How does SARS-CoV-2 cause lymphopenia when T cells barely express ACE-2 receptors?

In a recent review published in the journal Cell Communication and Signaling, a team of researchers in Egypt and the United States explored the direct and indirect mechanisms of T lymphocyte-linked adaptive anti-viral immune responses that might contribute to lymphopenia associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections.

Schematic representation of possible mechanisms of lymphopenia in SARS-CoV-2 viral infection. Study: SARS-CoV-2-associated lymphopenia: possible mechanisms and the role of CD147Schematic representation of possible mechanisms of lymphopenia in SARS-CoV-2 viral infection. Study: SARS-CoV-2-associated lymphopenia: possible mechanisms and the role of CD147

Background

Although the spread and severity of the coronavirus disease 2019 (COVID-19) pandemic have been contained after worldwide vaccination efforts, SARS-CoV-2 continues to evolve due to accumulating mutations in its ribonucleic acid (RNA). While some of these mutations have led to lower virulence and transmissibility, others have also helped the virus evade vaccine-induced immunity.

The major immunopathological characteristics observed when SARS-CoV-2 triggers host immunity are low adaptive immune responses and uncontrolled inflammatory responses, including cytokine storms and abnormal interferon production. Of particular concern is the decrease in lymphocytes observed in patients with severe COVID-19.

The invasion of a cell by SARS-CoV-2 occurs when the spike protein binds to the angiotensin-converting enzyme-2 (ACE-2) receptor on the cell surface. Given that T helper cells (CD4+) and cytotoxic T cells (CD8+) do not express many ACE-2 receptors on their surface, the cause for the lymphopenia associated with SARS-CoV-2 remains unclear.

Mechanisms for SARS-CoV-2-associated lymphopenia

The review discusses the possible direct and indirect mechanisms through which SARS-CoV-2 infections could decrease CD8+ and CD4+ T cells. The detection of the viral RNA or antigens against SARS-CoV-2 in T-cells from autopsies suggests that the virus could directly result in lymphopenia without manifesting as a viral infection in the lymphocytes.

The increased production of interferon-γ (IFN-γ), perforin, granzyme, and interleukins (IL) 17 and 2 in the T cells due to the uptake of viral particles by the T cells could lead to exhaustion and cell death. This mechanism also suggests that SARS-CoV-2 might have a method of infecting cells that is independent of the ACE-2 receptor.

Computational analyses have identified various chemokine receptors, adhesion molecules, and other molecules on leukocyte surfaces that can bind to the SARS-CoV-2 spike protein’s receptor binding domain.

SARS-CoV-2 infections could also lower the number of lymphocytes through indirect mechanisms. The increased recruitment and stimulation of reactive T cells, neutrophils, and macrophages by the immune system to shed the virus also result in the excessive production of pro-inflammatory cytokines such as IL-6, known as cytokine storm. This cytokine storm can cause lymphopoiesis to get aborted, eventually resulting in lymphopenia.

Patients with severe COVID-19 have shown elevated levels of lactate in their plasma, which causes metabolic acidosis and inhibits lymphocyte proliferation, and often leads to multiple organ failure. The accumulation of reactive oxygen species derived from the mitochondria during the infection also causes stabilization of hypoxia-inducible factor 1 (HIF-1), which promotes the stimulation of pro-inflammatory monocytes and inhibits T-cell response.

Additionally, studies on the avian infectious bronchitis virus, human immunodeficiency virus, and murine hepatitis virus have shown that viral infections can directly cause apoptosis of T cells. However, whether the same is true for SARS-CoV-2 remains to be determined. Notably, human peripheral blood mononuclear cells infected with SARS-CoV-2 have shown an up-regulation of apoptosis-related genes.

Another possible mechanism through which SARS-CoV-2 can indirectly cause lymphopenia includes the dysregulation of hematopoiesis by directly affecting the hematopoietic stem cells or progenitor cells. The virus can also impact the secondary lymphoid organs, such as the spleen and the lymph nodes, by infecting the dendritic cells and macrophages in these organs and increasing the production of pro-inflammatory cytokines.

The presence of lipid rafts rich in cholesterol on the cell membranes of activated T cells could also provide a platform for the entry of SARS-CoV-2 into the cells, resulting in the virus's infection of T cells despite the absence of ACE-2 receptors.

Viral entry through CD147

The review also explores the potential entry of the virus into T cells through the type-1 transmembrane glycoprotein CD147. This pleiotropic molecule belonging to the immunoglobulin superfamily could provide the virus with an alternate route to enter T cells since it is involved in various cellular processes, such as interactions with and regulation of matrix metalloproteinases, cyclophilins, and monocarboxylate transporters.

The ability of matrix metalloproteinases to stimulate cell fusion could also increase the dissemination of the virus. Furthermore, the interaction between CD147 and cyclophilin A mediates the intracellular pathways that result in inflammation.

Conclusions

To summarize, the review discussed numerous possible direct and indirect mechanisms through which SARS-CoV-2 infections could lower the number of T helper cells and cytotoxic T cells, resulting in lymphopenia.

The findings show that although T cells barely express the ACE-2 receptor through which SARS-CoV-2 generally infects the host cell, there are various mechanisms through which the virus can infect T cells, including direct infection through other potential routes and receptors, such as CD147 and lipid rafts. Furthermore, the resulting cytokine storm, which has already been observed in numerous cases of severe COVID-19, is also believed to cause T-cell exhaustion and reduced lymphopoiesis.

Journal reference:
  • Shouman, S., El-Kholy, N., Hussien, A. E., El-Derby, Azza M, Magdy, S., Abou-Shanab, A. M., Elmehrath, A. O., Abdelwaly, A., Helal, M., & El-Badri, N. (2024). SARS-CoV-2-associated lymphopenia: possible mechanisms and the role of CD147. Cell Communication and Signaling, 22(1), 349. DOI:10.1186/s12964024017183 https://biosignaling.biomedcentral.com/articles/10.1186/s12964-024-01718-3
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

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