Download parasitic infection and the human host haemostasis

parasitic infection and the human host haemostasis
To illustrate how the parasite can be transferred from an arthropod vector to a
human host and how this may lead to a parasitic infection, after evasion.
To explain the haemostatic process used by the host to prevent continuous
exposure of blood to the parasite and how the parasite has adapted to hinder
this response.
The use of a vector as mode of transport in carrying an infectious agent has
evolved into an effective and efficient procedure, exploiting the interaction
between the parasite, and that of the host. The widespread use of Arthropods
(as a vector), signify it as a model organism for this process. They can consist
of hard ticks, mosquitoes and sand flies to name a few, and can provide the
vectors for the infectious diseases of, Babesiosis, Malaria and Leishmaniasis
respectively. The infectious agent can be part of an adverse cycle, and is
continuously transmitted from both the vector and the host. However this
requires adequate quantities of the parasitic microorganism present within the
host, which can then be ingested into a vector via a blood meal and hence be
multiplied, and discharged into a fresh host. This type of transmission is
biological as it requires an incubation period. Infectious diseases may also be
transmitted mechanically, in which the parasitic agent has contaminated the
mouth parts of an arthropod and is then transmitted to a host.
Haematophagous arthropods successfully feed on their hosts, assisted by the
various haemostatic, inflammatory and immunodulatory molecules present in
their saliva (Andrade et al. 2005). These are known to create a suitable
microenvironment for parasitism, disrupting the initial local physiology of the
host. Once the tissues and capillaries are lacerated by the parasite, exposing
pools of blood in which the parasite gains essential nutrients, the vertebrate
host haemostasis is immediately activated. This mechanism prevents further
blood loss and involves the triad of vasoconstriction, platelet aggregation and
the blood coagulation cascade. However these haemostatic mechanisms are
remotely hindered by an anticoagulant, vasodilator, and an anti-platelet which
are found within the salivary secretions of blood-feeding arthropods. These
pharmacological components can aid the entry of the infectious agents via
the puffs of saliva into the human host, which then evade the vascular system
infecting the red blood cells. Once infected, the erythrocytes burst, infecting
further cells and eventually depleting the oxygen supply.
At the site of lesion in the host, various agonists are released which activates
the platelets, due to the vascular damage. Due to the damaged endothelial
cells by the piercing of the proboscis threading along the vessel, the collagen
becomes exposed, promoting the platelets to adhere to the affected site. This
induces the release of cytoplasmic granules which contain serotonin and
adenosine diphosphate (ADP). This leads to a positive feedback loop as
further platelets are activated and recruited, which enables platelet
aggregation and clot formation. The enzyme apyrase also known as ATPdiphosphohydrolase is most commonly known to be released by female
mosquitoes, which hydrolyses adenosine diphosphate and adenosine
triphosphate (ATP) forming adenosine monophosphate (AMP) and
orthophosphate (Steen et al. 2006). This prevents the clotting of blood when
taking a blood meal. Along with nociceptor-mediated reflexes and the
activation of sympathetic vasoconstrictive neurons, serotonin and
thromboxane A2 – (also synthesised by the binding of the platelets to the
collagen) allow the vessels to narrow. This increases the resistance and
slows the rate of blood flow, hence reducing the loss of blood. Many different
vasodilatory compounds have been found in the salivary glands of
arthropods, the most potent being maxadilan, present in the sand fly
Lutzomyia longipalpis.
Blood coagulation is the final event towards the excessive loss of blood and
consists of two intricate systems, involving a number of factors. The extrinsic
pathway, so called as it is activated via factors from outside the blood, is
initiated when blood comes into contact with disrupted tissue. Contrary, the
intrinsic pathway, the slower of the two systems, is initiated by intravascular
factors, in which high molecular weight kininogen, prekallikrein, Factor XI and
XII are exposed to the negatively charged surfaces (Hoffman, 2003). The
initiation of the intrinsic pathway, also known as the contact phase, involves
the conversion of prekallikrein to kallikrein which in turn activates Factor XII to
activated XIIa (Francischetti et al. 2010). This also leads to the synthesis of
bradykinin (Ribeiro, 1987). Both systems merge activating Factor X, which
can be initiated by either pathway. Once activated, (activated Factor Xa)
combines with platelet phospholipids and Factor V which promotes the
conversion of Prothrombin to Thrombin. This cleavage also requires a
Prothrombin activator, which is activated by platelet thromboplastic factor.
Once thrombin is formed, it allows the polymerization of fibrinogen, a soluble
plasma protein, to form long strands of fibrin. The strands of fibrin allow the
formation of a mesh-like structure in which the fibrin bridges the platelets and
blood constituents together, thus forming a stable thrombus (clot).
Furthermore the binding of thrombin to thrombomodulin activates the protein
C system (in the presence of protein S), which inactivates Factor Va and
Factor VIII. This step acts to ‘shut-off’ the coagulation cascade. Thrombin can
be regulated by the presence of the tissue factor pathway inhibitor (TFPI)
which binds the tissue factor and Factor VIIa complex. This inhibits the
activation of Factor X therefore affects the production of thrombin. In the hard
tick Ixodes scapularis, an anti- coagulant known as Ixolaris, has been found
to inhibit tissue factor (Moneiro et al. 2005).This protein was identified as a
serine protease inhibitor, and when purified and sequenced, it was found to
contain Kunitz domains.
Many of the steps above require calcium as a cofactor and phospholipids
which become negatively exposed on activated platelets allowing the binding
of vitamin-k dependant coagulation factors in the presence of calcium ions.
The protozoan parasite Trypansoma Cruzi, infamously known as the cause
for Chagas disease, contains a calcium binding protein – calreticulin, which
binds calcium ions inactivating it, as it does. The presence of calcium is also
known to activate the enzyme apyrase, which is found in the salivary
secretions of the parasite.
To complete the healing process, serum is extruded from the thrombin,
shrinking the clot and it is eventually removed by lysis. This is known as clot
dissolution and requires the fibrinolytic system. This system restores the initial
circulation of the vessel and is mediated by plasminogen (Nordenhem, 2006).