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

Abstract

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.

Keywords: bacteria; dengue; infection; inflammation; malaria; platelet; sepsis; thromboinflammation.

Figure 1

Platelets are key sentinel and effector cells during dengue infection. Platelets can directly bind dengue virus (DENV) and virus: IgG immune complexes through DC-SIGN and other receptors as listed. This binding leads to altered gene and protein expression in platelets and the activation of platelets. Some of these responses include the expression of IFITM3, assembly of NLRP3 inflammasomes, production and release of IL-1β, secretion of α-granule and dense granule contents, translocation of P-selectin to the platelet surface (allowing platelet-leukocyte interactions and signaling), and integrin α_IIbβ₃ activation. Changes in platelets further trigger the platelet aggregation and thrombosis, endothelial inflammation and vascular leakage, and monocyte activation and cytokine production, and more. These responses span the classic pathogenesis of thrombosis and inflammation, and may contribute to hemorrhagic symptoms and shock in some patients.

Figure 2

Platelet activities during malaria infection. During malaria infection, platelets may be found in the vasculature closely surrounding plasmodium-infected RBCs (PRBCs) or interacting with monocytes (platelet-monocyte aggregates) or lymphocytes. Toxins generated during malaria infection (e.g., hemozoin) may active platelets. Platelet interactions with monocytes trigger pro-inflammatory cytokine synthesis by monocytes. Figure is adapted from Rondina et al. (94) with permission obtained from Elsevier.

Figure 3

Activated platelets induce formation of neutrophil extracellular traps (NETs). (A) Platelets are commonly activated during Gram-negative bacteria infections, and express multiple receptors that could facilitate the process of NET formation (NETosis), such as P-selectin_. The lattices of chromatin, histones, and granule enzymes (NETs) play a critical role in pathogen clearance and may also induce thromboinflammatory responses, potentially contributing to vascular and tissue injury. (B) Activated platelets interact with monocytes, inducing the synthesis of inflammatory mediators. (C) Upper panel: isolated human platelets and monocytes incubated under control conditions. Lower panel: formation of platelet-monocyte aggregates and nuclear translocation of nuclear factor kappa B (NF-κB) in monocytes when the platelets were activated with nanomolar concentrations of thrombin. Figure is adapted from Rondina et al. (94) with permission obtained from Elsevier.

Figure 4

Platelets sequester S. aureus and promote thromboinflammation. (A) Confocal and (B) transmission electron microscopy of cultured staphylococcus aureus (Sa) incubated in the presence (right panels) or absence of platelets (P, time = 240 min). (C) Differential interference contrast (left panel) and transmission electron (right panel) microscopy of clusters of S. aureus (Sa, white arrows) surrounded by platelets (P). Scale bars = 5 μm. After sequestration of S. aureus, platelets become activated, form aggregates in vitro and microthrombosis in vivo, interact with macrophages and neutrophils, trigger NETs formation, and also shuttle bacteria to splenic dendritic cells to activate CD8⁺ T cell responses. Figure adapted from Kraemer et al. (151) with permission.