SARS-CoV-2 Actively Infects And Kills Lymphoid Cells

(Posted on Thursday, April 14, 2022)

Cell lysis. Destruction of a cell.

GETTY IMAGES/ISTOCKPHOTO

Much of the public discussion surrounding SARS-CoV-2 infection has focused on the interactions between the SARS-CoV-2 spike protein and cellular ACE2 receptors. Now, researchers at the University of the Chinese Academy of Sciences have found that this may only be part of the story. In a recent paper published by the journal Nature, scientists describe a new target for the SARS-CoV-2 virus that is independent of ACE2 receptors—our T cells.

One of the critical symptoms of SARS-CoV-2 infection is lymphopenia. Lymphopenia is a condition in which patients exhibit reduced levels of white blood cells called lymphocytes. Lymphocytes are the fundamental defense cells of our adaptive immune system. They consist of natural killer cells, T cells, and B cells. When any of these cells are reduced, it can inhibit our body’s ability to protect itself from viruses. Recent reports have shown that marked lymphopenia is observed in 83.2% of SARS-CoV-2 patients, but little is known about how SARS-CoV-2 effectively dismantles one of our primary tools of defense.

Shen et al. explored this question by first determining which lymphocytes SARS-CoV-2 targeted. Researchers collected blood cell samples from 22 patients with severe SARS-CoV-2 and from 15 healthy donors. They then tested each sample for three major lymphocyte cell types to determine any differences in lymphocyte counts between the healthy and infected donors. To their surprise, patients with severe SARS-CoV-2 exhibited a significant decline in T cells only. This suggested that SARS-CoV-2-induced lymphopenia is due to a decline in T cells and that T cells are the primary lymphocyte targets of the SARS-CoV-2 virus.

How does SARS-CoV-2 attack T cells? Shen et al. hypothesized that the virus might directly infect T cells, killing them in the process. To test this theory, they analyzed the T lymphocytes of infected patients for the presence of viral antigens. This analysis confirmed that SARS-CoV-2 antigens were present inside the T lymphocytes and that the virus could directly infect T cells. To confirm this result, Shen et al. examined lung sections from patients who had suffered from fatal SARS-CoV-2 infections. They found that the lung tissue contained high levels of T lymphocytes and that many T lymphocytes tested positive for SARS-CoV-2 proteins, indicating infection of those T cells (Figure 1).

These results were further corroborated by in vitro experiments. Shen et al. infected three model T cell types with SARS-CoV-2—Jurkat cells, MT4 cells, and T cells isolated from healthy donors. After initial infection, Shen et al. tested the cells for viral subgenomic mRNA. Subgenomic mRNA is an ideal marker for SARS-CoV-2 because it is only produced in infected cells during viral replication. If the researchers found SARS-CoV-2’s subgenomic mRNA in the cells, this would indicate that those cells were actively infected and that the virus was replicating.

After the experiment, not only did Shen et al. find substantial levels of subgenomic mRNA in the infected cells (Figure 2), but subgenomic mRNA levels grew significantly after 24 hours. These results were consistent across all three cell types.

Next, the researchers investigated whether SARS-CoV-2 infection could induce T cell death. To do so, Shen et al. analyzed infected cells for markers of apoptosis. Apoptosis is a natural consequence of infection and occurs when an infected cell self-destructs to prevent a virus from replicating and spreading to other healthy cells. Surprisingly, T lymphocytes from SARS-CoV-2 patients displayed nearly ten times the number of apoptotic cells than healthy individuals. In many of the patients, the apoptotic cells also contained viral antigens, further indicating that apoptosis was a direct consequence of SARS-CoV-2 infection.

It is common knowledge that SARS-CoV-2 primarily infects cells by interacting with ACE2 receptors expressed on the cell membrane. However, lymphocytes are known to contain very few, if any, ACE2 receptors. How then, could SARS-CoV-2 have such a profound effect on T cells?

Shen et al. conducted an experiment using model T cells (Jurkat cells) and non-lymphocyte cells (Caco2 cells) as control cells. To test whether SARS-CoV-2 infected the T cells through the ACE2 receptors, the researchers inactivated the genes responsible for producing ACE2 receptors in both the Jurkat and Caco2 cells. They then exposed both cell types to SARS-CoV-2. Surprisingly, a lack of ACE2 receptors decreased SARS-CoV-2 infection in the Caco2 control cells but had no effect on infection in the Jurkat cells. This finding demonstrated that SARS-CoV-2 infection of T cells occurs independently from the ACE2 receptors.

Motivated by this finding, Shen et al. sought to discover which T cell receptors were involved in SARS-CoV-2 infection. Two of the most common receptors found on T cell membranes are AXL and LFA-1. These two receptors are also highly expressed in the model Jurkat cells. Once again, the researchers inactivated the genes for these receptors in Jurkat cells. They then infected Jurkat cells with SARS-CoV-2. After running this experiment for 24 hours, they found that an absence of AXL receptors did not block SARS-CoV-2 infection. However, when AXL was overexpressed on the membrane, it seemed to increase SARS-CoV-2 infection.

An absence of LFA-1 receptors significantly decreased viral infection. When LFA-1 was overexpressed, it also promoted SARS-CoV-2 infection. This indicated that while AXL may play a small role in SARS-CoV-2 infection of T cells, LFA-1 is a far more convincing candidate and may be the key to developing medications that limit SARS-CoV-2-induced lymphopenia.

Currently, there are several theories surrounding SARS-CoV-2-induced lymphopenia and how the virus can attack lymphocytes in the absence of ACE2 receptors. However, this paper represents real progress in our understanding of the scope of SARS-CoV-2 infections and provides an interesting theory about how SARS-CoV-2-induced lymphopenia occurs. As research continues to develop, it will be interesting to discover exactly how this virus attacks and dismantles one of our key defense systems.

Read the full article on Forbes.