Keywords
platelets - virus - bacteria - thrombocytopenia - immune response
Infections, both bacterial and viral, are associated with a profound immune response
to the infecting pathogen. Platelets are important contributors to the multifaceted
response to infection, where they have the ability to modulate various immune cells.
Platelets engage the immune system through direct cell-to-cell interaction and through
the release of various soluble mediators.[1]
[2]
[3]
[4]
[5] Furthermore, platelets participate in the interaction between pathogens and host
defense.[6]
[7]
[8]
[9]
[10]
[11]
[12] In the absence of platelets, bacteremia, tissue damage, and mortality are greatly
enhanced.[13]
[14]
[15] Similarly, thrombocytopenia is associated with a dysregulated host response and
worse outcomes in sepsis patients.[16]
[17] Platelets are also active participants in the host response to viruses, and have
been shown to be protective in viral infections.[18]
[19]
[20]
Platelets possess receptors that allow them to survey for danger signals from pathogens
(pathogen-associated molecular patterns; PAMPs) and cell damage (damage-associated
molecular patterns; DAMPs), and trigger hemostatic and inflammatory responses against
bacterial and viral infections.[3]
[21]
[22] During infection, the platelet is activated, mobilized, and actively participates
in the resultant hemostatic and inflammatory responses. These signaling processes
involve many feedback loops that self-amplify initial activation,[23] and platelets can manifest dysfunction even in cases where no bacteremia is present.[10] These processes are irreversible and undoubtedly lead to consumption of the platelet.
Activation of platelets leads to their consumption into aggregates with other platelets,
leukocytes, and the endothelium.[24] Platelets with bound antibody are targets of phagocytes, and platelets with a bacterial
or viral load are sequestrated and also cleared from the circulation. Further, pathogenic
compounds induce apoptosis and cytotoxic effects in platelets.[25] In this sense, activated platelets and platelets interacting with pathogens have
shortened survival spans and experience increased destruction. The outcome for the
patient will be a decrease in normal circulating platelets, and if this manifests
widely enough it can be measured as thrombocytopenia.[3]
[25]
Other mechanisms of platelet decline in infection exist and include the formation
of autoantibodies against platelet surface proteins, which leads to clearance of immunoglobulin
G (IgG)-coated platelets by the reticuloendothelial system,[26]
[27] as well as by impaired platelet production in the bone marrow,[3]
[6] among others.[6] However, a general view of platelet destruction is the simple characteristic that
their involvement in thrombotic, hemostatic, immune, and host defense responses is
irreversible. Even if platelets are positive contributors to the host response against
invading pathogens, they can become dysfunctional, especially in the context of an
excessive and unbalanced systemic inflammatory response.[16]
[28] Indeed, the dysfunctional state of thrombocytopenia is commonly associated with
sepsis and infections.[3]
[29]
[30]
[31]
The focus of the current review is platelets and their role in infection. We will
examine the interaction of platelets, their receptors, and secretory product with
bacteria and viruses, and discuss how this may contribute to platelet dysfunction
and ultimately lead to thrombocytopenia. [Fig. 1] provides the rationale of this review and [Table 1] lists the abbreviations used in this article.
Fig. 1 Layout of the review. During infection, inflammatory stimuli, and the presence of
bacteria, viruses and their products mobilize platelets to exert their immune, antibacterial,
and antiviral actions. However, these processes can also lead to platelet dysfunction
and ultimately depletion.
Table 1
List of abbreviations
|
Abbreviation
|
Full term
|
Synonyms
|
|
αIIbβ3
|
|
GPIIb/IIIa
|
|
αMβ2
|
Macrophage-1 antigen
|
CD11b/CD18, CR3; Mac-1
|
|
cAMP
|
Cyclic adenosine monophosphate
|
|
|
CAR receptor
|
Coxsackievirus and adenovirus receptor
|
|
|
(s)CD40L
|
(Soluble) CD40 ligand
|
CD154
|
|
cGMP
|
Cyclic guanosine monophosphate
|
|
|
CR2
|
Complement receptor 2
|
CD21, C3dR
|
|
CR3
|
Complement receptor 3
|
αMβ2, CD11b/CD18, Mac-1
|
|
CR4
|
Complement receptor 4
|
αxβ2, CD11c/CD18
|
|
DAMP
|
Damage-associated molecular pattern
|
|
|
DNA
|
Deoxyribonucleic acid
|
|
|
Eap
|
Extracellular adherence protein
|
|
|
Efb
|
Extracellular fibrinogen binding protein
|
|
|
FcγRIIa
|
Low affinity immunoglobulin gamma Fc region receptor II-a
|
CD32
|
|
GPIb
|
Glycoprotein Ib
|
CD42
|
|
GPVI
|
Glycoprotein VI
|
|
|
HIV
|
Human immunodeficiency virus
|
|
|
HLA-DR
|
Human leukocyte antigen—DR isotype
|
|
|
HRgpA
|
Recombinant gingipain R1 protease (high molecular mass form)
|
|
|
Ig
|
Immunoglobulin
|
|
|
IL
|
Interleukin
|
|
|
LCMV
|
Lymphocytic choriomeningitis virus
|
|
|
LPS
|
Lipopolysaccharide
|
|
|
LTA
|
Lipoteichoic acid
|
|
|
MyD88
|
Myeloid differentiation primary response 88
|
|
|
NET
|
Neutrophil extracellular trap
|
|
|
P-selectin
|
|
CD62P, GMP-140, PADGEM
|
|
PAF
|
Platelet-activating factor
|
|
|
PAMP
|
Pathogen-associated molecular pattern
|
|
|
PAR
|
Protease-activated receptor
|
|
|
PF4
|
Platelet factor 4
|
CXCL4
|
|
PKG
|
cGMP-dependent protein kinase
|
|
|
PSGL-1
|
P-selectin glycoprotein ligand-1
|
CD162
|
|
RANTES
|
Regulated on activation, normal T-cell expressed and secreted
|
CCL5
|
|
RgpB
|
Recombinant gingipain R2 protease
|
|
|
RNA
|
Ribonucleic acid
|
|
|
ROS
|
Reactive oxygen species
|
|
|
SSL
|
Staphylococcal superantigen-like
|
|
|
TLR
|
Toll-like receptor
|
|
|
TNF
|
Tumor necrosis factor
|
|
|
TREM-1(L)
|
Triggering receptor expressed on myeloid cells 1 (ligand)
|
CD354
|
Platelet and the Immune Response to Infections
Platelet and the Immune Response to Infections
A common feature of many infections, both viral and bacterial, is a systemic inflammatory
response that involves a dysregulated proinflammatory biomarker presence in the circulation.[3]
[5]
[32] These biomarkers may include cytokines (e.g., interleukins [ILs], tumor necrosis
factor [TNF]-α, and interferons) but also molecules originating from bacteria and
viruses themselves (e.g., proteases, ribonucleic acid [RNA], and membrane components
like lipopolysaccharide [LPS], lipoteichoic acid [LTA], and viral glycoproteins).
The presence of such circulating biomarkers has profound agonistic effects on platelets.
Platelets contribute to the thromboinflammatory response through the plethora of membrane
and cytosolic molecules that they express and release, which possess hemostatic, immunomodulatory,
and inflammatory activity.[1]
[2]
[3]
[4] Platelets possess receptors that enable pathogen sensing, and which allow platelets
to regulate leukocytes and other cells at the site of infection. During platelet activation,
degranulation leads to the surface expression of receptors and the release of abundant
proinflammatory mediators, which contribute to numerous signaling events.[1]
[2]
[3]
[4]
[5] Platelets also adhere and aggregate to other platelets and to endothelial cells,
leukocytes, and erythrocytes.[5]
[9]
[24] This response is also characteristic during bacterial and viral infections, and
can be induced by pathogens directly.[33] This section describes the role of platelets in the immune response. See [Fig. 2] for a general overview of platelet receptors and secretory products.
Fig. 2 General platelet structure. Platelets express various receptors that allow them to
detect danger signals and engage other cells. Platelets are activated by various agonists
that interact with surface receptors. Platelets are also replete with secretory granules
that store bioactive molecules, which are released into the circulation or translocate
to the surface upon platelet activation. These characteristics allow platelets to
communicate and modulate the functions of other cells, and trigger hemostatic, inflammatory,
and host defense responses against infections (created with https://biorender.com/). ADP, adenosine diphosphate; CAR, coxsackievirus and adenovirus receptor; CCR/CXCR, chemokine receptor; CLEC, C-type
lectin-like receptor; CR, complement receptor; DC-SIGN, dendritic cell-specific ICAM-grabbing nonintegrin;
FcγRIIa, low-affinity immunoglobulin gamma Fc region receptor II-a; gC1Qr, receptor
for the globular heads of C1q; JAM, junction adhesion molecule; MCP, monocyte chemoattractant
protein; MHC, major histocompatibility complex; MIP, macrophage inflammatory protein;
PAFR, platelet-activating factor receptor; PAR, protease-activated receptor; PDGF,
platelet-derived growth factor; PF, platelet factor; RANTES, regulated on activation,
normal T-cell expressed and secreted; TGF, transforming growth factor; TLR, toll-like
receptor; TNSF14, tumor necrosis factor superfamily member 14; TREM, triggering receptor
expressed on myeloid cells; vWF, von Willebrand factor.
Platelet–Endothelium Interactions: Endowing a Proinflammatory Phenotype
Endothelial activation markers are raised during infection, and are associated with
a thrombotic state.[34] During activation, platelets can bind to the endothelium.[24] This especially occurs upon endothelial damage due to trauma or microbial colonization,[35] as well as in viral infections.[36] Platelets become activated during the adhesion process, and the inflammatory and
mitogenic substances that are released alter the chemotactic, adhesive, and proteolytic
properties of endothelial cells.[37] Platelet adhesion therefore endows the endothelium with a proinflammatory phenotype.[24] Moreover, platelets that are bound to the endothelium can form a bridging connection
with circulating leukocytes.[24] Overall, these mechanisms amplify and facilitate leukocyte recruitment and enhance
inflammation. [Fig. 3] provides an overview of the contact between platelets and cells at the vascular
wall to emphasize the involvement of platelets in multiple interactions at the vessel
wall.
Fig. 3 Platelet interactions at the vascular wall. Platelet activation and adhesion to the
vascular wall is facilitated by various receptor interactions with endothelial cells.
An inflamed vessel wall will adopt a prothrombotic phenotype and release platelet
binding and stimulating agents. The adhesion of platelets activates endothelial cells,
and together with potent inflammatory mediators released by platelets induces the
expression of integrins, adhesion molecules, and other receptors on the endothelial
surface, as well as causes the endothelium to secrete chemokines and other mediators.
Platelets similarly bind and activate leukocytes, contributing to leukocyte recruitment
to the endothelium. In turn, leukocytes are activated and are able to adhere to the
inflamed vessel, with platelets also serving as bridging connections between the endothelium
and circulating leukocytes (created with https://biorender.com/). (Adapted from van Gils et al[24].) ADP, adenosine diphosphate; GM-CSF, granulocyte-macrophage colony-stimulating
factor; ICAM, intercellular adhesion molecule; IL, interleukin; JAM, junction adhesion
molecule; MCP, monocyte chemoattractant protein; MMP, matrix metalloproteinase; MTP1-MMP,
membrane type-1 MMP; PF, platelet factor; PSGL, P-selectin glycoprotein ligand-1;
RANTES, regulated on activation, normal T-cell expressed and secreted; ROS, reactive
oxygen species; TNSF14(R), tumor necrosis factor superfamily member 14 (receptor);
tPA, tissue plasminogen activator; TREM, triggering receptor expressed on myeloid
cells; uPA, urokinase-type plasminogen activator; uPAR, urokinase receptor; VCAM,
vascular cell adhesion protein; vWF, von Willebrand factor.
Platelet–Leukocyte Interactions: Promoting Immune Cell Effector Functions against
Pathogens
Interactions between platelets and leukocytes are important for the regulation of
the immune response and for the clearance of infectious agents. By binding and activating
leukocytes, platelets promote their effector functions. Coordination of immune cells
by platelets ensures a rapid and targeted host defense response. In a dynamic cross-talk,
leukocytes can also release factors that modulate platelet function.
Platelets adhere to phagocytes and deliver signals that enhance the killing of internalized
pathogens. Platelets are able to modulate neutrophil responses where they enhance
neutrophil phagocytosis in a process involving toll-like receptor (TLR) 2 and P-selectin/P-selectin
glycoprotein ligand (PSGL)-1.[38] This was demonstrated for both Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis.[38] Platelets can augment the respiratory burst in neutrophils in response to opsonized
Escherichia coli and Staphylococcus aureus.[39] Platelet–neutrophil complexes have more activated adhesion molecules, greater phagocytic
ability, and greater toxic oxygen metabolites than noncomplexed neutrophils.[40] Activated platelets can also induce superoxide anion release by monocytes and neutrophils
through P-selectin.[41] Soluble CD40 ligand (CD40L) further interacts with CD40 and αMβ2 on neutrophils
to induce the adhesive functions of neutrophils as well as cause CD40-dependent reactive
oxygen species (ROS) generation.[42]
Additionally, the triggering receptor expressed on myeloid cells (TREM)-1 ligand is
expressed on platelets and has been shown to induce neutrophil activation, and platelets
enhance the neutrophil respiratory burst and release of IL-8 in a TREM-1-specific
manner in the presence of LPS.[43] The TREM-1 receptor is an important receptor in the innate immune response as well
as in severe sepsis where it amplifies the immune response to microbial products.[44] TREM-1 has also been shown to contribute to neutrophil activation in viral infections.[45]
Furthermore, platelets induce the release of neutrophil extracellular traps (NETs),
deoxyribonucleic acid (DNA) covered with various antimicrobial nuclear and granule-derived
molecules[46] that ensnare and kill pathogens, in response to bacterial (septic) stimuli.[39]
[47]
[48] This NET response has been documented in E. coli gram-negative sepsis and S. aureus gram-positive sepsis.[47] Platelets have further been shown to interact with neutrophils following viral challenge,
leading to the release of NETs.[49]
[50]
[51] NETs also deliver antiviral factors such as myeloperoxidase[46] and α-defensin,[50] and capture viruses and promote their elimination.[51]
[Fig. 4] provides an overview of the interactions between platelets and immune cells to emphasize
the involvement of platelets in the immune response.
Fig. 4 Platelet interactions with immune cells. Platelets are important contributors to
the multifaceted immune response to infection and have the ability to engage the immune
system. Degranulation leads to the surface expression of receptors and the release
of abundant proinflammatory mediators that regulate leukocytes at the site of infection.
Platelets also modulate leukocytes involved in adaptive immunity. Ultimately, platelets
promote the effector functions of immune cells and enable an optimal immune response
(created with https://biorender.com/). IL, interleukin; MCP, monocyte chemoattractant protein; MHC, major histocompatibility
complex; MIP, macrophage inflammatory protein; PAF, platelet-activating factor; PDGF,
platelet-derived growth factor; PF, platelet factor; RANTES, regulated on activation,
normal T-cell expressed and secreted; ROS, reactive oxygen species; TGF, transforming
growth factor; TNF, tumor necrosis factor; Treg, regulatory T cell.
Platelet Involvement in Adaptive Immunity: Ensuring an Optimal Adaptive Response
Further to the innate immune response, platelets are also important for an optimal
adaptive immune response. The periodontopathogens A. actinomycetemcomitans and P. gingivalis have been shown to induce expression of CD40L on human platelets via TLR2 and TLR4.[52] Platelets can modulate B and T cell responses to microbial pathogens through CD40L,
and are able to induce isotype switching by B cells and augment CD8+ T cell function.[53]
[54] CD40L on platelets enable T cell priming and augment CD8+ T cell responses against bacterial pathogens by enhancing maturation signals to dendritic
cells and lowering the threshold for cell activation[55]
[56]
[57] (compare with reports that platelets can have an inhibitory effect on dendritic
cells[58]
[59]).
Platelet-mediated modulation of the adaptive immune system has also been shown to
enhance protection against viral re-challenge.[53] Platelets expressing integrin β3 and CD40L are essential for lymphocytic choriomeningitis
virus (LCMV) clearance by virus-specific cytotoxic T cells, and protect the host from
virus-induced interferon-α/β lethal hemorrhage.[18] Activated platelets can also contribute to immunopathology (e.g., liver damage)
by accumulating virus-specific cytotoxic T cells at the site of inflammation in models
of acute viral hepatitis.[60] Serotonin released from platelets is vasoactive and can further support viral persistence
in the liver by reducing microcirculation, which aggravates virus-induced immunopathology
in a model of LCMV-induced hepatitis.[61]
Platelets can further shuttle blood-borne gram-positive bacteria to splenic CD8α+ dendritic cells after the bacterium becomes associated to platelets via glycoprotein
(GP)-Ib and complement C3 to balance bacterial clearance with immune induction.[62] Activated platelets also form aggregates with CD16+ inflammatory monocytes and human leukocyte antigen (HLA)-DR+ CD38+ memory T cells in human immunodeficiency virus (HIV) infection.[7]
Platelet-Derived Microparticles: Further Driving the Inflammatory Response
Activated platelets produce microparticles during bacterial[63]
[64] and viral infection[65]
[66] that contain both soluble (e.g., regulated on activation, normal T cell expressed
and secreted [RANTES]) and surface mediators (e.g., P-selectin, GPIb, and αIIbβ3),
which can exit the vasculature and enter tissues where they are able to activate leukocytes
to further drive the inflammatory response.[67]
[68] For example, platelet microparticles enhance the expression of cell adhesion molecules
such as leukocyte αMβ2 for monocyte adhesion,[69] and can mediate leukocyte activation[70] and leukocyte–leukocyte interactions.[71] Microparticles promote platelet interaction with the endothelium by acting as a
substrate for further platelet binding.[72] Further, microparticles can deliver platelet-derived CD40L signals[54]
[73] and activate dendritic cells.[74] Platelet microparticles also promote endothelial activation by secreting IL-1β,[75] and can deliver RANTES to the endothelium for monocyte recruitment.[76] Lastly, these microparticles can cause complement activation.[77]
Platelet Interactions with Bacteria
Platelet Interactions with Bacteria
Platelets are active role players in antimicrobial defense, and exhibit complex interactions
with bacteria and viruses due to the variety of platelet receptors involved in pathogen
recognition. Platelets are able to recognize, bind, and internalize pathogens to sequester
and neutralize the pathogen. This section describes the interactions of platelets
with bacteria, which are summarized in [Fig. 5].
Fig. 5 Platelet interactions with bacteria. Platelets are able to sense and bind bacteria
through a variety of platelet receptors, and various bacterial products stimulate
platelets, modulating their function. Platelets typically become activated and aggregate,
but bacterial products may exert inhibitory actions or cause platelet destruction.
Platelets additionally mediate antimicrobial actions by releasing microbicidal proteins,
engulfing bacteria, and interacting with immune cells. These interactions further
enhance the immune response and lead to platelet clearance (created with https://biorender.com/). C3, complement component 3; Eap, extracellular adherence protein; Efb, extracellular fibrinogen-binding protein;
FcγRIIa, low-affinity immunoglobulin gamma Fc region receptor II-a; gC1Qr, receptor
for the globular heads of C1q; Ig, immunoglobulin; LPS, lipopolysaccharide; LTA, lipoteichoic
acid; PAF(R), platelet-activating factor (receptor); PAR, platelet-activating factor;
PLC, phospholipase C; Rgp, recombinant gingipain; ROS, reactive oxygen species; SSL,
staphylococcal superantigen-like; TLR, toll-like receptor; vWF, von Willebrand factor.
Platelet Receptors in Bacterial Pathogen Sensing
It has long been known that bacteria can cause platelet aggregation and degranulation.[78]
[79] A diverse range of platelet receptors can mediate interactions with bacteria, including
αIIbβ3, low-affinity immunoglobulin gamma Fc region receptor II-a (FcγRIIa), GPIb,
complement receptors (CRs), and TLRs,[80]
[81] either directly or indirectly through bridging molecules.[11]
[12]
[81] Alternatively, products shed by bacteria[82] may cause a platelet response independently of direct bacterial attachment to the
platelet.[10] Ultimately, engagement of receptors by bacteria and their products leads to common
and species-specific intracellular signaling events in platelets.[83]
[Table 2] summarizes platelet receptors that mediate binding of bacteria to cause platelet
activation and aggregation. A key mechanism for bacterial adhesion to platelets, which
is described for various bacteria, involves αIIbβ3 integrin activation, the FcγRIIa
receptor, and IgG,[84] where platelet factor (PF)-4 may potentiate further binding of additional bacteria
by forming an immunocomplex with bacteria that bind through FcγRIIa.[85]
Table 2
Platelet receptors that mediate bacterial adhesion and platelet activation
|
Bacteria
|
Bacterial component
|
Platelet receptors/host factors
|
References
|
|
Borrelia burgdorferi
|
|
αIIbβ3
|
[182]
|
|
Chlamydia pneumoniae
|
|
αIIbβ3
|
[183]
|
|
Helicobacter pylori
|
|
IgG-FcγRIIa, GPIb, vWF
|
[184]
|
|
Porphyromonas gingivalis
|
Hgp44
|
GPIb, IgG-FcγRIIa
|
[185]
|
|
Streptococcus agalactiae
|
FbsA
|
αIIbβ3, fibrinogen, IgG-FcγRIIa
|
[186]
|
|
Staphylococcus aureus
|
ClfA, ClfB, FnBPA, SdrE, SpA, IsdB
|
αIIbβ3, fibrinogen, fibronectin, IgG-FcγRIIa, complement gC1qR, thrombospondin, vWF
|
[84]
[187]
[188]
[189]
[190]
[191]
[192]
[193]
[194]
[195]
[196]
[197]
[198]
[199]
[200]
[201]
|
|
Staphylococcus epidermidis
|
SdrG
|
αIIbβ3, fibrinogen, IgG- FcγRIIa
|
[202]
|
|
Streptococcus gordonii
|
PadA, SspA/SspB, GspB/Hsa
|
αIIbβ3, GPIb, IgG-FcγRIIa
|
[84]
[203]
[204]
[205]
[206]
|
|
Staphylococcus lugdunensis
|
Fbl
|
Fibrinogen
|
[207]
|
|
Streptococcus mitis
|
PblA, PblB, lysin
|
αIIbβ3, fibrinogen, membrane ganglioside GD3
|
[208]
[209]
|
|
Streptococcus oralis
|
|
GPIb, IgG-FcγRIIa
|
[84]
[210]
|
|
Streptococcus pneumoniae
|
Pav, PspC/Hic
|
αIIbβ3, fibrinogen, IgG-FcγRIIa, thrombospondin, PAF receptor
|
[84]
[211]
[212]
[213]
|
|
Streptococcus pyogenes
|
M protein
|
αIIbβ3, fibrinogen, IgG-FcγRIIa
|
[201]
[214]
|
|
Streptococcus sanguis
|
SrpA
|
αIIbβ3, fibrinogen, IgG-FcγRIIa, GPIb
|
[84]
[215]
[216]
[217]
|
Abbreviations: Clf, clumping factor; FnBPA, fibronectin-binding protein A; IsdB, iron-regulated
surface determinant B; PadA, platelet adherence protein A; PavB, pneumococcal adherence
and virulence factor B; PspC, pneumococcal surface protein C; Sdr, serine-aspartate
repeat protein; SpA, staphylococcal protein A; SrpA, serine-rich protein A; Ssp, stringent
starvation protein; vWF, von Willebrand factor.
Platelets also express C–C motif and C–X–C motif chemokine receptors such as CCR1,
CCR2, CCR4, and CXCR4,[86] which can detect all four classes of chemokines (C, CC, CXC, and CX3C). These receptors allow platelets to recognize and prioritize chemotactic signals
and result in rapid vectoring of platelets to sites of infection.[9] They are also involved in stimulating platelet adhesion, aggregation, and secretion.[87] Additionally, platelet activation leads to activation of the complement system,[88]
[89] and platelets also express various complement receptors after activation such as
CR2, CR3, CR4, C3aR, C5aR, cC1qR, and gC1qR.[3] These may therefore serve as potential receptors for bacteria coated with complement
factors, and lead to platelet aggregation.[11] Furthermore, an important class of receptors for pathogen sensing are TLRs, and
platelets express numerous TLRs to detect the molecular features of microbes.[21]
[90]
[91]
[92] Platelets express, among others, functional TLR4,[93] as well as the accessory component for LPS signaling, including CD14, MD2, and myeloid
differentiation primary response (MyD)-88.[94]
Bacterial Products Affect Platelet Functions
Platelets are able to respond to many bacterial products, and these products modulate
platelet function.[25] LPS can stimulate platelet secretion of dense and α-granules through TLR4/MyD88
and cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase (PKG) signaling
pathways.[94] This potentiates secretion-dependent integrin activation and platelet aggregation.
Further to this, platelets recognize and discriminate between various isoforms of
bacterial LPS and secrete differential cytokine profiles against these danger signals.[95]
[96] LPS also induces sCD40L release from platelets[97] as well as ROS generation.[98] Some sources of LPS can activate TLR2,[99]
[100]
[101] and this has also been implicated in LPS-induced cGMP elevation and platelet activation.[94] However, LPS is described as not always generating conventional platelet activation
(e.g., typical P-selectin release from α-granules).[25] Bacterial structures from gram-positive bacteria such as lipoproteins, peptidoglycan,
and LTA are TLR2 ligands, and also trigger platelet activation.[92]
[102] TLR activation in platelets induces a thromboinflammatory response, including platelet
aggregation, formation of platelet–leukocyte complexes, and ROS generation[103] as well as the elaboration of acute-phase reactants like TNF-α.[91] However, studies have shown mixed effects of TLR2 agonists and LTA on platelet aggregation.[104]
[105]
Platelets can migrate toward the chemotactic signal of bacterial N-formyl peptide
by their receptors for this peptide.[106] The gingipain proteases HRgpA and RgpB from P. gingivalis activate platelet protease-activated receptor (PAR)-1 and PAR4, leading to platelet
aggregation.[107]
[108]
S. aureus α-toxin also causes platelet activation and leads to enhanced prothrombinase activity
on the platelet surface.[109]
[110] Staphylococcal superantigen-like (SSL)-5 from S. aureus additionally induces platelet activation via platelet receptors GPVI and GPIb,[111]
[112] whereas the Panton–Valentine leukocidin toxin leads to platelet activation via neutrophil
secretion products from damaged neutrophils.[113]
Another class of exotoxins from S. aureus, extracellular adherence protein (Eap) and extracellular fibrinogen-binding protein
(Efb) fibrinogen-binding proteins, also interacts with platelets. On the one hand,
Eap enhances αIIbβ3 integrin activation, granule secretion, and aggregation,[114] whereas Efb inhibits platelet activation and aggregation[115]
[116] and has powerful antiplatelet actions.[117]
Staphylococcus aureus enterotoxin B similarly inhibits platelet aggregation.[118] LTA from S. aureus has also been reported to inhibit platelet activation through platelet-activating
factor (PAF) receptor and raised cyclic adenosine monophosphate (cAMP),[119] as well as to inhibit platelet aggregation,[120]
[121]
[122] but may support platelet adhesion to Staphylococcus epidermidis.[123] Additional products released by S. aureus also have opposing functions on platelet aggregation. While staphylothrombin mediates
fibrin formation that supports aggregation,[124] staphylokinase prevents aggregation by degrading fibrinogen.[125]
Bacterial toxins can also cause platelet destruction. For example, α-toxin from S. aureus and α-hemolysin from E. coli
[126] as well as peptidoglycan from S. aureus
[127] can induce platelet apoptosis. Indeed, these pore-toxins stimulate disturbances
in the platelet membrane and can be cytotoxic.[3]
[128]
Escherichia coli Shiga toxin causes downregulation of platelet CD47 expression, which leads to enhanced
platelet activation and phagocytosis of platelets by macrophages.[129] Toxins such as pneumolysin from Streptococcus pneumoniae
[130] and α-toxin from S. aureus
[131] can cause platelet lysis, whereas streptolysin O from Streptococcus pyogenes
[132] and phospholipase C from Clostridium perfringens
[133] induce the formation of platelet–leukocyte complexes.
Platelets Mediate Antimicrobial Attack
A further function of platelets in bacterial infection is mediating antimicrobial
attack. Platelets mediate some of their antimicrobial actions through the secretion
of potent antimicrobial proteins from their α-granules.[8]
[35] Moreover, platelets rapidly form clusters around bacteria that have been captured
by Kupffer cells in the liver sinusoids (specialized macrophages in the liver), encasing
the bacterium and facilitating its destruction.[13] Further, sCD40L causes increased generation and release of reactive oxygen (e.g.,
superoxide) and nitrogen (e.g., nitric oxide) species by platelets, which assists
in pathogen destruction.[134]
[135]
Platelets are able to bind and endocytose/phagocytose bacteria through engulfing endosome-like
vacuoles that are formed by membrane endocytosis and become the site of α-granule
release for the granular proteins to access the pathogen.[136]
[137] A mechanism of internalizing bacteria via the open canalicular system has also been
proposed[138] (compare with Boukour and Cramer[139]). Nonetheless, the platelet FcγRIIa receptor can bind IgG complexes and allows platelets
to clear these complexes from the circulation.[140] Internalization of IgG-coated particles results in platelet activation and the release
of RANTES and sCD40L.[141] Platelets opsonized by IgG can be destroyed by Fc-mediated platelet phagocytosis,
contributing to the clearance of IgG-containing complexes from the circulation.[142]
[143] More broadly, activated platelets expose phosphatidylserine, and neutrophils have
been shown to phagocytose activated platelets in a clearance program involving phosphatidylserine
and P-selectin.[144]
[145]
[146]
Platelet Interactions with Viruses
Platelet Interactions with Viruses
Viruses have been observed to interact directly with platelets. Various viruses have
been identified adsorbed to or inside platelets, including influenza virus,[147]
[148] HIV,[136]
[149]
[150] hepatitis C,[151]
[152]
[153] and herpes simplex virus[154] as well as others such as vaccinia virus[155] and dengue virus.[156]
[157]
[158] However, the interactions between viruses and platelets are less well characterized
compared with those of gram-positive bacteria. This section describes the interaction
of platelets with viruses, which are summarized in [Fig. 6].
Fig. 6 Platelet interactions with viruses. Various platelet receptors can mediate binding
to viral particles; however, the direct effect of this binding on platelets is less
well described than for bacteria. Pattern recognition receptors recognize classical
viral signals, and viral products also modulate platelet function. Platelets mediate
viral attack by secreting virucidal proteins and by engulfing viral particles, as
well as by interacting with immune cells and enhancing the immune response. Overall,
platelets may be activated and aggregate, but also face apoptosis. Virus–platelet
aggregates and platelets with a viral load are targeted by leukocytes, and platelets
are ultimately cleared from the circulation (created with https://biorender.com/). CAR, coxsackievirus and adenovirus receptor; CCR/CXCR, chemokine receptor; CLEC,
C-type lectin-like receptor; CR, complement receptor; DC-SIGN, dendritic cell-specific
ICAM-grabbing nonintegrin; FcγRIIa, low-affinity immunoglobulin gamma Fc region receptor
II-a; HIV, human immunodeficiency virus; Ig, immunoglobulin; RNA, ribonucleic acid;
ROS, reactive oxygen species; Tat, trans-activator of transcription; TLR, toll-like
receptor; vWF, von Willebrand factor.
Platelet Receptors in Viral Pathogen Sensing
Several platelet receptors have been identified to mediate binding to viral particles,[6]
[7]
[30]
[159] and are summarized in [Table 3]. Similarly to bacteria, IgG is important for the adhesion of viral particles to
platelets, where IgG-coated particles can interact with the FcγRIIa receptor[151]
[160]
[161]
[162] to be internalized into the platelet.[140] However, other antibody-dependent mechanisms that enhance viral binding to platelets
are also described,[156] and platelets can further bind viruses in a receptor-independent manner.[163] For example, although the coxsackievirus and adenovirus receptor (CAR) is expressed
on platelets, coxsackie B virus interaction with platelets has also been described
independently of CAR and can result in P-selectin and phosphatidylserine exposure.[163] More broadly, β3 integrins are important platelet-adhesion receptors, and these
receptors appear to facilitate viral adhesion to platelets.[18]
[65]
[164] Even though various receptors that are expressed on platelets have been implicated
in viral adhesion and cell entry, the direct effect of this interaction on the platelet
has not always been described.
Table 3
Platelet receptors that mediate viral binding
|
Virus
|
Viral component
|
Platelet receptors/host factors
|
Effect on platelet
|
References
|
|
Adenoviruses
|
Penton base (RGD ligand site)
|
Fibrinogen, laminin, vitronectin and vWF, αIIβ3, αvβ3, CAR receptor
|
Platelet activation, platelet–leukocyte aggregate formation
|
[30]
[218]
[219]
[220]
[221]
|
|
Dengue virus
|
|
DC-SIGN
|
Platelet activation, platelet apoptosis
|
[178]
[222]
[223]
|
|
Ebola virus
|
|
DC-SIGN
|
|
[224]
|
|
Enterovirus echovirus 9 strain Barty
|
VP1 capsid protein (RGD ligand site)
|
αvβ3
|
|
[225]
|
|
Epstein–Barr virus
|
|
CR2
|
Platelet activation
|
[226]
|
|
Hantaviruses
|
|
αIIβ3, αvβ3
|
|
[227]
|
|
Hepatitis C virus
|
|
GPVI
|
|
[228]
|
|
HIV
|
Mannose-type carbohydrates
|
CXCR4, DC-SIGN, CLEC2
|
|
[174]
[229]
[230]
|
|
Herpes simplex virus-1
|
|
αvβ3
|
|
[231]
|
|
Human parechovirus-1
|
VP1 capsid protein (RGD ligand site)
|
αvβ3
|
|
[232]
|
|
Lassa virus
|
|
DC-SIGN, Axl, Tyro3
|
|
[233]
|
|
Rotavirus
|
Spike protein VP4 (DGE ligand site)
|
α2β1
|
|
[234]
[235]
|
Abbreviations: CLEC2, C-type lectin-like receptor 2; DC-SIGN, dendritic cell-specific
ICAM-grabbing nonintegrin; DGE, Asp-Gly-Glu tripeptide; HIV, human immunodeficiency
virus; RGD, Arg-Gly-Asp tripeptide; VP, viral (capsid) protein; vWF, von Willebrand
factor.
Platelets can also detect viruses through TLRs. Platelet TLR2 can bind cytomegalovirus,
which triggers platelet activation, degranulation, and the formation of platelet–leukocyte
aggregates.[165] TLR7 recognizes the classical viral PAMP, single-stranded RNA.[92] Platelets express functional TLR7, and activation via TLR7 leads to expression of
CD40L and P-selectin, and P-selectin supports the adhesion of virally activated platelets
to neutrophils.[22]
[166] Moreover, platelet TLR7 mediates complement C3 release from platelets, which in
turn leads to platelet–neutrophil aggregation and NET release by neutrophils.[167] Encephalomyocarditis virus has been shown to interact with platelet TLR7.[166] Platelet TLR9 recognizes unmethylated CpG islands found in bacterial and viral DNA,
which also leads to P-selectin surface expression.[92]
[168]
Viral Products Affect Platelet Functions
Viruses secrete various products that modulate platelet function. The secreted HIV
Tat protein directly interacts with platelets in a process requiring the platelet
receptors CCR3 and β3 integrin as well as calcium influx. This leads to platelet activation
and CD40L expression as well as microparticle formation.[65] Indeed, platelet activation persists even in virologically suppressed HIV infection.[169] Viral enzymes such as neuraminidase can cause desialylation of platelet surface
receptors,[6] and desialylation might promote platelet clearance in the liver.[170]
[171]
Platelets Mediate Antiviral Attack
The secretory products of platelets can also exert virucidal effects, including the
inactivation of adenovirus, poliovirus and vaccinia virus,[172] and HIV suppression.[20] Moreover, platelets exhibit phagocytic behavior toward viruses such as HIV and can
form engulfing vacuoles that lead to granular components being secreted on the virus
particle, as described for bacteria.[136] Indeed, intact HIV-1 particles enclosed in endocytic vesicles have been found in
the open canalicular system.[173]
[174] Recently, it has been proposed that platelets may also potentially phagocytose influenza
virus.[175]
[176] Platelets may then cause disruption of viral integrity.[174] Overall, it has been suggested that internalization of viral particles by platelets
may function to clear viruses from the circulation.[177]
Viruses can cause the expression of P-selectin and phosphatidylserine exposure on
platelets, and these components promote interactions with leukocytes as well as lead
to phagocytosis of the platelet.[163]
[178] Interaction between platelets and viruses can also lead to sequestration to the
reticuloendothelial system of the liver, where virus–platelet aggregates can be taken
up by Kupffer cells and degraded.[179] Spleen macrophages also assist in clearing platelets with a viral load.[30]
Conclusion
Platelets are among the first cells to accumulate at sites of infection and inflammation,
and can be considered as first responders to invading pathogens. Here, platelets have
a key role in sensing and effecting the first wave of responses to microbial and viral
threat.[8]
[9] This is achieved by the inflammatory activity of platelets but also through direct
antibacterial and antiviral actions that facilitate the clearance of pathogens from
the circulation. Platelets are therefore represented at the interface of hemostasis,
inflammation, and antimicrobial host defense. Their position at the crossroads of
these processes emphasizes their role as signaling entities in infection and inflammation.
Various stimuli that are relevant to infection impinge on platelets, activating and
forcing them to exert their effector actions. Recursive stimulation of activation
receptors and successive activation of bystander platelets intensify the host-defense
functions of platelets even at threshold stoichiometric ratios of platelets to pathogens.[180] Platelets face inappropriate activation and immunological destruction, and are inevitably
consumed by their participation in host defense. An inflammatory milieu can thereby
drive platelet dysfunction. In this review, we emphasize that platelet dysfunction
can arise as a general consequence of an exaggerated systemic (immune) response to
infection. Increased platelet consumption and removal can lead to thrombocytopenia,
which is frequently observed during infection. [Fig. 7] summarizes and links together the various processes we have discussed, to show a
general mechanism of platelet depletion during infection.
Fig. 7 A generic large-scale cause for platelet dysfunction and depletion in infection.
Platelets are intimately involved in the immune and host defense response to infection,
where various stimuli challenge the platelet. Platelets operate in close connection
with other cells and processes. Platelets are cells of one-time use, and their involvement
in the diverse and interconnected processes against infection leads to their irreversible
consumption. In the context of abundant stimulation, inappropriate and excessive activation
of platelets results in their expenditure and exhaustion (created with https://biorender.com/). (Adapted from Yeaman[9].) DAMP, damage-associated molecular pattern; NET, neutrophil extracellular trap;
PAMP, pathogen-associated molecular pattern.
Because of their largely protective role, lower platelet counts are associated with
worse prognosis and greater likelihood of infection; however, platelets are also presented
as having an ambivalent role in infections by possibly sheltering pathogens in certain
cases.[6]
[7]
[9]
[12]
[30]
[181] Nonetheless, in the context of impairment of the immune system, the functions of
platelets become more important. Following the contribution of platelets to diverse
immunological processes, dysregulation of platelet–leukocyte interactions, which are
important for inflammatory and immune reactions, together with dysregulation of inflammatory
mediators, establish an excessive and unbalanced systemic inflammatory response. In
this context, platelets can contribute to pathophysiological processes and immunopathology,
and become dysfunctional.
Achieving a balance between pro- and anti-inflammatory responses during infection
is difficult to manipulate effectively in a therapeutic context. Following from the
diverse functions of platelets in infections, platelets are also placed at an interface
between health and disease. Platelets are acutely affected by the surrounding environment.
This, together with other characteristics of platelets such as their fast turnover,
might position platelets as relevant signaling entities with clinical potential in
disease tracking and targeting to evaluate or manage the course of infections. Although
platelets are perhaps a lesser-known participant in the host-defense system, their
large-scale depletion may cause significant health issues. Managing a generic depletion
of platelets during the presence of infection should possibly be a more actively pursued
clinical goal. The key points encapsulating the main ideas of this review are presented
in [Table 4].
Table 4
Key points
|
• Platelets are versatile cells positioned at the interface of hemostasis, inflammation,
and antimicrobial host defense, and their immune, antibacterial, and antiviral actions
establish them as active participants in infection.
• By nature of their normal functioning, platelets are invariably and irreversibly
expended in the processes to which they contribute.
• During infection, an onslaught of inflammatory and pathogen-derived stimuli can
evoke and challenge platelets, leading to inappropriate activation, immunological
destruction, and sequestration.
• In the context of a dysregulated host response to infection, platelets can experience
overwhelming activation and, consequently, consumption, and this represents a generic
large-scale mechanism for platelet depletion in infection.
|
