SARS-CoV-2-associated lymphopenia: possible mechanisms and the role of CD147

Abstract

T lymphocytes play a primary role in the adaptive antiviral immunity. Both lymphocytosis and lymphopenia were found to be associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While lymphocytosis indicates an active anti-viral response, lymphopenia is a sign of poor prognosis. T-cells, in essence, rarely express ACE2 receptors, making the cause of cell depletion enigmatic. Moreover, emerging strains posed an immunological challenge, potentially alarming for the next pandemic. Herein, we review how possible indirect and direct key mechanisms could contribute to SARS-CoV-2-associated-lymphopenia. The fundamental mechanism is the inflammatory cytokine storm elicited by viral infection, which alters the host cell metabolism into a more acidic state. This "hyperlactic acidemia" together with the cytokine storm suppresses T-cell proliferation and triggers intrinsic/extrinsic apoptosis. SARS-CoV-2 infection also results in a shift from steady-state hematopoiesis to stress hematopoiesis. Even with low ACE2 expression, the presence of cholesterol-rich lipid rafts on activated T-cells may enhance viral entry and syncytia formation. Finally, direct viral infection of lymphocytes may indicate the participation of other receptors or auxiliary proteins on T-cells, that can work alone or in concert with other mechanisms. Therefore, we address the role of CD147-a novel route-for SARS-CoV-2 and its new variants. CD147 is not only expressed on T-cells, but it also interacts with other co-partners to orchestrate various biological processes. Given these features, CD147 is an appealing candidate for viral pathogenicity. Understanding the molecular and cellular mechanisms behind SARS-CoV-2-associated-lymphopenia will aid in the discovery of potential therapeutic targets to improve the resilience of our immune system against this rapidly evolving virus.

Keywords: CD147 receptor; COVID-19; Lymphopenia; T-cells SARS-CoV-2.

Fig. 1

Schematic representation of possible mechanisms of lymphopenia in SARS-CoV-2 viral infection

Fig. 2

Indirect mechanisms of SARS-CoV-2 associated lymphopenia: (1) FASL expressed on cytotoxic T-lymphocytes (CTLs) activation of the extrinsic pathway of FAS. Fas-associated death domain (FADD) adaptor with pro–caspase-8 modulates caspase-8 activation. The activation of caspase-8 regulates the proteolytic cleavage of caspase-3 and − 7, priming the extrinsic pathway of apoptosis. (2) The intrinsic apoptotic pathway is triggered by various cellular stress pathways such as oxidative stress, cytotoxic chemicals, hypoxia, ER stress, or/and DNA damage. (3) COVID-19 patients cytokine storm is derived by recognition of viral nucleic acids through TLRs in the endosome [139]

Fig. 3

Possible mechanisms of hematopoiesis and secondary lymphoid organ malfunction in SARS-CoV-2 infection. (1) direct viral infection to HSCs/ HSPCs via ACE2 dependent or/and independent manner, (2) inflammation triggered by viral infection results in assembly of NLRP3 inflammasome, which in turn leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18, and to gasdermin D-mediated (GSDMD) pyroptotic cell death [156], (3) effector cytotoxic T-cells (CTLs) release INFγ upon viral infection that is in turn promotes IL-6 secretion by MSCs, leading to boosting myeloid lineage differentiation at the expense of lymphoid lineage differentiation, (4) in the lymph nodes and spleen, SARS-CoV-2 may directly infect macrophages and dendritic cells, causing tissue damage and indirect lymphocyte depletion due to enhanced pro-inflammatory cytokines IL-6 and IL-1β secretions, (5) erythroid progenitors express several co-receptors, including ACE2, CD147, and CD26, allowing infection by SARS-CoV-2. They also cause immunosuppression of the proliferation of CD8⁺ T, CD4⁺ T, CD3⁺ T and B cells of the adaptive immune system in COVID-19 patients [151].Abbreviations; MLPs, multi-lymphoid progenitors; GMPs, granulocyte-macrophage progenitors; MMPs, multi-myeloid progenitors; MEPs, megakaryocyte erythroid progenitor. Created by Biorender.com

Fig. 4

Multiple interactions of CD147 with different partners such as MCTs, MMPs and cyclophilin facilitate the viral infection. A The upstream event of direct virus binding and invasion are not well characterized (represented as ‘?’). CD147 directly binds with the viral spike protein to enter to host cells. B CD147 acts as the major chaperone protein for MCTs increasing lactate export leading to increased blood lactate levels and disease severity in COVID-19 patients. C SARS-CoV-2 binding with CD147 increases synthesis of MMPs, allowing syncytium formation and escape from immune cells. D Cyclophilin binds to and activates CD147, leading to better interaction between the viral S protein and CD147. CypA was secreted in response to inflammatory stimuli to interact back with CD147 on the surface of T-cells. CypA makes a stable complex with Tyrosine-protein kinase (ITK) in the cytoplasm of T-cells and activates nuclear factor of activated T cells (NFAT) by downstream signaling cascade. NFAT eventually regulates gene expression and activates T-cells and cytokine generation