Distinctive Roles of Furin and TMPRSS2 in SARS-CoV-2 Infectivity

Essalmani, Rachid; Jain, Jaspreet; Susan‐Resiga, Delia; Andréo, Ursula; Evagelidis, Alexandra; Derbali, Rabeb Mouna; Huynh, David; Dallaire, Frédéric; Laporte, Mélanie; Delpal, Adrien; Sutto-Ortiz, Priscila; Coutard, Bruno; Mapa, Claudine; Wilcoxen, Keith; Decroly, Étienne; Pham, Tram N. Q.; Cohen, Éric A.; Seidah, Nabil G.

doi:10.1128/jvi.00128-22

Cited by 106 publications

(141 citation statements)

References 75 publications

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“…This conclusion was later supported by a large meta-analysis that suggested that statins significantly reduce the risk of adverse outcomes of COVID-19 [75]. While the convertase Furin plays a key role in SARS-CoV-2 infection by activating its spike glycoprotein [76], no association between plasma PCSK9 levels and the severity of COVID-19 infection and associated inflammation is yet available. Therefore, randomized clinical trials are urgently needed to establish the usefulness of routine combined use of statins and PCSK9 inhibitors in the treatment of SARS-CoV-2 or other coronavirus infections and their associated cardiovascular complications.…”

Section: Pcsk9 In Viral Infectionsmentioning

confidence: 99%

Expanding Biology of PCSK9: Roles in Atherosclerosis and Beyond

Seidah

Garçon

2022

Curr Atheroscler Rep

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Purpose of Review Since the discovery of PCSK9 in 2003, this proprotein convertase was shown to target specific receptors for degradation in endosomes/lysosomes, including LDLR and other family members and hence to enhance the levels of circulating LDL-cholesterol (LDLc). Accordingly, inhibitors of PCSK9, including monoclonal antibodies blocking its circulating activity and siRNA silencers of its hepatic expression, are now used in clinics worldwide to treat hypercholesterolemia patients effectively and safely in combination with statins and/or ezetimibe. These powerful treatments reduce the incidence of atherosclerosis by at least 20%. Since 2008, novel targets of PCSK9 began to be defined, thereby expanding its roles beyond LDLc regulation into the realm of inflammation, pathogen infections and cellular proliferation in various cancers and associated metastases. Recent Findings Some pathogens such as dengue virus exploit the ability of PCSK9 to target the LDLR for degradation to enhance their ability to infect cells. Aside from increasing the degradation of the LDLR and its family members VLDLR, ApoER2 and LRP1, circulating PCSK9 also reduces the levels of other receptors such as CD36 (implicated in fatty acid uptake), oxidized LDLR receptor (that clears oxidized LDLc) as well as major histocompatibility class-I (MHC-I) receptors (implicated in the immune response to antigens). Thus, these novel targets provided links between PCSK9 and inflammation/ atherosclerosis, viral infections and cancer/metastasis. The functional activities of PCSK9, accelerated the development of novel therapies to inhibit PCSK9 functions, including small molecular inhibitors, long-term vaccines, and possibly CRISPRbased silencing of hepatic expression of PCSK9. Summary The future of inhibitors/silencers of PCSK9 function or expression looks bright, as these are expected to provide a modern armamentarium to treat various pathologies beyond hypercholesterolemia and its effects on atherosclerosis.

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Section: Pcsk9 In Viral Infectionsmentioning

confidence: 99%

Expanding Biology of PCSK9: Roles in Atherosclerosis and Beyond

Seidah

Garçon

2022

Curr Atheroscler Rep

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“…Viral entry is also dependent on the activity of cathepsin B/L which can be a substitute for TMPRSS. Then, virus recognition occurs when the S protein interacts with the membrane protease, which facilitates membrane fusion at the plasma membrane [ 61 , 62 ].…”

Section: Resultsmentioning

confidence: 99%

Role of Dipeptidyl Peptidase-4 (DPP4) on COVID-19 Physiopathology

et al. 2022

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DPP4/CD26 is a single-pass transmembrane protein with multiple functions on glycemic control, cell migration and proliferation, and the immune system, among others. It has recently acquired an especial relevance due to the possibility to act as a receptor or co-receptor for SARS-CoV-2, as it has been already demonstrated for other coronaviruses. In this review, we analyze the evidence for the role of DPP4 on COVID-19 risk and clinical outcome, and its contribution to COVID-19 physiopathology. Due to the pathogenetic links between COVID-19 and diabetes mellitus and the hyperinflammatory response, with the hallmark cytokine storm developed very often during the disease, we dive deep into the functions of DPP4 on carbohydrate metabolism and immune system regulation. We show that the broad spectrum of functions regulated by DPP4 is performed both as a protease enzyme, as well as an interacting partner of other molecules on the cell surface. In addition, we provide an update of the DPP4 inhibitors approved by the EMA and/or the FDA, together with the newfangled approval of generic drugs (in 2021 and 2022). This review will also cover the effects of DPP4 inhibitors (i.e., gliptins) on the progression of SARS-CoV-2 infection, showing the role of DPP4 in this disturbing disease.

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“…Theoretically, any spike-specific CD4 T cells should be able to help B cells that are able to take up spike protein via specificity for RBD. However, spike protein is very large and is designed to be cleaved during viral entry into target cells, involving multiple proteases (52)(53)(54), so it is possible that spike available for B cell recognition in germinal centres may also be cleaved to smaller protein fragments, only some of which link B cell and T cell epitopes around RBD. Clearly this needs further study with defined epitopes, along with the clonal relationships between germinal centre Tfh cells during acute infection and memory cells during convalescence.…”

Section: Discussionmentioning

confidence: 99%

High titre neutralizing antibodies in response to SARS-CoV-2 infection require RBD-specific CD4 T cells that include proliferative memory cells

Phetsouphanh

Khoo

Jackson

et al. 2022

Preprint

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Long-term immunity to SARS-CoV-2 infection, including neutralizing antibodies and T cell-mediated immunity, is required in a very large majority of the population in order to reduce ongoing disease burden. We have investigated the association between memory CD4 and CD8 T cells and levels of neutralizing antibodies in convalescent COVID-19 subjects. Higher titres of convalescent neutralizing antibodies were associated with significantly higher levels of RBD-specific CD4 T cells, including specific memory cells that proliferated vigorously in vitro. Conversely, up to half of convalescent individuals had low neutralizing antibody titres together with a lack of receptor binding domain (RBD)-specific memory CD4 T cells. These low antibody subjects had other, non-RBD, spike-specific CD4 T cells, but with more of an inhibitory Foxp3+ and CTLA-4+ cell phenotype, rather than the effector T-bet+, cytotoxic granzymes+ and perforin+ cells seen in high antibody subjects. Single cell transcriptomics of antigen-specific CD4+ T cells from high antibody subjects revealed heterogenous RBD-specific CD4+ T cells that comprised central memory, transitional memory and Tregs, as well as cytotoxic clusters containing diverse TCR repertoires, that were absent in individuals with low antibody levels. However, vaccination in low antibody convalescent individuals led to a slight but significant improvement in RBD-specific memory CD4 T cells and increased neutralizing antibody titres. Our results suggest that targeting CD4 T cell epitopes proximal to and within the RBD-region should be prioritized in booster vaccines.

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Distinctive Roles of Furin and TMPRSS2 in SARS-CoV-2 Infectivity

Abstract: SARS-CoV-2, the etiological agent of COVID-19, has so far resulted in >6.1 million deaths worldwide. The spike protein (S) of the virus directs infection of the lungs and other tissues by binding the angiotensin-converting enzyme 2 (ACE2) receptor.

Cited by 106 publications

References 75 publications

Expanding Biology of PCSK9: Roles in Atherosclerosis and Beyond

Expanding Biology of PCSK9: Roles in Atherosclerosis and Beyond

Role of Dipeptidyl Peptidase-4 (DPP4) on COVID-19 Physiopathology

High titre neutralizing antibodies in response to SARS-CoV-2 infection require RBD-specific CD4 T cells that include proliferative memory cells

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