecting appropriate samples very early on in the pandemic," says Vijayanand. Researchers studied samples from 40 COVID-19 patients in two groups. The hospitalized group included 22 patients (including nine treated in the ICU). The non-hospitalized group had 18 patients who experienced milder COVID-19 symptoms.

Single-cell RNA-seq was used to analyze the types of CD4+ T cells that respond to SARS-COV-2 in these patients. Each type of T cell has a role in fighting viruses: some (the "helper" CD4+ T cells) alert the body to infection and recruit other immune cells, while other T cells (TFH cells) - signal B cells to make antibodies. Finally, some (Tregs) do the important job of inhibiting other T cells, keeping the immune system from damaging the body's own tissues.

"There are multiple flavors of T cells that respond to this virus," explains Vijayanand. Researchers caution that human studies are only correlative and cannot conclude which T cell populations are driving disease severity. Although they do believe some findings warrant a closer look.
For example, scientists found hospitalized patients have higher levels of "cytotoxic" TFH cells, which could potentially make an infection worse.

Instead of doing their job and helping B cells make antibodies, cytotoxic TFH cells were seen in this study as very similar to cells that have been seen killing B cells in previous studies.

Researchers then examined SARS-CoV-2-specific antibody concentrations in patients. Those with dysfunctional TFH cells also had fewer antibodies.

"TFH cells in hospitalized patients displayed gene signatures suggesting they are dysfunctional and aren't giving the help to B cells that we would expect," added Meckiff.

A Baseline for Future Investigations

Overall, the study gives the scientific community a starting place to explore CD4+ T cell responses to SARS-CoV-2, and establishes a baseline for comparing responses over time or with different disease severities. To support their research efforts, the researchers made all data immediately available online, just two months after the project began.

"We had to be quick," says study co-first author Ciro Ramírez-Suástegui, a bioinformatics specialist at LJI. "Having the data available for everyone is essential."

"There's definitely more to explore," adds study co-author Vicente Fajardo, an LJI research technician who spearheaded the bioinformatics analysis alongside Ramírez-Suástegui. In fact, the data and the research method could be important for more than infectious disease research.

A better understanding of how the body responds to viruses will also guide future research into cancer immunotherapies, which use the body's own immune system to target and kill cancer cells, explains Ottensmeier. He and Vijayanand are continuing their analysis of COVID-19 patients and plan to expand their collaboration within the University of Liverpool community.

"With this study, we levied our long-standing collaboration for a new human health puzzle. Going forward, we can extend this understanding of what's going on in blood in response to new viruses - into understanding what goes on in tissue when our immune system deals with cancer."

Christian H. Ottensmeier, La Jolla Institute for Immunology, La Jolla, CA 92037, USA Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Institute of Translational Medicine, Department of Molecular & Clinical Cancer Medicine, University of Liverpool, United Kingdom; and senior author.

Kaposiform lymphangiomatosis (KLA) is a rare lymphatic anomaly primarily affecting the mediastinum with high mortality rate. We present a patient with KLA and significant disease burden harboring a somatic point mutation in the Casitas B lineage lymphoma (CBL) gene. She was treated with MEK inhibition with complete resolution of symptoms, near-complete resolution of lymphatic fluid burden, and remodeling of her lymphatic system. While patients with KLA have been reported to harbor mutations in NRAS, here we report for the first time a causative mutation in the CBL gene in a patient with KLA, successfully treated with Ras pathway inhibition.

Jessica B Foster, Dong Li, Michael E March, Sarah E Sheppard, Denise M Adam, Hakon Hakonarson and Yoav Dori.

The study, titled, "Imbalance of regulatory and cytotoxic SARS-CoV-2-reactive CD4+ T cells in COVID-19," was supported the National Institutes of Health (grants U19AI14274, U19AI142742-0S1, U19AI118626, R01HL114093, R35-GM128938, S10RR027366, S10OD025052), the William K. Bowes Jr Foundation, the Whittaker Foundation, the Wessex Clinical Research Network and the National Institute of Health Research UK.

This work was supported by Institute Development Fund to the Center for Applied Genomics from the Children's Hospital of Philadelphia. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number TL1TR001880. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Research reported in the publication was supported by the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania.

About Children's Hospital of Philadelphia: Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 564-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu

About La Jolla Institute for Immunology

The La Jolla Institute for Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading toward its goal: life without disease.


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Scanning electron microscope image of SARS-CoV-2 (round blue objects) emerging
from the surface of cells cultured in the lab. CREDIT NIAID

Phospholid by Wikipedia