ZIKA VIRUS: Possible immune-prophylaxis and inhibition of biological sequelae and clinical presentation after primary exposure.

ZIKA VIRUS: Possible immune-
prophylaxis and inhibition of biological
sequelae and clinical presentation after
primary exposure.
DMITRI POPOV. PHD, RADIOBIOLOGY.
MD (RUSSIA)
ADVANCED MEDICAL TECHNOLOGY AND SYSTEMS INC. CANADA.
INTERVACCINE@GMAIL.COM

ZIKA virus.
 Research Proposal: ZIKA VIRUS: Possible immune prophylaxis and inhibition
of biological sequelae and clinical presentation after primary exposure.
 Dmitri Popov
 Full-text · Research Proposal · Jan 2016
 Add resources
 File name: ZIKA.pptx
DOI: 10.13140/RG.2.1.2985.8320

ZIKA virus.
 Flaviviridae is a family of viruses. Humans and other mammals serve as
natural hosts. They are primarily spread through arthropod vectors (mainly
ticks and mosquitoes).
 The family gets its name from the Yellow Fever virus, the type virus
of Flaviviridae; flavus means yellow in Latin. (Yellow fever in turn was named
because of its propensity to cause jaundice in victims.)
 There are currently over 100 species in this family, divided among four
genera. Diseases associated with this family include: hepaciviruses: hepatitis;
pestiviruses: hemorrhagic syndromes, abortion, fatal mucosal disease;
flavivirus: hemorrhagic fever, encephalitis.

ZIKA virus
 Genus Flavivirus (type species Yellow fever virus, others include West Nile
virus, Dengue Fever and Zika virus)—contains 67 identified human and
animal viruses.
 Flaviviridae have monopartite, linear, single-stranded RNA genomes of
positive polarity, 9.6 to 12.3 kilobase in length. The 5'-termini of flaviviruses
carry a methylated nucleotide cap, while other members of this family are
uncapped and encode an internal ribosome entry site.
 https://en.wikipedia.org/wiki/Flaviviridae

ZIKA virus.
 Viral replication is cytoplasmic. Entry into the host cell is achieved by
attachment of the viral envelope protein E to host receptors, which mediates
clathrin-mediated endocytosis. Replication follows the positive stranded
RNA virus replication model. Positive stranded RNA virus transcription is the
method of transcription. Translation takes place by viral initiation. The virus
exits the host cell by budding. Humans and mammals serve as the natural
host. The virus is transmitted via a vector (ticks and mosquitoes)

ZIKA virus.
 Major diseases caused by the Flaviviridae family include:
 Dengue fever
 Japanese encephalitis
 Kyasanur Forest disease
 Murray Valley encephalitis
 St. Louis encephalitis
 Tick-borne encephalitis
 West Nile encephalitis
 Yellow fever
 Hepatitis C Virus Infection
 Zika Virus

ZIKA virus.
 About 1 in 5 people infected with Zika virus become ill (i.e., develop Zika).
 The most common symptoms of Zika are fever, rash, joint pain, or conjunctivitis
(red eyes). Other common symptoms include muscle pain and headache. The
incubation period (the time from exposure to symptoms) for Zika virus disease is
not known, but is likely to be a few days to a week.
 The illness is usually mild with symptoms lasting for several days to a week.
 Zika virus usually remains in the blood of an infected person for a few days but it
can be found longer in some people.
 Severe disease requiring hospitalization is uncommon.
 Deaths are rare.

ZIKA virus.
 The symptoms of Zika are similar to those of dengue and chikungunya,
diseases spread through the same mosquitoes that transmit Zika.
 See your healthcare provider if you develop the symptoms described above
and have visited an area where Zika is found.
 If you have recently traveled, tell your healthcare provider when and where
you traveled.
 Your healthcare provider may order blood tests to look for Zika or other
similar viruses like dengue or chikungunya.

ZIKA virus.
 No vaccine or medications are available to prevent or treat Zika infections.
 Treat the symptoms:
 Get plenty of rest
 Drink fluids to prevent dehydration
 Take medicine such as acetaminophen to relieve fever and pain
 Do not take aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), like
ibuprofen and naproxen. Aspirin and NSAIDs should be avoided until dengue can be ruled
out to reduce the risk of hemorrhage (bleeding). If you are taking medicine for another
medical condition, talk to your healthcare provider before taking additional medication.
 If you have Zika, avoid mosquito bites for the first week of your illness.
 During the first week of infection, Zika virus can be found in the blood and passed from
an infected person to another mosquito through mosquito bites.
 An infected mosquito can then spread the virus to other people.

ZIKA virus.
 Complications:
 ZIKA VIRUS INFECTION COMPLICATED BY GUILLAIN-BARRÉ SYNDROME –
CASE REPORT, FRENCH POLYNESIA, DECEMBER 2013
 Oehler E, Watrin L, Larre P, Leparc-Goffart I, Lastère S, Valour F, Baudouin L,
Mallet HP, Musso D, Ghawche F. Zika virus infection complicated by Guillain-
Barré syndrome – case report, French Polynesia, December 2013. Euro
Surveill. 2014;19(9):pii=20720. Article DOI: http://dx.doi.org/10.2807/1560-
7917.ES2014.19.9.20720
 http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20720

ZIKA virus.
 Zika fever, considered as an emerging disease of arboviral origin, because of
its expanding geographic area, is known as a benign infection usually
presenting as an influenza-like illness with cutaneous rash. So far, Zika virus
infection has never led to hospitalisation. We describe the first case of
Guillain–Barré syndrome (GBS) occurring immediately after a Zika virus
infection, during the current Zika and type 1 and 3 dengue fever co-
epidemics in French Polynesia.
 http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20720

ZIKA virus.
 Guillain-Barré syndrome (GBS) is a disorder in which the body's immune
system attacks part of the peripheral nervous system. The first symptoms of
this disorder include varying degrees of weakness or tingling sensations in
the legs. In many instances the symmetrical weakness and abnormal
sensations spread to the arms and upper body. These symptoms can
increase in intensity until certain muscles cannot be used at all and, when
severe, the person is almost totally paralyzed. In these cases the disorder is
life threatening - potentially interfering with breathing and, at times, with
blood pressure or heart rate - and is considered a medical emergency. Such
an individual is often put on a ventilator to assist with breathing and is
watched closely for problems such as an abnormal heart beat, infections,
blood clots, and high or low blood pressure.
http://www.ninds.nih.gov/disorders/gbs/detail_gbs.htm

ZIKA virus.
 Guillain-Barré syndrome can affect anybody. It can strike at any age and
both sexes are equally prone to the disorder. The syndrome is rare, however,
afflicting only about one person in 100,000. Usually Guillain-Barré occurs a
few days or weeks after the patient has had symptoms of a respiratory or
gastrointestinal viral infection. Occasionally surgery will trigger the
syndrome. In rare instances vaccinations may increase the risk of GBS.
 After the first clinical manifestations of the disease, the symptoms can
progress over the course of hours, days, or weeks. Most people reach the
stage of greatest weakness within the first 2 weeks after symptoms appear,
and by the third week of the illness 90 percent of all patients are at their
weakest.
 http://www.ninds.nih.gov/disorders/gbs/detail_gbs.htm

ZIKA virus.
 What scientists do know is that the body's immune system begins to attack
the body itself, causing what is known as an autoimmune disease. Usually
the cells of the immune system attack only foreign material and invading
organisms.
 In Guillain-Barré syndrome, however, the immune system starts to destroy
the myelin sheath that surrounds the axons of many peripheral nerves, or
even the axons themselves (axons are long, thin extensions of the nerve
cells; they carry nerve signals). The myelin sheath surrounding the axon
speeds up the transmission of nerve signals and allows the transmission of
signals over long distances.

ZIKA virus.
 In diseases in which the peripheral nerves' myelin sheaths are injured or
degraded, the nerves cannot transmit signals efficiently. That is why the
muscles begin to lose their ability to respond to the brain's commands,
commands that must be carried through the nerve network. The brain also
receives fewer sensory signals from the rest of the body, resulting in an
inability to feel textures, heat, pain, and other sensations. Alternately, the
brain may receive inappropriate signals that result in tingling, "crawling-
skin," or painful sensations. Because the signals to and from the arms and
legs must travel the longest distances they are most vulnerable to
interruption. Therefore, muscle weakness and tingling sensations usually first
appear in the hands and feet and progress upwards.

ZIKA virus.
 When Guillain-Barré is preceded by a viral or bacterial infection, it is possible
that the virus has changed the nature of cells in the nervous system so that
the immune system treats them as foreign cells. It is also possible that the
virus makes the immune system itself less discriminating about what cells it
recognizes as its own, allowing some of the immune cells, such as certain
kinds of lymphocytes and macrophages, to attack the myelin. Sensitized T
lymphocytes cooperate with B lymphocytes to produce antibodies against
components of the myelin sheath and may contribute to destruction of the
myelin. In two forms of GBS, axons are attacked by antibodies against the
bacteria Campylobacter jejuni, which react with proteins of the peripheral
nerves. Acute motor axonal neuropathy is particularly common in Chinese
children. http://www.ninds.nih.gov/disorders/gbs/detail_gbs.htm

ZIKA virus.
 Scientists are investigating these and other possibilities to find why the
immune system goes awry in Guillain-Barré syndrome and other
autoimmune diseases. The cause and course of Guillain-Barré syndrome is
an active area of neurological investigation, incorporating the cooperative
efforts of neurological scientists, immunologists, and virologists.

ZIKA virus. Conventional treatment.
 There is no known cure for Guillain-Barré syndrome. However, there are therapies that
lessen the severity of the illness and accelerate the recovery in most patients. There are
also a number of ways to treat the complications of the disease.
 Currently, plasma exchange (also called plasmapheresis) and high-dose immunoglobulin
therapy are used. Both of them are equally effective, but immunoglobulin is easier to
administer. Plasma exchange is a method by which whole blood is removed from the
body and processed so that the red and white blood cells are separated from the plasma,
or liquid portion of the blood. The blood cells are then returned to the patient without the
plasma, which the body quickly replaces. Scientists still don't know exactly why plasma
exchange works, but the technique seems to reduce the severity and duration of the
Guillain-Barré episode. This may be because plasmapheresis can remove antibodies and
other immune cell-derived factors that could contribute to nerve damage.

ZIKA virus.
 In high-dose immunoglobulin therapy, doctors give intravenous injections
of the proteins that, in small quantities, the immune system uses naturally to
attack invading organisms. Investigators have found that giving high doses
of these immunoglobulins, derived from a pool of thousands of normal
donors, to Guillain-Barré patients can lessen the immune attack on the
nervous system. Investigators don't know why or how this works, although
several hypotheses have been proposed.

ZIKA virus.
 The use of steroid hormones has also been tried as a way to reduce the
severity of Guillain-Barré, but controlled clinical trials have demonstrated
that this treatment not only is not effective but may even have a deleterious
effect on the disease.

ZIKA virus.
 The most critical part of the treatment for this syndrome consists of keeping
the patient's body functioning during recovery of the nervous system. This
can sometimes require placing the patient on mechanical ventilatory
assistance, a heart monitor, or other machines that assist body function. The
need for this sophisticated machinery is one reason why Guillain-Barré
syndrome patients are usually treated in hospitals, often in an intensive care
ward. In the hospital, doctors can also look for and treat the many problems
that can afflict any paralyzed patient - complications such as pneumonia or
bed sores. http://www.ninds.nih.gov/disorders/gbs/detail_gbs.htm

ZIKA virus. Original, experimental
method of therapy.
 Vascular injury,
 acutely endothelial damage can lead to vasogenic oedema
 chronically fibrosis, hyalinization and stenosis can occur with eventual
thrombosis and infarction
 vascular ectasia, and telangiectasia are also seen frequently, with capillary
telangiectasias.

ZIKA virus. ZIKA virus. Original,
experimental method of therapy.
 a viral or bacterial infection, it is possible that the virus has changed the nature
of cells in the nervous system so that the immune system treats them as foreign
cells. It is also possible that the virus makes the immune system itself less
discriminating about what cells it recognizes as its own, allowing some of the
immune cells, such as certain kinds of lymphocytes and macrophages, to attack
the myelin.
 oligodendrocytes and white matter damage
 oligodendrocytes are sensitive to viral infection.
 loss of white matter accounts for the majority of volume loss
 effects on the fibrinolytic enzyme system
 increase in urokinase plasminogen activator and simultaneous decrease in
tissue plasminogen activator may contribute to cytotoxic oedema and tissue
necrosis

 Perforin and Granzyme Inhibition with monoclonal antibodies.
 Protease Inhibition – Protease Inhibitors.
 MAC - Membrane Attack Complex Inhibition with monoclonal antibodies.

 Perforin and Granzyme Inhibition with monoclonal antibodies.
 http://www.slideshare.net/dlpopov/radiation-cytotoxicity
 http://www.slideshare.net/dlpopov/leukocyte-and-lymphocyte-
cytotoxicity?related=1
 Granzymes are serine proteases that are released by cytoplasmic granules
within cytotoxic T cells and natural killer (NK) cells. They
induce programmed cell death in the target cell, thus eliminating cells that
have become cancerous or are infected with viruses or bacteria. The
granzymes also kill bacteria and inhibit viral replication. In NK cells and T
cells, the granzymes are packaged in cytotoxic granules with perforin. Other
locations that granzymes can be detected are in the rough endoplasmic
reticulum, golgi complex, and the trans-golgi reticulum.

 The contents of the cytotoxic granules function to permit entry of the
granzymes into the target cell cytosol. The granules are released into an
immune synapse formed with a target cell, where perforin mediates the
delivery of the granzymes into endosomes in the target cell, and finally into
the target cell cytosol.
 Granzymes are identified as being part of the serine esterase family. They
are closely related to other immune serine proteases expressed by innate
immune cells, such asneutrophil elastase and cathepsin G.

 Granzyme B activates apoptosis by activate caspases (especially caspase-3),
which cleaves many substrates, including caspase-activated DNase to
execute cell death. Granzyme B also cleaves the protein Bid, which recruits
the proteins Bax and Bak to change the membrane permeability of the
mitochondria, causing the release of cytochrome c(which is one of the parts
needed to activate caspase-9 via the apoptosome), Smac/Diablo and
Omi/HtrA2 (which suppress the inhibitor of apoptosis proteins (IAPs)),
among other proteins. Granzyme B also cleaves many of the proteins
responsible for apoptosis in the absence of caspase activity. The other
granzymes activate cell death by caspase-dependent and caspase-
independent mechanisms

method of therapy.
 In addition to killing their target cells, granzymes can target and kill
intracellular pathogens.
 Granzymes A and B induce lethal oxidative damage in bacteria by cleaving
components of the electron transport chain, while granzyme B cleaves viral
proteins to inhibit viral activation and replication.
 The granzymes bind directly to the nucleic acids DNA and RNA; this
enhances their cleavage of nucleic acid binding proteins.

method of therapy.
 More recently, in addition to T lymphocytes, granzymes have been shown to
be expressed in other types of immune cells such as dendritic cells, B cells
and mast cells. In addition, granzymes may also be expressed in non-
immune cells such as keratinocytes, pneumocytes and chondrocytes. As
many of these cell types either do not express perforin or do not form
immunological synapses, granzyme B is released extracellularly. Extracellular
granzyme B can accumulate in the extracellular space in diseases associated
with dysregulated or chronic inflammation leading to the degradation of
extracellular matrix proteins and impaired tissue healing and
remodelling. Extracellular granzyme B has been implicated in the
pathogenesis of atherosclerosis, aneurysm, vascular leakage, chronic wound
healing, and skin aging.

method of therapy.
 Excessive Perforin and Granzyme possible play important role in endothelial
damage and nervous system damage.
 Perforine and Granzyme inhibition by monoclonal antibodies significantly
reduce nervous system damage.

method of therapy.
 Protease Inhibition:
 http://www.slideshare.net/dlpopov/radiation-protectionprotease-inhibition
 Proteases occur in all organisms, from prokaryotes to eukaryotes to viruses.
These enzymes are involved in a multitude of physiological reactions from
simple digestion of food proteins to highly regulated cascades (e.g., the blood-
clotting cascade, the complement system, apoptosis pathways, and the
invertebrate prophenoloxidase-activating cascade). Proteases can either break
specific peptide bonds (limited proteolysis), depending on the amino
acid sequence of a protein, or break down a complete peptide to amino acids
(unlimited proteolysis). The activity can be a destructive change (abolishing a
protein's function or digesting it to its principal components), it can be an
activation of a function, or it can be a signal in a signalling pathway.
 https://en.wikipedia.org/wiki/Protease

method of therapy.
 The activity of proteases is inhibited by protease inhibitors. One example of
protease inhibitors is the serpin superfamily, which includes alpha 1-
antitrypsin, C1-inhibitor,antithrombin, alpha 1-antichymotrypsin, plasminogen
activator inhibitor-1, and neuroserpin.
 Natural protease inhibitors include the family of lipocalin proteins, which play a
role in cell regulation and differentiation. Lipophilic ligands, attached to lipocalin
proteins, have been found to possess tumor protease inhibiting properties. The
natural protease inhibitors are not to be confused with the protease
inhibitors used in antiretroviral therapy. Some viruses,
with HIV/AIDS among them, depend on proteases in their reproductive cycle.
Thus, protease inhibitors are developed as antiviral means.
 https://en.wikipedia.org/wiki/Protease

method of therapy.
 Venoms.
 Certain types of venom, such as those produced by venomous snakes, can
also cause proteolysis. These venoms are, in fact, complex digestive fluids
that begin their work outside of the body. Proteolytic venoms cause a wide
range of toxic effects,including effects that are:
 cytotoxic (cell-destroying)
 hemotoxic (blood-destroying)
 myotoxic (muscle-destroying)
 hemorrhagic (bleeding) https://en.wikipedia.org/wiki/Proteolysis#Venoms

method of therapy.
 Inhibitors of Serine Protease.
 Inhibitors of Cysteine Protease.
 Inhibitors of Metallo-Proteases.
 Inhibitors of Aspartic Proteases.

method of therapy.
 Example of Inhibitors of proteases.
 http://iti.stanford.edu/content/dam/sm/iti/documents/himc/immunoassays/
ProteaseInhibitionGuide.pdf
 Classes of Protease Inhibitors available from Roche Applied Science

method of therapy.
 Protease Inhibitors can significantly reduce clinical symptoms of ZIKA virus
disease and complications.

 MAC - Membrane Attack Complex Inhibition with monoclonal antibodies.
 The membrane attack complex (MAC) or terminal complement
complex (TCC) is a structure typically formed on the surface
ofpathogenic bacterial cells as a result of the activation of the
host's alternative pathway, classical pathway, or lectin pathway of
thecomplement system, and it is one of the effector proteins of the immune
system. The membrane-attack complex (MAC) forms transmembrane
channels. These channels disrupt the cell membrane of target cells, leading
to cell lysis and death

 MAC - Membrane Attack Complex Inhibition with monoclonal antibodies
significantly reduce symptoms and biological sequelae of Zika virus
Diseases.

 A number of proteins participate in the assembly of the MAC. Freshly
activated C5b binds to C6 to form a C5b-6 complex, then to C7 forming the
C5b-6-7 complex. The C5b-6-7 complex binds to C8, which is composed of
three chains (alpha, beta, and gamma), thus forming the C5b-6-7-8 complex.
C5b-6-7-8 subsequently binds to C9 and acts as a catalyst in the
polymerization of C9.
 Active MAC has a subunit composition of C5b-C6-C7-C8-C9{n}.
 https://en.wikipedia.org/wiki/Complement_membrane_attack_complex

 It is composed of a complex of four complement proteins (C5b, C6, C7, and
C8) that bind to the outer surface of the plasma membrane, and many
copies of a fifth protein (C9) that hook up to one another, forming a ring in
the membrane. C6-C9 all contain a common MACPFdomain. This region
is homologous to cholesterol-dependent cytolysins from Gram-positive
bacteria.
 The ring structure formed by C9 is a pore in the membrane that allows
free diffusion of molecules in and out of the cell. If enough pores form, the
cell is no longer able to survive.
 If the pre-MAC complexes of C5b-7, C5b-8 or C5b-9 do not insert into a
membrane, they can form inactive complexes with Protein S (sC5b-7, sC5b-8
and sC5b-9). These fluid phase complexes do not bind to cell membranes
and are ultimately scavenged by clusterin and vitronectin, two regulators of
complement

 CD59 acts to inhibit the complex. This exists on body cells to protect them
from MAC. A rare condition, paroxysmal nocturnal haemoglobinuria, results
in red cells that lack CD59. These red cells can, therefore, be lysed by MAC.

 The complement system functions as an immune surveillance system that
rapidly responds to infection. Activation of the complement system by
specific recognition pathways triggers a protease cascade, generating
cleavage products that function to eliminate pathogens, regulate
inflammatory responses, and shape adaptive immune responses. However,
when dysregulated, these powerful functions can become destructive and
the complement system has been implicated as a pathogenic effector in
numerous diseases, including infectious diseases. This review highlights
recent discoveries that have identified critical roles for the complement
system in the pathogenesis of viral infection.

 Complement and viral pathogenesis
 Virology
 Volume 411, Issue 2, 15 March 2011, Pages 362–373
 Special Reviews Issue 2011
 Kristina A. Stoermer
 Thomas E. Morrisona

 CD59 is a cell surface protein that prevents formation of the
terminal membrane attack complex (MAC) involved in membrane disruption
and cell lysis.

ZIKA VIRUS: Possible immune-prophylaxis and inhibition of biological sequelae and clinical presentation after primary exposure.

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