SARS-Cov-2 Can Infect T Cells Via Its Spike Protein

Original Article: Wang, X., Xu, W., Hu, G. et al. SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion, Cell Mol Immunol (2020)

Author of Summary: Sonia Fanelli

Original Article Published on Apr 7th, 2020

Lymphocytopenia is commonly observed in SARS-CoV-2 positive individuals and may be related to the mortality rate for COVID-19. In this study, the authors demonstrate the ability of SARS-CoV-2 to infect T lymphocytes. Furthermore, the authors confirm that the viral spike protein (protein S) -mediated membrane fusion process is responsible for the entry of SARS-CoV-2 into T cells, and propose that other membrane receptors may mediated SARS-CoV-2 entry site for SARS-CoV-2, in addition to the already confirmed hACE2 receptor.

In vitro evidence that SARS-CoV-2 can infect T cells. MERS-CoV infect human T lymphocytes, induce apoptosis without replicating into the cells, and, in some patients, causes lymphocytopenia.  Some COVID-19 patients also present lymphocytopenia, which might be related to mortality, and upregulation of apoptosis, autophagy, and p53 pathways in peripheral blood mononuclear cells (PBMCs). Direct infection of two T lymphocyte cell lines, i.e. MT-2 and A3.01, with pseudotyped SARS-CoV and SARS-CoV-2 revealed that T cells were significantly more sensitive, thus more permissive, for SARS-CoV-2 compared with SARS-CoV.

Interestingly, MT-2 and A3.01 expressed very low level of human ACE2, a fundamental mediator of viral infection. Conceivably, the high affinity of SARS-CoV-2 S protein for hACE2 could explain the high infectivity even in low hACE2-expressing cells and its elevated transmission rate in the population. Alternatively, SARS-CoV-2 could exploit receptor other than hACE2 to infect cells. Indeed, recent evidence proposed the transmembrane glycoprotein CD147 of T cells as novel invasion route for SARS-CoV-2.

SARS-CoV-2 can infect T cells through receptor-dependent S protein-mediated membrane fusion.

To assess how SARS-CoV-2 enters T lymphocytes, the researchers inhibited SARS-CoV-2 S protein-mediated cell–cell fusion and pseudovirus infection via peptide EK1. This peptide binds the HR1 repeat region in the S1 subunit of the S protein and interferes with the docking and fusion of the virus to the host cell. 

Upon EK1 treatment, the ability of SARS-CoV-2 pseudovirus to infect MT-2 T cell lines declined, suggesting that virus entry depends on receptor-mediated fusion. 

In support of this observation, S-mediated cell–cell fusion assay demonstrated that permissive 293T cells expressing SARS-CoV-2 protein fuses with T cells after 48h in coculture. This was not observed in 293T cells expressing SARS-CoV under the same experimental conditions.

In addition, direct infection of T cells lines with SARS-CoV-2 demonstrated that the virus could penetrate several T cells within 24 h and led to an increase of SARS-CoV-2 nucleoprotein.

Therefore, it is likely that SARS-CoV-2 could infect T cells through S protein-mediated membrane fusion by 24 h.

SARS-CoV-2 infection of T cells is abortive. The number of viral genome copies in cell lysate at 6 h post infection was significantly higher than at other time points. However, the viral titer in the supernatant remained steady, suggesting that SARS-CoV-2 may enter T cells but does not replicate. In these conditions, the viral RNA might ultimately degrade. Therefore, comparably to MERS-CoV, SARS-CoV-2 fail to replicate in T cell lines.

Conclusion. The results provide evidence that SARS-CoV-2 can infect T cells through receptor-dependent S protein-mediated membrane fusion. Moreover, the infection appeared to be abortive as the virus do not replicate in T cells. Importantly, the T cell lines showed low levels of hACE2 expression, supporting the idea that a novel receptor – such as CD147 – might be responsible of SARS-CoV-2 entry into T cells. Further investigation is still needed also to validate whether the infection induces T cells apoptosis, leading to lymphocytopenia as observed in COVID-19 patients.

Be the first to comment on "SARS-Cov-2 Can Infect T Cells Via Its Spike Protein"

Leave a comment

Your email address will not be published.