Platelet gene expression and function in patients with COVID-19.

Platelets are anucleate cells produced by megakaryocytes. In recent years, a robust body of literature supports the evolving role of platelets as key sentinel and effector cells in infectious diseases, especially critical in bridging hemostatic, inflammatory, and immune continuums. Upon intravascular pathogen invasion, platelets can directly sense viral, parasitic, and bacterial infections through pattern recognition receptors and integrin receptors or pathogen: immunoglobulin complexes through Fc and complement receptors-although our understanding of these interactions remains incomplete. Constantly scanning for areas of injury or inflammation as they circulate in the vasculature, platelets also indirectly respond to pathogen invasion through interactions with leukocytes and the endothelium. Following antigen recognition, platelets often become activated. Through a diverse repertoire of mechanisms, activated platelets can directly sequester or kill pathogens, or facilitate pathogen clearance by activating macrophages and neutrophils, promoting neutrophil extracellular traps (NETs) formation, forming platelet aggregates and microthrombi. At times, however, platelet activation may also be injurious to the host, exacerbating inflammation and promoting endothelial damage and thrombosis. There are many gaps in our understandings of the role of platelets in infectious diseases. However, with the emergence of advanced technologies, our knowledge is increasing. In the current review, we mainly discuss these evolving roles of platelets under four different infectious pathogen infections, of which are dengue, malaria, Esterichia coli (E. coli) and staphylococcus aureus S. aureus, highlighting the complex interplay of these processes with hemostatic and thrombotic pathways.

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The Era of Thromboinflammation: Platelets Are Dynamic Sensors and Effector Cells During Infectious Diseases.

Coronavirus Disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has affected over 30 million globally to date. Although high rates of venous thromboembolism and evidence of COVID-19-induced endothelial dysfunction have been reported, the precise aetiology of the increased thrombotic risk associated with COVID-19 infection remains to be fully elucidated. Therefore, we assessed clinical platelet parameters and circulating platelet activity in patients with severe and nonsevere COVID-19. An assessment of clinical blood parameters in patients with severe COVID-19 disease (requiring intensive care), patients with nonsevere disease (not requiring intensive care), general medical in-patients without COVID-19, and healthy donors was undertaken. Platelet function and activity were also assessed by secretion and specific marker analysis. We demonstrated that routine clinical blood parameters including increased mean platelet volume (MPV) and decreased platelet:neutrophil ratio are associated with disease severity in COVID-19 upon hospitalisation and intensive care unit (ICU) admission. Strikingly, agonist-induced ADP release was 30- to 90-fold higher in COVID-19 patients compared with hospitalised controls and circulating levels of platelet factor 4 (PF4), soluble P-selectin (sP-selectin), and thrombopoietin (TPO) were also significantly elevated in COVID-19. This study shows that distinct differences exist in routine full blood count and other clinical laboratory parameters between patients with severe and nonsevere COVID-19. Moreover, we have determined all COVID-19 patients possess hyperactive circulating platelets. These data suggest abnormal platelet reactivity may contribute to hypercoagulability in COVID-19 and confirms the role that platelets/clotting has in determining the severity of the disease and the complexity of the recovery path.

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COVID-19 induces a hyperactive phenotype in circulating platelets.

Platelets are chief cells in hemostasis. Apart from their hemostatic roles, platelets are major inflammatory effector cells that can influence both innate and adaptive immune responses. Activated platelets have thromboinflammatory functions linking hemostatic and immune responses in several physiological and pathological conditions. Among many ways in which platelets exert these functions, platelet expression of pattern recognition receptors (PRRs), including TLR, Nod-like receptor, and C-type lectin receptor families, plays major roles in sensing and responding to pathogen-associated or damage-associated molecular patterns (PAMPs and DAMPs, respectively). In this review, an increasing body of evidence is compiled showing the participation of platelet innate immune receptors, including PRRs, in infectious diseases, sterile inflammation, and cancer. How platelet recognition of endogenous DAMPs participates in sterile inflammatory diseases and thrombosis is discussed. In addition, platelet recognition of both PAMPs and DAMPs initiates platelet-mediated inflammation and vascular thrombosis in infectious diseases, including viral, bacterial, and parasite infections. The study also focuses on the involvement of innate immune receptors in platelet activation during cancer, and their contribution to tumor microenvironment development and metastasis. Finally, how innate immune receptors participate in platelet communication with leukocytes, modulating leukocyte-mediated inflammation and immune functions, is highlighted. These cell communication processes, including platelet-induced release of neutrophil extracellular traps, platelet Ag presentation to T-cells and platelet modulation of monocyte cytokine secretion are discussed in the context of infectious and sterile diseases of major concern in human health, including cardiovascular diseases, dengue, HIV infection, sepsis, and cancer.

Innate immune receptors in platelets and platelet-leukocyte interactions.

Background Dengue is an arboviral disease caused by dengue virus. Symptomatic dengue infection causes a wide range of clinical manifestations, from mild dengue fever (DF) to potentially fatal disease, such as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). We conducted a literature review to analyze the risks of DHF and current perspectives for DHF prevention and control. Methods According to the PRISMA guidelines, the references were selected from PubMed, Web of Science and Google Scholar database using search strings containing a combination of terms that included dengue hemorrhagic fever, pathogenesis, prevention and control. Quality of references were evaluated by independent reviewers. Results DHF was first reported in the Philippines in 1953 and further transmitted to the countries in the region of South-East Asia and Western Pacific. Plasma leakages is the main pathophysiological hallmark that distinguishes DHF from DF. Severe plasma leakage can result in hypovolemic shock. Various factors are thought to impact disease presentation and severity. Virus virulence, preexisting dengue antibodies, immune dysregulation, lipid change and host genetic susceptibility are factors reported to be correlated with the development of DHF. However, the exact reasons and mechanisms that triggers DHF remains controversial. Currently, no specific drugs and licensed vaccines are available to treat dengue disease in any of its clinical presentations. Conclusion This study concludes that antibody-dependent enhancement, cytokine dysregulation and variation of lipid profiles are correlated with DHF occurrence. Prompt diagnosis, appropriate treatment, active and continuous surveillance of cases and vectors are the essential determinants for dengue prevention and control.

Dengue Hemorrhagic Fever- A Systemic Literature Review of Current Perspectives on Pathogenesis, Prevention and Control

Dengue virus (DENV) infection, the most common mosquito-transmitted viral infection, can cause a range of diseases from self-limiting dengue fever to life-threatening dengue hemorrhagic fever and shock syndrome. Thrombocytopenia is a major characteristic observed in both mild and severe dengue disease and is significantly correlated with the progression of dengue severity. Previous studies have shown that DENV nonstructural protein 1 (NS1), which can be secreted into patients' blood, can stimulate immune cells via Toll-like receptor 4 (TLR4) and can cause endothelial leakage. However, it is unclear whether DENV NS1 can directly induce platelet activation or cause thrombocytopenia during DENV infection. In this study, we first demonstrated that DENV but not Zika virus cell culture supernatant could induce P-selectin expression and phosphatidylserine (PS) exposure in human platelets, both of which were abolished when NS1 was depleted from the DENV supernatant. Similar results were found using recombinant NS1 from all four serotypes of DENV, and those effects were blocked in the presence of anti-NS1 F(ab')2, anti-TLR4 antibody, a TLR4 antagonist (Rhodobacter sphaeroides lipopolysaccharide, LPS-Rs) and a TLR4 signaling inhibitor (TAK242), but not polymyxin B (an LPS inhibitor). Moreover, the activation of platelets by DENV NS1 promoted subthreshold concentrations of adenosine diphosphate (ADP)-induced platelet aggregation and enhanced platelet adhesion to endothelial cells and phagocytosis by macrophages. Finally, we demonstrated that DENV-induced thrombocytopenia and hemorrhage were attenuated in TLR4 knockout and wild-type mice when NS1 was depleted from DENV supernatant. Taken together, these results suggest that the binding of DENV NS1 to TLR4 on platelets can trigger its activation, which may contribute to thrombocytopenia and hemorrhage during dengue infection.

Wei Chueh Wu

Papers

Dengue virus nonstructural protein 1 activates platelets via Toll-like receptor 4, leading to thrombocytopenia and hemorrhage.