ACE2-independent infection of T lymphocytes by SARS-CoV-2

Abstract

SARS-CoV-2 induced marked lymphopenia in severe patients with COVID-19. However, whether lymphocytes are targets of viral infection is yet to be determined, although SARS-CoV-2 RNA or antigen has been identified in T cells from patients. Here, we confirmed that SARS-CoV-2 viral antigen could be detected in patient peripheral blood cells (PBCs) or postmortem lung T cells, and the infectious virus could also be detected from viral antigen-positive PBCs. We next prove that SARS-CoV-2 infects T lymphocytes, preferably activated CD4 + T cells in vitro. Upon infection, viral RNA, subgenomic RNA, viral protein or viral particle can be detected in the T cells. Furthermore, we show that the infection is spike-ACE2/TMPRSS2-independent through using ACE2 knockdown or receptor blocking experiments. Next, we demonstrate that viral antigen-positive T cells from patient undergone pronounced apoptosis. In vitro infection of T cells induced cell death that is likely in mitochondria ROS-HIF-1a-dependent pathways. Finally, we demonstrated that LFA-1, the protein exclusively expresses in multiple leukocytes, is more likely the entry molecule that mediated SARS-CoV-2 infection in T cells, compared to a list of other known receptors. Collectively, this work confirmed a SARS-CoV-2 infection of T cells, in a spike-ACE2-independent manner, which shed novel insights into the underlying mechanisms of SARS-CoV-2-induced lymphopenia in COVID-19 patients.

Immunosenescence and COVID-19

“…Among the other is, notably, the LFA-1 molecule, which was very recently (March 2022) demonstrated to mediate the entry of SARS-CoV-2 into human T lymphocytes, making them another target (or victim) of the virus. Admittedly, neither human T and B cells nor monocyte/macrophages express ACE2 or TMPRSS2( Shen et al, 2022 ). Direct SARS-CoV-2 infection of T cells is proposed to be the mechanism of lymphopenia seen in severe COVID-19 patients ( Gao et al, 2021 ).…”

“…The former (mainly monocyte/macrophages and dendritic cells) detect viral RNA via (mainly) the intracellular TLR7/8 and TLR3 receptors built in in the membranes of endosomes. It is necessary to mention here, that monocyte/macrophage cells can also be infected by functional, replicating viruses (which might affect their functions or even lead to their death), although the details of ways of entry of the virus into these cells are not yet established; surface TLR species and LFA-1 are proposed as the entryways, but conclusive research is still missing ( Codo et al, 2020 , Shen et al, 2022 , Zheng et al, 2021 ). Ligation of TLR7/8 provides strong activating signal in the monocyte/macrophages which stimulates the inflammasome and leads to the production and secretion of IL‐1β which stimulates the secretion of IL‐6, MCP‐1, MIP‐1 A, TNF‐α, and virus-protective type 1 interferons ( Khanmohammadi and Rezaei, 2021 ).…”

The constellation of cholesterol-dependent processes associated with SARS-CoV-2 infection

“…T lymphocytes from COVID-19 patients have been found to contain SARS-CoV-2 RNA and viral antigen, and SARS-CoV-2 induces marked lymphopenia, suggesting that these cells are targets of the coronavirus. Using ACE2 knockdown or receptor blocking experiments, Shen and coworkers recently found that SARS-CoV-2 infection of T lymphocytes is spike-ACE2/TMPRSS2-independent [ 61 ]. Another ACE2-independent mechanism of SARS-CoV-2 internalisation has recently been reported by Liu and coworkers, who showed that upon initial contact with ACE2 in cells of the respiratory tract, cell invasion by SARS-CoV-2 proceed via the ubiquitous cell-surface integrin α5β2 [ 62 ].…”

T Lymphocytes as Targets for SARS-CoV-2

“…In March 2022, Shen et al presented a study in which they used an expanded range of methods to confi rm the previously obtained data [40]. Thus, the presence of the SARS-CoV-2 antigen (nucleocapsid protein, N protein) has been shown in peripheral blood T lymphocytes (CD3 + cells) and post-mortem lung sections of COVID-19 patients [40]. Moreover, the level of N protein in CD4 + T lymphocytes of the patients' peripheral blood was signifi cantly higher than that in CD8 + T cells.…”