Platelets and infection - an emerging role of platelets in viral infection

Abstract

Platelets are anucleate blood cells that play a crucial role in the maintenance of hemostasis. While platelet activation and elevated platelet counts (thrombocytosis) are associated with increased risk of thrombotic complications, low platelet counts (thrombocytopenia) and several platelet function disorders increase the risk of bleeding. Over the last years, more and more evidence has emerged that platelets and their activation state can also modulate innate and adaptive immune responses and low platelet counts have been identified as a surrogate marker for poor prognosis in septic patients. Viral infections often coincide with platelet activation. Host inflammatory responses result in the release of platelet activating mediators and a pro-oxidative and pro-coagulant environment, which favors platelet activation. However, viruses can also directly interact with platelets and megakaryocytes and modulate their function. Furthermore, platelets can be activated by viral antigen-antibody complexes and in response to some viruses B-lymphocytes also generate anti-platelet antibodies. All these processes contributing to platelet activation result in increased platelet consumption and removal and often lead to thrombocytopenia, which is frequently observed during viral infection. However, virus-induced platelet activation does not only modulate platelet count but also shape immune responses. Platelets and their released products have been reported to directly and indirectly suppress infection and to support virus persistence in response to certain viruses, making platelets a double-edged sword during viral infections. This review aims to summarize the current knowledge on platelet interaction with different types of viruses, the viral impact on platelet activation, and platelet-mediated modulations of innate and adaptive immune responses.

Keywords: immune response; platelets; thrombocytopenia; thrombosis; viruses.

Figure 1

Mechanisms of virus-induced thrombocytopenia: thrombocytopenia occurs either via decreased platelet production or increased platelet destruction. Viruses can trigger a decrease in platelet production by (I) infection of megakaryocytes, which can lead to (A) apoptosis of megakaryocytes, (B) decreased maturation and ploidy of megakaryocytes, or (C) decreased expression of thrombopoietin receptor c-Mpl. Viruses can also infect hematopoietic stem cells (II), which results (A) in a decrease of progenitor cells and (B) the induction of growth deficient megakaryocyte colony forming units, due to disturbed cytokine production by the infected cells in the bone marrow. Viruses can further indirectly influence platelet production (III) via induction of IFNα/β, which suppresses proplatelet formation or (IV) by targeting and modulating liver functions, which are important for the production of megakaryocyte growth and development factor thrombopoietin. Another mechanism for how viruses cause thrombocytopenia is by favoring platelet destruction, which frequently occurs during viremia. Viruses can either (V) directly interact with platelets or (VI) platelets recognize immunocomplexes of IgGs and viral antigens. Antiviral antigens often show cross-reactivity with platelet surface integrins (VII), which provides another mechanism of virus-induced destruction of platelets. The virus-induced pro-inflammatory environment itself often leads to further platelet activation in viremic patients (VIII). Additionally, changes in the portal vein pressure (IX) and an enlarged spleen (X) can serve as trigger for platelet activation. Once activated, platelets are recognized by circulating leukocytes or by cells in spleen and liver and rapidly cleared from the circulation. IFN, interferon, TPO, thrombopoietin; FcγRII, Fc receptor γ R II.

Figure 2

Platelet receptors for viruses: platelets and viruses can directly interact via a plethora of surface receptors. CMV binds to platelets via TLR2, EMCV interacts via TLR7, rotavirus utilizes GPIa/IIa to bind to platelets and hantavirus and adenovirus interact with platelets via GPIIb/IIIa. EBV–platelet interaction occurs via CR2. HIV and DV bind to lectin receptors such as CLEC-2 and DC-SIGN. HIV further interacts with CXCR4 and CCL3 and CCL5. Platelets express the Coxsackie virus-specific receptor, CAR, and HCV interacts with platelets via GPVI. CAR, Coxsackie-adenovirus receptor; CLEC-2, C-type lectin domain family 2; CCL, chemokine (C–C motif) ligand; CMV, cytomegalovirus; CR, complement receptor; CXCR4, C–X–C chemokine receptor type 4; EBV, Epstein–Barr virus; EMCV, encephalomyocarditis virus; DC-SIGN, dendritic cell-specific intercellular adhesion molecule-3-grapping non-integrin; DV, Dengue virus; FcγRII, Fc receptor γ II; GP, glycoprotein; HCV, hepatitis virus C; HIV, human immunodeficient virus; IgG, immunoglobulin G; TLR, toll-like receptor;

Figure 3

Effects of activated platelets on virus infection: upon activation, platelets release their α-granules, containing high amounts of CXCL4, which up-regulates coagulation and leukocyte recruitment. Moreover, CXCL4 decreases HIV infection but also enhances liver fibrosis. CCL5, another α-granule-derived chemokine, also decreases HIV infection and enhances T_h1 lymphocyte responses in HCV infection and serves as a survival signal for macrophages in influenza infection. Platelets release PMPs and β-defensins from their α-granules, which mediate virus neutralization. They protect splenocytes from necrosis in LCMV infection. Platelet dense granules contain 5-HT, which enables liver regeneration but also HBV and HCV infection. Platelet activation leads to the expression and release of CD154 and CD62P, which allow direct interaction between platelets and leukocytes. Platelet interaction with B-lymphocytes enhances germinal center formation and antiviral IgG production. Platelets trigger T-lymphocyte differentiation and cytotoxicity as well as survival and differentiation of monocytes. In neutrophils, platelet adhesion stimulates ROS production and boosts phagocytosis. Platelet interaction with dendritic cells promotes their maturation and facilitates antigen presentation. Finally, platelet activation results in interaction and activation of further platelets, which triggers platelet aggregation and amplifies the above described processes. CCL5, chemokine (C–C motif) ligand 5; CXCL4, C–X–C chemokine ligand 4, GP, glycoprotein; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficient virus; IgG, immunglobulin G; LCMV, lymphocytic choriomeningitis; PMPs, Platelet antimicrobial peptides; PSGL-1, P-selectin (CD62P) glycoprotein ligand-1; sCD154, soluble CD154/CD40 ligand; Th1, T-helper lymphocyte type 1; 5-HT, serotonin.

Figure 4

Adverse effects of platelets in viral infections: platelets can shelter viruses like HIV, HVC, HBV, and influenza and facilitate their transportation throughout the circulation, thereby enabling de novo infections at distal sites. Platelet–virus interaction often results in platelet activation and subsequent release of α-granules and dense granules. CXCL4 from α-granules has been demonstrated to enhance HIV infection of macrophages and enhance liver fibrosis in hepatitis. CCL5 enhances T-lymphocyte recruitment and thereby promotes HIV infection of T-lymphocytes. Dense granule-derived 5-HT was shown to boost HBV and HCV infection by decreasing the entry of cytotoxic T-lymphocytes. Direct interaction of platelets with leukocytes facilitates infection of leukocytes and enhances both leukocyte activation and inflammation. Activation of platelets leads to activation and recruitment of further platelets and enhances pro-coagulatory processes.CCL5, chemokine (C–C motif) ligand 5; CXCL4, C–X–C chemokine ligand 4, GP, glycoprotein; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficient virus; sCD154, soluble CD154/CD40 ligand; 5-HT, serotonin.