Human megakaryocytes possess intrinsic antiviral immunity through regulated induction of IFITM3

Abstract

Evolving evidence indicates that platelets and megakaryocytes (MKs) have unexpected activities in inflammation and infection; whether viral infections upregulate biologically active, antiviral immune genes in platelets and MKs is unknown, however. We examined antiviral immune genes in these cells in dengue and influenza infections, viruses that are global public health threats. Using complementary biochemical, pharmacological, and genetic approaches, we examined the regulation and function of interferon-induced transmembrane protein 3 (IFITM3), an antiviral immune effector gene not previously studied in human platelets and MKs. IFITM3 was markedly upregulated in platelets isolated from patients during clinical influenza and dengue virus (DENV) infections. Lower IFITM3 expression in platelets correlated with increased illness severity and mortality in patients. Administering a live, attenuated DENV vaccine to healthy subjects significantly increased platelet IFITM3 expression. Infecting human MKs with DENV selectively increased type I interferons and IFITM3. Overexpression of IFITM3 in MKs was sufficient to prevent DENV infection. In naturally occurring, genetic loss-of-function studies, MKs from healthy subjects harboring a homozygous mutation in IFITM3 (rs12252-C, a common single-nucleotide polymorphism in areas of the world where DENV is endemic) were significantly more susceptible to DENV infection. DENV-induced MK secretion of interferons prevented infection of bystander MKs and hematopoietic stem cells. Thus, viral infections upregulate IFITM3 in human platelets and MKs, and IFITM3 expression is associated with adverse clinical outcomes. These observations establish, for the first time, that human MKs possess antiviral functions, preventing DENV infection of MKs and hematopoietic stem cells after local immune signaling.

Platelets Can Associate With SARS-CoV-2 RNA and Are Hyperactivated in COVID-19

“…Dengue virus can infect megakaryocytes, 47 and megakaryocytes can upregulate type-I interferon genes in response to dengue and influenza viruses. 48 While dengue virus can replicate in platelets, 49 influenza virus can be internalized by platelets and is transported through the circulatory system in humans. 50 , 51 Influenza virus-induced lung injury in mice can be prevented by targeting of platelet αIIbβ3 by an antagonist or other antiplatelet compounds such as clopidogrel, an antagonist of ADP (adenosine diphosphate) receptors, or blockers of protease-activated receptor-4, thus pointing to an active role by platelets in influenza pathogenesis.…”

Dysregulated primary hemostasis in critically ill COVID-19 patients

“…Intriguingly, we found that the hemostasis gene signature was able to further distinguish critical from severe COVID-19 patients, underlying the hypothesis that deregulated hemostasis, in a continuum with in ammation, could drive COVID-19 progression into critical disease. Viral infection and sepsis models have been associated with platelet gene expression and functional alterations (35,36). However, some unique features may characterize SARS-CoV-2-mediated platelet dysregulation.…”

Animal models of mechanisms of SARS‐CoV‐2 infection and COVID‐19 pathology

“…Furthermore, a shift in platelet-lymphocyte ratio may indicate the occurrence of an acute inflammatory or thrombotic event and therefore have prognostic value (Qu et al, 2020). Thus, thrombocytopaenia may reflect (a) alteration in thrombopoiesis due to the bone marrow or lungs (and potentially spleen) being inflamed or receiving inflammatory and trauma-related thrombopoietic cues; (b) localised lung recruitment of platelets as a facet of their role in the immune response or alveolar coagulation; (c) disseminated intravascular coagulation (DIC) throughout the body (Xu, Zhou, & Xu, 2020); or (d) platelet-viral interaction, although this remains hypothetical as an engagement of platelets with SARS-CoV-2 has not been described (Amgalan & Othman, 2020 Results of studies in mice modelling influenza agree on the necessity for platelets in the immune response and inflammation but conflict as to whether this is beneficial (Campbell et al, 2019;Guo et al, 2017), or detrimental (Boilard et al, 2014;Lê et al, 2015). Additionally, platelets respond to influenza virus by increasing complement availability and encourage the release of NETs into blood, and so platelets may be important integrators linking viral infection to neutrophil responses that are associated with coagulopathy and venous thrombosis (Koupenova et al, 2019).…”