Role of Platelets in Detection and Regulation of Infection

Abstract

Platelets are classically known as essential mediators of hemostasis and thrombosis. However, in recent years, platelets have gained recognition for their inflammatory functions, which modulate the immune response during infectious diseases. Platelets contain various immunoreceptors that enable them to act as sentinels to recognize intravascular pathogens. Upon activation, platelets directly limit pathogen growth through the release of AMPs (antimicrobial proteins) and ensure pathogen clearance through activation of immune cells. However, aberrant platelet activation can lead to inflammation and thrombotic events.

Keywords: blood platelets; hemostasis; immunology; infection; inflammation.

Figure 1:. During infectious diseases, platelets sense pathogens via receptors and respond through secretion and expression of antimicrobial proteins, cytokines and adhesion molecules.

Platelets sense pathogens and host damage through recognition of pathogen- or damage-associated molecular patterns (PAMPs or DAMPs) using receptors. A) Toll-like receptors (TLRs) include surface receptors TLR2 and −4 with a broad tropism for bacterial pathogens as well as cytomegalovirus (CMV) and histones. Endosomal TLR7 and −9 recognize ssRNA viruses and unmethylated CpG DNA, respectively. TLR4 activation by NS1 or other TLR4 agonist induces splicing and synthesis of pro-IL-1ß, while caspase-1-mediated cleavage of pro-IL-1ß is activated by secondary signals. NLRP3 inflammasome activation results in the production IL-1ß-rich microparticles (MP). B) C-type lectin receptors DC-SIGN and CLEC-2 are involved in the binding of different viruses as well as the recognition of DAMPs such as hemin and mitochondrial DNA (Mt-DNA). C) Hemostatic platelet receptors GPIb, GPVI and α_IIbß₃ also interact with gram-positive and -negative bacteria either directly or indirectly using von Willebrand factor (VWF) or fibrinogen as bridging proteins. Engagement of the discussed receptors with their ligand results in the recognition of invading pathogens and triggers platelet activation and the release of α-granules. Released antimicrobial proteins such as platelet factor 4 (PF4) act as a first-line defense against the invading pathogens, killing Plasmodium parasites in infected red blood cells (RBCs) or coating gram-negative bacteria resulting in recognition of the opsonized bacterium with IgGs through FcγRIIa. Finally, surface receptors such as major histocompatibility complex class I (MHC-I) along with α-granules releasing proteins such as P-selectin and CD40L, result in recruitment and activation of both innate and adaptive immune responses.