Platelets as Immune Cells in Infectious

Diseases (Cornelia Speth, Jrgen Lffler, Sven

Krappmann, Cornelia Lass-Flrl, Gnter
Rambach)
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Abstract and Introduction
Platelets have been shown to cover a broad
range of functions. Besides their role in
hemostasis, they have immunological functions
and thus participate in the interaction between
pathogens and host defense. Platelets have a
broad repertoire of receptor molecules that
enable them to sense invading pathogens and
infection-induced inflammation. Consequently,
platelets exert antimicrobial effector
mechanisms, but also initiate an intense
crosstalk with other arms of the innate and
adaptive immunity, including neutrophils,
monocytes/macrophages, dendritic cells, B cells
and T cells. There is a fragile balance between
beneficial antimicrobial effects and detrimental
reactions that contribute to the pathogenesis,
and many pathogens have developed
mechanisms to influence these two outcomes.
This review aims to highlight aspects of the
interaction strategies between platelets and
pathogenic bacteria, viruses, fungi and
parasites, in addition to the subsequent
networking between platelets and other
immune cells, and the relevance of these
processes for the pathogenesis of infections.

Introduction

Platelets, are small cell fragments in the
circulating blood. Their primary role includes
sensing of damaged blood vessel endothelium,
accumulating at the site of injury and then
causing blood clotting to close the wound.[1] In
addition, they are part of the innate and
adaptive immune system, play a role in the
initiation of inflammation by interacting with
leukocytes, and are further involved in
atherosclerosis and tumor growth.[13]

Platelets originate from megakaryocytes, which
are precursor cells in the bone marrow that
develop from pluripotent stem cells by a
multistep process.[47]

With an irregular size of 2.05.0 m in
diameter, the 150400 109 platelets per liter
of human blood have a life span of 810
days.[1] Despite lacking a nucleus, platelets
contain mRNA and the full translation
machinery for protein synthesis.[1] The discoid
shape in their resting stage is stabilized by a
membrane skeleton, microtubules and
microfilaments.[8] Periodic invaginations
punctuate the even-textured surface to an open
canalicular system that permeates the
cytoplasm resulting in a large surface area for
protein uptake.[9] Most of those proteins are
stored in secretory vesicles called granules,
which can be divided into lysosomal granules,
dense bodies and -granules.

Per platelet, three to eight dense bodies contain
molecules involved in platelet activation and
aggregation such as nucleotides, cations,
phosphates and bioactive amines such as
serotonin.[10,11] Lysosomal granules store
enzymes such as proteases, phosphatases and
glycosidases, which are responsible for matrix
and protein degradation.[10] With 4080 per
platelet, -granules are the most abundant
secretory vesicles and they contain over 300
soluble and membrane-bound molecules
including microbicidal peptides, growth factors,
soluble adhesion molecules and coagulation
proteins.[10,12,13] Additionally,
proinflammatory molecules, such as cytokines,
chemokines and interleukins, are stored in -
granules.[11]

Intact vessel endothelial cells suppress platelet
activation.[14] In case of vessel injury, platelets
adhere to and become activated by the
subendothelial collagenvon Willebrand factor
(vWF) complex and thrombin. Hereon, a shape
change from smooth disks to spiculated spheres
with filopodia and pseudopodia is performed by
actin reorganization.[8,15] Thereby, the cargo
of the granules becomes released in the
surrounding bloodstream and recruits and
activates further platelets.[16] In addition,
membrane-bound molecules, for example, P-
selectin become translocated to the platelet
surface, promoting platelet aggregation and
interaction with immune and endothelial
cells.[17] The chemokines and interleukins
stored in -granules link platelets to
antimicrobial host defense and
inflammation.[11,18] Furthermore, platelets
generate microparticles[19] with P-selectin,
glyoproteins (GPs) and CD154 on their
surface.[20,21]
Immunocompetence of Platelets
Despite being acaryote cell fragments, platelets
share a number of properties of host defense
with their big nucleated relatives and represent
important elements in innate immunity. For
these purposes, they have developed a number
of physiological skills (Box 1 & Figure 1). They
sense pathogens by various surface receptors,
attach to them and become activated, thereby
releasing the content of their granules.
Consequently, antimicrobial peptides exert
direct effects against pathogens, and a number
of cytokines/chemokines attract and activate
other immune cells. Endocytosis of pathogens,
production of reactive oxygen species (ROS) and
various interactions with the complement
system and cells of the innate and adaptive
immune systems could be shown, as described
in the following sections. All these mechanisms
support the fight against infections, but can also
harbor deleterious sequelae such as thrombosis
and exceeding inflammatory reactions. Since
platelets can be described as immune cells with
a broad range of antimicrobial functions, it is
difficult to decide which function or aspect is
the most relevant for the clinical outcome. To
answer this, additional studies are necessary in
the future.
Interaction of Platelets With Bacterial
Pathogens
Bacteria enter the bloodstream in response to
infectious insults, via surgical procedures or
indwelling catheters, and sepsis occurs in up to
630% of all intensive care unit patients.[94,95]
The balance of pro- and anti-inflammatory
reactions critically determines the severity and
lethality of sepsis, a fact that turns the spotlight
onto understanding the immune reaction in
order to develop appropriate therapies.[96]

Bacterial contact with the platelets is a key
event for the pathogenesis of sepsis, as
deduced from the correlation between sepsis
outcome and decreased platelet numbers: the
more profound the thrombocytopenia the more
severe the sepsis and the greater the mortality
of affected patients.[9799]

There are two main causes for the bacteria-
induced thrombocytopenia:

Bacteria induce platelet activation. Activated
platelets show shortened survival and are
targets of phagocytic clearance;

Bacterial compounds induce apoptosis and
cytotoxic effects in platelets. Both main
mechanisms can complement and overlay each
other and are described below in more detail
(see also Box 2 & Figures 2 & 3).

Additional mechanisms are known for selected
bacteria and listed in Box 2; however,
exhaustive discussion goes beyond the scope of
this article. Although they further augment and
reinforce the thrombocytopenia in affected
sepsis patients.

The mechanisms that finally lead to the loss of
platelets and their attributed immune functions
can decisively compromise the antibacterial
immune defense (Box 1). The subsequent
thrombocytopenia might be regarded as a
normal consequence of immune exhaustion.
However, it might also be regarded as targeted
bacterial evasion strategies to eliminate a
central innate immune cell from circulation with
a kinetic that exceeds de novo generation in the
bone marrow (Box 2 & Figure 3); thus,
thrombocytopenia represents a status that
helps the bacteria to survive in the
bloodstream. There is yet a third aspect: those
mechanisms of platelet activation or apoptosis
that finally result in thrombocytopenia can also
lead to thrombosis, thus contributing to tissue
damage in the pathogenesis of bacterial
infections.
Platelets in Viral Infections
The relevance of virusplatelet 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.[125127] Thrombocytopenia is observed
as one of the first clinical signs in approximately
1050% 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.
Future Perspective
Platelets circulate within the whole body and
exert two principle functions: protection against
bleeding and invading pathogens. Their multiple
antimicrobial facets are beneficial, such as
direct attack of the pathogens and recruitment
and stimulation of other immune cells;
however, the functional spectrum is balanced
by harmful aspects, such as the contribution to
tissue damage or even the support of microbe
dissemination and survival. Further research in
the coming years aims to implement and
highlight these aspects for various infectious
diseases.

The increasing insight into the connection
between platelets and immune defense
highlights the burning question whether drugs
that affect the activation of the platelets also
influence their antimicrobial capacity. However,
a deeper understanding of the antimicrobial
capacity of platelets and the role of platelets in
the immune network might also open some
new options to correct insufficient or
exaggerated reactions of the platelets to
pathogen contact. Future approaches might aim
to interfere with microbial exploitation of the
platelets, thus interfering with survival,
dissemination and replication of the pathogens
in the host.

There are other aspects that might alter the
medication of patients in the far future.
Platelet-derived antimicrobial peptides and
synthetic peptides derived thereof are
increasingly studied as new antimicrobial agents
that might broaden our current therapeutic
arsenal. Since some PMPs impair survival of
different microbes, they could provide the base
for effective broad-spectrum antimicrobials.

Furthermore, insights that viruses can exploit
platelets for dissemination could be converted
into new medical strategies. Since platelets can
internalize recombinant lentiviruses without
fusion of their envelope with the cell plasma
membrane, platelets might be used in gene
therapy for the transport of lentiviral vectors
carrying therapeutic genes.