Platelets as Immune Cells in Infectious Diseases

Cornelia Speth; Jürgen Löffler; Sven Krappmann; Cornelia Lass-Flörl; Günter Rambach

Disclosures

Future Microbiol. 2013;8(11):1431-1451. 

In This Article

Platelets in Viral Infections

The relevance of virus–platelet interactions for the pathogenesis of viral infections can be deduced from the fact that thrombocytopenia is a common complication of a variety of viral infections; for example, by HIV, dengue virus or HCV.[125–127] Thrombocytopenia is observed as one of the first clinical signs in approximately 10–50% of HIV patients.[126] A study with Japanese HCV-patients revealed thrombocytopenia in 41% of patients with chronic hepatitis.[128] Similar to bacteria, viruses can trigger the loss of platelets by a broad spectrum of mechanisms.

Platelet Surface Molecules Interacting With Viruses

A number of platelet surface molecules mediate adhesion of viral particles, followed by either fusion between viral and cellular membranes or by endocytotic uptake. Viral particles coated with IgG can interact with the platelet receptor FcγRIIa.[129] In addition, specific receptors allow binding of viruses independently from the presence of antibodies. The C-type lectins DC-SIGN and CLEC-2, as well as chemokine receptors (e.g., CXCR4) on megakaryocytes and platelets are involved in HIV binding and in initiating endocytosis.[63,130,131] Endocytotic uptake is also described for HCV after binding to GPVI.[28] For other viruses, infection of platelets has not yet been explicitly proven; however, their known receptors were detected on platelets. Examples are the complement receptor CR2, which is the main receptor for EBV, and the glycoprotein GPIa–IIa that is known to allow attachment of rotavirus.

Mechanisms of Platelet Loss in Viral Infections

A well-described mechanism that triggers platelet loss in viral infections is immune thrombocytopenia (ITP), frequently found in patients with HIV or HCV infection.[28,126,127] In the case of pathogen-induced ITP, antiviral antibodies are produced by the host cross-reacting with glycoproteins on the platelet membrane. As a consequence, the antibody-coated platelets are cleared by the reticuloendothelial system.[132] The direct correlation between high titers of autoantibodies against platelet glycoproteins and accelerated platelet destruction in affected patients was shown for HCV.[127,133] Detailed studies identified the molecular mimicry of the HCV core envelope protein 1 with the platelet protein GPIIIa as the main reason for HCV-induced thrombocytopenia.[134]

Platelet GPIIIa, and even the same epitope within this surface protein, are also targets of autoantibodies, which are generated in HIV-infected patients. Similarly, an inverse correlation of α-GPIIIa-autoantibody titers and the platelet count was demonstrated, underlining the relevance of this immune-mediated platelet destruction. When these α-GPIIIa-antibodies were injected into mice, a severe thrombocytopenia was induced by triggering oxidative platelet fragmentation.[134]

A similar mechanism is described for dengue fever, where thrombocytopenia is one major clinical manifestation. Molecular mimicry between the viral proteins NS1, prM and E and some platelet surface proteins explains the cross-reactivity of the corresponding antibodies.[135] The level of antiplatelet autoantibodies is higher in severe dengue cases than in patients with mild fever. Binding of these autoantibodies to platelets results in dysfunction, impaired aggregation and complement-mediated cell lysis.[136]

The origin of HCV- or HIV-induced thrombocytopenia is not only based on ITP, but is generally considered to have a multifactorial origin. Other mechanisms include platelet activation with shortening of survival, splenic platelet sequestration and impaired platelet production in the bone marrow.

Virus-induced platelet activation and thus shortened survival might be triggered by direct contact to the viral surface; however, secreted viral proteins such as HIV Tat protein can also induce activation and release of microparticles,[90] thus further contributing to thrombocytopenia.

Early reports already described that HCV-infected patients with portal hypertension show platelet sequestration in the enlarged spleen and pooling of platelets.[137] This was confirmed by newer results showing an inverse correlation between spleen size and platelet count in HCV-patients.[138–140] Thus, this mechanism of platelet pooling in the spleen could further contribute to thrombocytopenia in the peripheral blood.

Viral impairment of thrombopoiesis can further augment virus-induced thrombocytopenia. HCV-associated liver dysfunction reduced production of thrombopoietin, the main cytokine governing megakaryocyte proliferation and maturation.[141] Studies demonstrated a direct correlation between fibrosis staging, reduced thrombopoietin levels and severity of thrombocytopenia.[142,143] Effective platelet production can also be impaired directly by viral infection of the megakaryocytes. HIV binds to CD4 and coreceptors expressed on immature megakaryocytes, followed by internalization of the virus.[63,144,145] HIV replication in the megakaryocytes results in dysplasia, blebbing of the surface membrane and vacuolization of peripheral cytoplasm.[146] In addition to HIV, HCV is also capable of infecting megakaryocytes; disappearance of HCV after therapy with IFN-α leads to concomitant improvement of thrombocytopenia.[147–149] Furthermore, megakaryocytes and their precursors are targets of human CMV infection; the subsequent rapid loss of viability might be one mechanism for the thrombocytopenia observed in CMV-infected patients.[150]

Further putative causes of thrombocytopenia include opportunistic infections and malignancies in HIV-infected patients, and medications against HIV or HCV.[132,142,146]

Further Consequences of Virus–Platelet Interaction

The virucidal effects of activated platelets and their PMPs are rarely and insufficiently investigated. Platelet concentrates achieve efficient inactivation of adenovirus, poliovirus and vaccinia virus.[151] Another report demonstrated that synthetic peptides derived from the PMPs PD3 and PD4 potently reduced viral titers of vaccinia virus.[152] Interestingly, the platelet-derived chemokine PF-4 is a broad-spectrum inhibitor of HIV-1,[153] which binds to the envelope protein gp120 of primary HIV variants. By blockage of virus attachment and entry, PF-4 is capable of impairing infection of both CD4 T cells and macrophages.[153] Platelets also produce significant amounts of the chemokines CCL5 (RANTES) and MIP-1,[154] which are major HIV-suppressive factors.[155]

Besides the positive effect of virus-induced platelet activation, viruses can also exploit platelets and force them to act for viral advantage (Box 2 & Figure 2). HIV particles, which are enclosed in endocytic platelet vesicles, are protected from platelet granule and PMP release, in addition to attack by other immune weapons.[25,62] Platelet-derived chemokines that are secreted after virus-induced activation might also support viral replication by chemotactically attracting new susceptible host cells to the site of infection. One example is the chemokine CCL5, that recruits monocytes and T lymphocytes,[66] which are host cells for HIV. Furthermore, platelets with endocytosed HIV particles might serve as Trojan horses, disseminating the virus within the entire human body.[25]

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