AC-73 and Syrosingopine Inhibit SARS-CoV-2 Entry into Megakaryocytes by Targeting CD147 and MCT4, 2024, Spinello et al.

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AC-73 and Syrosingopine Inhibit SARS-CoV-2 Entry into Megakaryocytes by Targeting CD147 and MCT4
Spinello, Isabella; Saulle, Ernestina; Quaranta, Maria Teresa; Pelosi, Elvira; Castelli, Germana; Cerio, Annamaria; Pasquini, Luca; Morsilli, Ornella; Dupuis, Maria Luisa; Labbaye, Catherine

Coagulation disorders are described in COVID-19 and long COVID patients. In particular, SARS-CoV-2 infection in megakaryocytes, which are precursors of platelets involved in thrombotic events in COVID-19, long COVID and, in rare cases, in vaccinated individuals, requires further investigation, particularly with the emergence of new SARS-CoV-2 variants. CD147, involved in the regulation of inflammation and required to fight virus infection, can facilitate SARS-CoV-2 entry into megakaryocytes. MCT4, a co-binding protein of CD147 and a key player in the glycolytic metabolism, could also play a role in SARS-CoV-2 infection.

Here, we investigated the susceptibility of megakaryocytes to SARS-CoV-2 infection via CD147 and MCT4. We performed infection of Dami cells and human CD34+ hematopoietic progenitor cells induced to megakaryocytic differentiation with SARS-CoV-2 pseudovirus in the presence of AC-73 and syrosingopine, respective inhibitors of CD147 and MCT4 and inducers of autophagy, a process essential in megakaryocyte differentiation.

Both AC-73 and syrosingopine enhance autophagy during differentiation but only AC-73 enhances megakaryocytic maturation. Importantly, we found that AC-73 or syrosingopine significantly inhibits SARS-CoV-2 infection of megakaryocytes. Altogether, our data indicate AC-73 and syrosingopine as inhibitors of SARS-CoV-2 infection via CD147 and MCT4 that can be used to prevent SARS-CoV-2 binding and entry into megakaryocytes, which are precursors of platelets involved in COVID-19-associated coagulopathy.

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See also Unconventional CD147‐dependent platelet activation elicited by SARS‐CoV‐2 in COVID‐19 (2022, Journal of Thrombosis and Haemostasis)

 

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Recent studies have reported the possibility of viral persistence as a driver of long COVID; viral proteins and/or RNA have indeed been found in lymph nodes, hepatic tissue, lung tissue, plasma, stool, and urine of some patients. Studies performed by analyzing the coagulation profile of long COVID patients have described a pro-coagulant state with an ongoing process of thrombi formation and/or persistent microthrombosis in 30% of patients after 12–18 months of follow-up, underlying the need to further investigate the etiology of COVID-19-associated coagulopathy for the early management of coagulation disorders.

However, the mechanism promoting platelet activation by SARS-CoV-2 is still not well understood. Nonetheless, the observation that megakaryocytes (including lung MKs) rather than platelets may directly interact with SARS-CoV-2 in the blood, is supported by several studies. [...] In line with previous data, we observed that SARS-CoV-2 can interact, as an alternative to ACE2, with megakaryocytes via CD147, that we found expressed in human CB and PB CD34+ HPCs, and during MK differentiation of these cells, thus indicating megakaryocytes as potential direct target of SARS-CoV-2.

Our data show that MCT4 expression increases during MK differentiation of PMA-Dami cells and CD34 + HPCs, possibly indicating an increased glycolytic metabolism in MK-differentiating HPCs. These data are in line with previous studies indicating that glucose metabolism is essential for pro-platelet formation from megakaryocytes, platelet biogenesis, and activation.

Altogether, our data indicate the glycolysis-related MCT4 as a potential new target for SARS-CoV-2 entry into megakaryocytes and platelets in vivo, which may be involved in the hypothetical reservoir for SARS-CoV-2 described in long COVID.