What is the connection between COVID-19 severity and gene expression in immune cells?

COVID-19 Tebu Bio

The immune system, responsible for fighting off infections and diseases, refers to multiple biological processes that have different functions and contributions to the immune system and its response to threats.
The immune system consists of two major subsystems: the innate immune system provides a default response to broad groups of situations and stimuli; and the adaptive immune system provides a more specific response to each stimulus by learning to recognize molecules it has previously encountered.
The innate immune system acts as a “first responder”, before the adaptive one can identify the pathogens more clearly and react more accordingly. Both use many different types of immune cells and molecules to perform their functions.

Understand the immune system

Figuring out how each of these types of cells react to COVID is key in understanding the entire immune system’s reaction. And new research has come out concerning the immune system’s reaction to COVID-19 infection.
This research was led by scientists at the La Jolla Institute for Immunology (LJI), a non-profit research organisation located in La Jolla, California and specialising in immunology and immune system diseases.
It offered an in-depth analysis of the relation between COVID-19 severity and gene expression in multiple types of immune cells. The implications of this work could help create new therapies to bolster the immune system against the virus.
Their work could very well lead to the development of new therapies to help the immune system fend off the virus.

How studying the immune system could help create new therapies to help against COVID-19?

The scientists found out that a gene in a cell type called classical monocytes – which are part of the innate immune system – could yield interesting information for COVID-19 therapies.
Science had already shown that certain gene polymorphisms – meaning the multiple alleles present in a gene can cause it to express itself differently in different people – were more at risk of developing a more severe form of the illness.
These polymorphisms are associated with gene expression, and we knew they could be used to predict case severity. Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product.
Gene regulation gives the cell control over structure and function, and is the basis for cellular differentiation, morphogenesis and the versatility and adaptability of any organism.
However, until now, scientists could not identify which immune cells were most affected by these risk variants. But the LJI’s new study combined patient genetic data and the LJI’s own Database of Immune Cell Epigenomes (DICE) to try and find out which genes and cell types were affected by the risk variants.
To do so, they had to scrutinise 13 subtypes of the body’s key protective and virus-fighting cells among T cells (T lymphocytes), B cells (B lymphocytes), NK cells (Natural Killer cells) and monocytes.
The latter are the largest white blood cells, including dendritic cells and macrophages; they are thus innate blood cells, part of the early responders to intruders in serious infections. Among them are classical and non-classical monocytes: the classical monocytes regulate the initial inflammatory response, notably by evolving into macrophages; the non-classical monocytes are anti-inflammatory and maintain vascular homeostasis (the adequate blood flow, blood pressure, distribution, and perfusion).
Understanding how each interacts with the body and the disease separately is key to understanding the body’s response to the virus.

Risk variants were identified in certain chromosomes

The study highlighted several important associations of genetic variants with genes. Notably, there is a risk variant that affects 12 of the 13 types of cells studied in relation to COVID-19 by the LJI.

Chromosome 21

This severe risk variant was identified in chromosome 21 (the smallest human chromosome and the one affected in Down syndrome) and it was linked to reduced expression of a receptor on cells called IFNAR2.
This receptor is part of a signalling pathway that alerts the immune system to infection. This finding may explain why some people’s immune system fails to respond correctly to the virus.

Chromosome 12

Another risk variant was identified in chromosome 12; it displayed the strongest effect in non-classical monocytes, a type of innate immune cell that roams the body and communicates with the help of molecules to alert other immune cells to threats.
This variant led non-classical monocytes to reduce expression of a gene called OAS1. A lack of OAS1 expression could reduce the immune system’s effectiveness by reducing the expression of a family of proteins that normally degrades viral RNA and activates the immune system’s antiviral responses.
RNA is ribonucleic acid, a key molecule in the coding, decoding, regulation and expression of genes. SARS‑CoV‑2, the virus causing COVID-19, is called an “RNA virus” since each virion (each “unit” of the virus, each “cell”) holds genetic information in the form of RNA within a protein membrane (which it injects in human cells to force them to produce more virions).
You can thus see why impeding the production of proteins that degrade viral RNA would be so impactful in the case of this disease.
Study first author Benjamin Schmiedel, Ph.D., an instructor at LJI, says: “Non-classical monocytes are a rare, understudied cell type. They only make up about two percent of immune cells.”
Ultimately, in the researchers’ own words, this study highlights the potential of COVID-19 genetic risk variants to impact the function of diverse immune cell types and influence severe disease manifestations.
These findings will also help scientists, through further pre-clinical research, understand how information about common genetic variations can be used to define molecular pathways and cell types that play a role in the development of a disease (also called pathogenesis), including but not limited to COVID-19.
This study, published in November 2021 in Nature, was authored by Benjamin J. Schmiedel, Job Rocha, Cristian Gonzalez-Colin, Sourya Bhattacharyya, Ariel Madrigal, Christian H. Ottensmeier, Ferhat Ay, Vivek Chandra & Pandurangan Vijayanand.


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