Platelets in Immune Response to Virus and Immunopathology of Viral Infections

Abstract

Platelets are essential effector cells in hemostasis. Aside from their role in coagulation, platelets are now recognized as major inflammatory cells with key roles in the innate and adaptive arms of the immune system. Activated platelets have key thromboinflammatory functions linking coagulation to immune responses in various infections, including in response to virus. Recent studies have revealed that platelets exhibit several pattern recognition receptors (PRR) including those from the toll-like receptor, NOD-like receptor, and C-type lectin receptor family and are first-line sentinels in detecting and responding to pathogens in the vasculature. Here, we review the main mechanisms of platelets interaction with viruses, including their ability to sustain viral infection and replication, their expression of specialized PRR, and activation of thromboinflammatory responses against viruses. Finally, we discuss the role of platelet-derived mediators and platelet interaction with vascular and immune cells in protective and pathophysiologic responses to dengue, influenza, and human immunodeficiency virus 1 infections.

Keywords: HIV infection; dengue; immunology and virology; influenza; platelet; viruses.

Figure 1

Platelet interaction with viruses and virus-related pathogen-associated molecular patterns (PAMPs): schematic representation of the main receptors and pathways involved in virus binding and internalization, and pattern recognition receptor involved in recognition of viral PAMP by platelets. See text for details and references.

Figure 2

Platelets participate in inflammatory, virologic, and prothrombotic responses in HIV infection: (A) platelets from HIV-infected subjects have increased activation at baseline and hyperreactive aggregation under suboptimal prothrombotic stimuli. Activated platelets also form aggregates with CD16⁺ inflammatory monocytes and HLADR⁺CD38⁺ memory T cells in people living with HIV. HIV-infected subjects undertaken antiplatelet therapy with aspirin had reduced platelet activation, platelet hyperreactivity, and platelet–monocyte aggregates, as well as reduced activation of monocytes (sCD14) and T cells (HLADR⁺CD38⁺). (B) Platelets infected with high inoculum of reporter lentivirus are able to trans-infect susceptible T cells in vitro. Activated platelets can also inhibit human immunodeficiency virus 1 infection through the secretion of the HIV suppressive chemokines PF4/CXCL4 and RANTES/CCL5. (C) Platelet-derived CD40L plays a major role in HIV-associated neurocognitive disorders. Platelet-derived CD40L increases blood–brain barrier permeability and adhesion of GR1⁺CCR2⁺ leukocytes on brain microvasculature. CD40L-activated platelets induce monocyte migration though brain microvascular endothelial cells, and platelet–monocyte aggregates accumulate in brain microvasculature and parenchyma. Activated monocytes and microglia are more sensitive to CD40L-induced TNF-α secretion, which contributes to neuronal apoptosis. See the text for details and references.

Figure 3

Platelets in dengue pathogenesis. (A) Peripheral mechanisms of thrombocytopenia in dengue: (i) platelet–leukocyte aggregates are formed with monocytes, lymphocytes, and neutrophils in the circulation of dengue patients; (ii) increased platelet sequestration in the liver of patients with dengue hemorrhagic fever/dengue shock syndrome and clearance of apoptotic platelets by resident macrophages through phosphatidylserine-mediated phagocytosis; and (iii) platelet adhesion and platelet clot formation on microvascular bed at the periphery may all contribute to thrombocytopenia in dengue. (B) Contributions of platelet activation and thrombocytopenia to inflammatory amplification and increased vascular permeability in dengue: (i) thrombocytopenia and reduced levels of platelet-derived endothelium-stabilizing factors alongside increased production of pro-inflammatory vasoactive factors by activated platelets that remain in circulation may contribute to dengue-associated vasculopathy; (ii) platelet synthesis of IL-1β and release of IL-1β-containing microparticles (MPs) associate with increased vascular permeability in dengue patients, and IL-1-β-rich MPs shed from dengue virus-infected platelets increase endothelial permeability in vitro; activated platelets from dengue-infected patients also induce pro-inflammatory cytokine secretion by monocytes. See the text for details and references.

Figure 4

Platelet activation and infiltration to airways in influenza pneumonia: pulmonary edema and microvascular thrombosis with platelet–fibrin clot deposition in areas of disrupted alveolar-capillary barrier integrity are histopathological features of influenza pneumonia. Platelets, platelet–platelet aggregates, and platelet–neutrophil aggregates have been also detected in extravascular space in the lungs, and platelet–monocyte aggregates have been demonstrated in circulation. Activated platelets secrete serotonin, sCD40L, sP-selectin, and PF4 in the airways. Platelet activation is involved in pathophysiologic mechanisms of lung injury and pulmonary edema in influenza. On the other hand, platelet secretion of PF4 is an essential mechanism for neutrophil recruitment to the lungs and innate immunity against influenza virus. See the text for details and references.