This is the tenth article in a series called “How SARS-CoV-2 Evades And Suppresses The Immune System,” which will explore an underappreciated but highly significant aspect of SARS-CoV-2 replication. The ability of SARS-CoV-2 to delay, evade, and suppress the immune system has myriad implications for drugs, vaccines, and other aspects of our pandemic response. The first set of pieces in this series are intended for a general audience; the second set, for the medical community; and the third and final set, for biomedical researchers looking for a deeper understanding of variants, how they’re generated, and what we might do to control them. Read parts 1, 2, 3, 4, 5, 6, 7, 8, and 9.

Dodging the Trashman

One of the things SARS-CoV-2 and other viruses must do to evade immunity and survive is change the environment of host cells in its favor. These mechanisms I call nonspecific since they affect cellular function broadly and indiscriminately, as opposed to specific mechanisms that have very precise targets. In previous installments I described how nonspecific suppression manifests during protein translation. In this piece I discuss how SARS-CoV-2 avoids ending up in the cell’s waste disposal systems.

The first is sparing viral proteins and nascent virus particles from destruction by autophagocytosis—literally the process by which cells eat their own proteins. The autophagosome is a double membrane vesicle. Its main task is to shuttle cellular detritus to the lysosome, an organelle containing digestive enzymes, where it can be chewed up and recycled. This process, called autophagy, clears out damaged and or dysfunctional proteins.

The second notable change occurs in another process, apoptosis. Similar to autophagy, apoptosis rids the body of that which it no longer needs, though instead of damaged cell parts, it eliminates actual cells—billions of them. In the average adult, apoptosis triggers the death of 50 to 70 billion cells within a single day. Apoptosis is distinct from necrosis, another form of cell death, in that it is highly controlled and thus doesn’t cause inflammation.

We have a fairly clear picture of how SARS-CoV-2 might inhibit autophagosomal activity. According to a study published in April 2020, mutations identified in the nonstructural protein NSP6 and open reading frame Orf10 likely prevent autophagosomes from delivering material to the lysosome. In NSP6, the authors of the study noted the presence of certain residues that, if consistent with previous studies of the first lethal human coronavirus SARS-CoV, promote stronger affinity for the endoplasmic reticulum and curb autophagosome expansion. The net result is the cell no longer has full capacity to degrade viral proteins and nascent virus particles which might otherwise be destroyed.

It may be the case that the same gene is involved in helping create and modify the endoplasmic reticulum Golgi intermediate compartment (ERGIC). In so doing, it would essentially remodel the intracellular membrane architecture, by expanding the dimension of the ERGIC to a size sufficiently accommodative of virus particles.

For apoptosis, our understanding is a bit murkier. It is unclear based on currently available data whether SARS-CoV-2 prevents apoptosis or encourages it. In general, cell death is not ideal for the virus. But if it is something of an inevitability, apoptosis would be the ideal pathway for elimination, or risk detection by the immune system.

A study from June 2020 shows that the SARS-CoV-2 open reading frame Orf3a is capable of inducing apoptosis (also the case for Orf3a of SARS-CoV. Comparisons of the two, however, revealed that the pro-apoptotic activity of SARS-CoV Orf3a was greater. The authors of the study speculate that the reduction in apoptosis-mediated cell death could be linked to the diminished virulence of SARS-CoV-2 relative to its predecessors. It is due to its ability to assume milder manifestations than SARS and MERS that Covid-19 spreads so far and wide. It is notable that mutations in Orf3a are amongst the most frequent in SARS-2 variants with the exception of changes in the spike protein.

In the next part of this series, I will discuss how SARS-CoV-2 inactivates individual proteins required for innate immune signaling.