How SARS-CoV-2 escapes and suppresses the immune system (part 4)

This is the fourth article in a 15-part series titled “Relevance of SARS-CoV-2 Immune Suppression to Understanding and Controlling the Covid-19 Pandemic”, which will explore an underestimated but very important aspect of SARS-CoV-2 replication. . The ability of SARS-CoV-2 to delay, evade, and suppress the immune system has many implications for drugs, vaccines, and other aspects of our response to the pandemic. The first series of plays in this series is intended for a general audience; the second, for the medical community; and the third and final set, for biomedical researchers seeking a deeper understanding of variants, how they are generated, and what we might do to control them. Read the first part, second part, and part three.

The following is the conclusion of the section of this series written for the general public. Before this exploration of SARS-CoV-2 immunology branches off into more technical detail, I’ll summarize what we’ve learned so far using the layered analogy of a serial burglar.

Imagine the virus being a burglar like the one Cary Grant plays in Alfred Hitchcock’s 1955 masterpiece Catch a thief– a master to creep in and out of hostile environments without being detected. This burglar is so skilled at his craft that he can perform a job even during a crowded cocktail party.

The first thing the burglar should do when arriving at the scene is to avoid immediate recognition. When it appears at the door, it is as a guest, not as an intruder, just as SARS-CoV-2, upon entering a human cell, has already changed its exterior in order to escape immune detection.

The burglar’s second objective is to surreptitiously anesthetize the guests. The virus, as we will see in future articles in this series, has an impressive ability to shut down the many checkpoints that the cell normally has in place to prevent infection.

Then the burglar must disarm the security system. The equivalent for SARS-CoV-2 occurs when the virus silences the many signals an infected cell typically sends to alert neighboring cells to the presence of an intruder.

Finally, to top it off, the burglar sets off the fire alarm and starts a fire to cover his tracks and distract from himself before moving on to the next function. Fire replaces the immune disruption the body can experience if a Covid-19 infection progresses to more critical stages of the disease, potentially ending in death.

As easy as this analogy may sound, it is very similar to what actually happens when SARS-CoV-2 imposes itself on a human host. I will now describe the mechanisms of the first part of this process, when the virus disarms our first line of immune defense.

Escape from innate immunity

When an invading pathogen activates the body’s extensive alert system, directed by interferon, it triggers three types of immune response. The first is the innate immune response. This line of defense goes on the offensive when the identity and purpose of a pathogen is unknown. The second is the adaptive immune response, which is made up of antibodies and T cells that recognize and attack specific pathogens. The third and final wave is the memory response of T and B cells.

Innate immunity involves proteins known as pattern recognition receptors which, during evolution, have been hardwired to identify molecular patterns associated with pathogens or PAMPs. Commonly found in many pathogens, recognition of these molecules allows the body to respond immediately to old and new invaders. Some of the more well-known PAMPs include bacterial lipopolysaccharides, acids, bacterial DNA, and single and double stranded RNA. Activation of these pathways is also necessary to trigger the adaptive immune response.

Is innate immune suppression observed in newly infected Covid-19 patients? The answer, according to laboratory studies of cultured viruses and Covid-19 patients, appears to be yes. A group of researchers conducted an exhaustive investigation of the proteins and peptides excreted in the urine of uninfected and infected but asymptomatic or mildly ill patients. Many proteins involved in the innate immune response were strongly downregulated, while proteins characteristic of a hyperimmune state were present in patients with severe disease. Another study monitored the expression of genes related to the immune system in the respiratory cells of infected patients. They found very little change in the activation of genes for the innate immune response during the first 24 hours after infection.

Together, these experiments demonstrate the ability of SARS-CoV-2 to suppress the immune response in the first days after infection. Remember that the first obvious symptoms of infection are the result of the immune response to the virus, not damage from the virus itself.

My next piece for this series will be the first of several that explores in depth the immune suppression mechanisms of the virus. We will start with the specialized compartment erected by SARS-CoV-2 to hide its replication activities from the rest of the cell.