New research shows how genetic variations linked to severe cases of COVID-19 affect our immune cells.
The study, led by scientists at the La Jolla Institute of Immunology (LJI), is one of the first in-depth studies on the links between the severity of COVID-19 and gene expression in many types immune cells. This work could guide the development of new COVID-19 therapies to stimulate immune cell function.
Among their findings, the researchers report that a gene of a cell type called unclassical monocytes, which is part of the body’s “first responder” team of innate immune cells, could be a potential target for COVID-therapies. 19.
“This study highlights the power of human genetics to discover new pathways related to disease,” says Professor LJI Pandurangan Vijayanand, MD, Ph.D., lead author of the Nature Communication Study.
The scientific community has identified many genetic differences, called polymorphisms, which they call “severe COVID-19 risk variants”. These genetic variants are associated with gene expression and appear to influence the severity of cases. Yet scientists weren’t sure which immune cells are most affected by these risk variants.
For the new study, Vijayanand and colleagues combined genetic data from patients from the COVID-19 Host Genetic Initiative and LJI’s Open Access Immune Cell Epigenome Database (DICE) to define genes and types sensitive cells affected by these risk variants. The team looked at 13 subtypes of the body’s major protective and anti-virus cells: T cells, B cells, NK cells, and monocytes.
There are many different types of immune cells, and they all contribute little functions to the big picture. We need to look at each type of immune cell separately to determine how the immune system is able to respond to COVID. “
Benjamin Schmiedel, Ph.D., first author of the study, instructor at LJI
Researchers have identified several important associations of genetic variants with genes. Among them was a risk variant that affected 12 of the 13 cell types studied. This serious risk variant of COVID-19 in chromosome 21 was associated with reduced expression of a receptor on cells called IFNAR2. This receptor is part of a signaling pathway that alerts the immune system to infection. This new association may help explain why some people fail to develop a strong immune response to SARS-CoV-2.
Meanwhile, a risky variant on chromosome 12 showed the strongest effect in unclassical monocytes, a type of innate immune cell that patrols the body and sends signaling molecules to alert other immune cells to threat. The risky variant caused unconventional monocytes to reduce the expression of a gene called OAS1. A lack of OAS1 Expression may interfere with the body’s defenses by reducing the expression of a family of proteins that normally breaks down viral RNA and activates the antiviral responses of the immune system.
“Unclassical monocytes are a rare and little studied cell type,” explains Schmiedel. “They only make up about two percent of immune cells.”
Schmiedel hopes to conduct further preclinical evaluations to determine the role of these genes in the pathogenesis of COVID-19. “The fact that we can identify these types of genetic mechanisms is a big step forward,” he says. “We can use the available information, combine it with our data on immune cells, and find potential targets for treatment.”
La Jolla Institute of Immunology
Schmiedel, BJ, et al. (2021) COVID-19 genetic risk variants are associated with the expression of multiple genes in various types of immune cells. Natural communications. doi.org/10.1038/s41467-021-26888-3.