Illustrating the Innate Immune Response to SARS-CoV-2
By Tianai Lou, Cliona O’Farrelly, and Trevor Butterworth
1. Normal lung function; a SARS-CoV-2 particle enters the lung
Within the lungs, the bronchi branch into smaller bronchi and even smaller tubes known as bronchioles. Bronchioles end in tiny air sacs, alveoli, where oxygen passes into the blood stream and carbon dioxide passes from red blood cells into the lungs to be exhaled.
The alveolus is lined with a mucous membrane that secretes mucus (shown in green), which traps smaller particles like pollen or smoke. The epithelial cells of the alveolus have hair‐like structures called cilia on their surface. The cilia move back and forward to help move particles trapped in mucus out of the lungs. The epithelial cell is the first line of defense against viral infection.
ASARS-CoV-2 viral particle contains a single stranded RNA genome covered with envelope and membrane proteins. The viral particle is surrounded by spike proteins, which project from the surface and enable it to attach itself to a cell by binding to ACE-2 receptor. The ACE-2 receptor is expressed (the ACE-2 receptor is synthesized and projected from the surface of cells) in almost all tissues in the human body. The ACE-2 receptor is highly expressed in the lungs, the brain, and the heart to reduce acute injury, inhibit the thickening of lung tissues, and protect the cardiovascular system. Because SARS-CoV-2 virus enters human body from the respiratory tract, alveolar epithelial cells (expressing ACE-2 receptors) are the main sites for SARS-CoV-2 viral infection.
3. After a SARS-CoV-2 binds to an ACE-2 receptor
The SARS-CoV-2 viral particle binds to the ACE-2 receptor, enters the epithelial cell, and releases its RNA genome. By hijacking the epithelial cell’s machinery, the viral particle replicates its viral genome and makes viral proteins and nucleic acids, which then assemble themselves into new viral particles. These are released from the infected epithelial cell in different ways. Some viral particles are released into the air, some infect other neighboring epithelial cells, and some viruses go into blood stream and circulate in the body.
4. Innate immune response: The infected epithelial cell fights back
Epithelial cells are also equipped with cellular receptors for detecting small fragments of virus or bacteria. For example, epithelial cells contain Toll-like receptor (TLR)-7 to detect viral RNA. Once a receptor detects the presence of viral RNA, a signaling cascade leads to the activation of transcription factor proteins. Activated transcription factor proteins (such as IRF-7 and NF-B) can enter the nucleus of an epithelial cell and drive production of cytokines and interferons which will lead to inflammation and anti-viral responses.
5. Viral replication and Innate immune activity are happened in the same epithelial cell at the same time
As with the expression of the ACE-2 receptor, epithelial cells also project receptors for interferon on their surfaces intrinsically. Viral infection drives the production of interferons, which functions both as a warning signal to neighbour healthy cells and as a secondary response to viral infection. The binding of interferons to the interferon receptor leads to a signaling cascade, activating antiviral defense mechanisms, such as interfering in the viral life cycle at different stages—entry, replication, assembly, and release.
White blood cells reside in the lung alveoli constantly. These white blood cells, known as alveolar macrophages, are responsible for engulfing and clearing out bacteria and infected cells. In healthy lungs, alveolar macrophages are in an inactive state. When infection happens, alveolus macrophages are activated by cytokines produced by epithelial cells, such as IFN-gamma. Activated macrophages are capable of engulfment and they are equipped with toxic proteins to kill engulfed bacteria or infected cells. In the case of viral infection, activated macrophages can kill viral infected epithelial cells
Chair in Comparative Immunology, Clinical Medicine, TBSI; Trevor Butterworth is editor of TBSI News.