User:Bentonm/sandbox

= Tick-borne Encephalitis + Virus (Additions) =

Epidemiology

The Tick-borne Encephalitis virus is considered endemic across many portions of the Eurasian forest steppe below altitudes of 1500m. The virus has three sub-types that span the breadth of it's reported range:

• The European, or Western, tick-borne encephalitis viral sub-type can be found most in rural areas of northern, central, and eastern Europe extending into western Russia. It's primary vector is Ixodid ricinus.
• The Siberian tick-borne encephalitis sub-type is prevalent in select areas of Eastern Europe, reaches all the way across Russia and into sections of northern Asia. It's primary vector is Ixodid persulcatus.
• The Far Eastern tick-borne encephalitis sub-type is most commonly found in forested regions of eastern Russia, China, and Japan. It's also carried by I. persulcatus.

The annual incidence rate of human infection can be highly varied depending on local environmental conditions. The trustworthiness of each country's reporting cannot always be relied upon, for example in Asia reports can be inconsistent and the full picture of the disease is still materializing. Europe reports around 3,000 cases each year. Russia alone can record between 3,000 and 10,000 cases annually. The WHO estimates that there are approximately 10,000 to 12,000 cases reported each year worldwide, but that most infections go unreported and the actual incidence rate is projected to be much higher. Travel to many endemic areas of Europe, Russia and parts of central and eastern Asia that are experiencing a budding tourism market is constantly broadening the definition of who is at risk of TBE infection. The highest risk of infection is in late spring and early summer when immature ticks are at their most active. Tick season extends through late fall when adult ticks are still looking for their last blood meal before laying a clutch of eggs, but there is less of a risk then as adults are easier to identify and remove. The number of TBE-infected ticks deviates within risk areas, but the average risk for human infection via a singular tick bite is considered to be between 1-in-200 and 1-in-1000.

Life cycle

Hard ticks of the Ixodid Genus are the primary vector of the virus, being capable of becoming infected during any of it's three life cycles and carrying that infection for the duration of it's life. Ticks have a well-developed innate immune system that generally allows them to fend off viral infections, and as such TBEV has had to develop mechanisms to avoid or dampen the tick's immune reaction in order for the infection to persist. It is hypothesized that TBEV, as well as flaviviruses as a whole, have developed to antagonize the IFN-mediated JAK-STAT signal transduction pathway, allowing the virus to inhibit the infected cell from mounting a response and generating an intracellular environment hostile to invading viruses. The precise mechanism remains unknown, but in related flaviviruses certain nonstructural proteins have been shown to be integral to this suppressive function. A mammalian host is need for virus maintenance, so while transovarial transmission between ticks is not unheard of, primarily new infections are picked up through sharing blood meals on small rodents such as voles and mice and occasionally through certain species of birds. Domestic livestock such as sheep, goats, and cattle can also be utilized as temporary hosts, however the virus cannot maintain a chronic infection in such animals. Very rarely viral transmission can occur in humans without the need of tick attachment through the consumption of unpasteurized dairy products from infected livestock, goats being the biggest contributor. Cases have also been recorded within members of the fur trade through handling infected muskrats while having exposed open cuts and abrasions.

In humans

TBE infection cannot be contracted through person-to-person interaction, with the exception of singular recorded instances of vertical transmission between mother and unborn child. Humans are accidental and dead-end hosts for the virus, and as such infection is relatively short-lived - although long term effects of the virus can follow individuals for years. The virus establishes a presence in the infected tick's saliva, resulting in incredibly fast infection of a naive human host. A study of the Powassan virus (a close relative of TBE) shows transmission to a mammalian host happening within 15 minutes of tick attachment. Rapid invasion of human cells is aided by certain proteins existing within tick saliva, which have been shown to have a variety of immunomodulatory effects that inhibit specific immune responses, including phagocytosis, macrophage pro-inflammatory cytokine production, the binding of chemokines that would otherwise recruit neutrophils and evasins, and inhibiting NK cell activity. The saliva of I. ricinus in particular is known to block dendritic cell (DC) maturation by interacting with virus-specific Toll-like receptors. TBEV effects upon DC are important as Langerhans cells (immature DC) are strategically located near the viral site of entry in the epidermis, and are a key piece in both initiating the body's immune response as well as becoming an early target for TBEV infection and replication in anticipation of proliferating the virus across more components of the immune system. The inability of langerhans cells to mature into fully-fledged antigen-presenting DC has an array of consequences for a T-cell mediated immune response to TBEV infection. A limited expression of MHC and other co-stimulatory molecules reduce the cell's ability to activate the T-cells necessary to effectively clear the virus from cell populations, and phenotypically immature DCs have also been shown to induce immunosuppressive regulatory T (Treg) cells. Treg cells are important for controlling immune response intensity, and their over-expression can contribute to virus survival and pathogenesis. Infected DC's will eventually transport the virus to nearby lymph nodes, where they will replicate and travel into the bloodstream and to CNS neurons within the theca. From there that TBEV infection can culminate in it's more serious second-stage symptoms.

Signs and symptoms

A range of symptoms can be observed in every sub-type, it's classic biphasic symptomatology (meaning there is a fever following by neurological complications) being most closely associated with the more mild European sub-type - where it is present in up to two-thirds of infected persons - but generally can be observed occurring in all three. Viral incubation lasts anywhere between one and two weeks with no ill effects, with the maximum recorded range of incubation lasting from 2 days at it's shortest to 28 days at the most drawn out. However when they do manifest, initial symptoms of infection in human hosts are similar to those of influenza, including a high fever, malaise, myalgia, headaches, general nausea and vomiting, and in some cases anorexia. Shorter incubation times have been reported for infections contracted via milk-borne exposure. First-stage symptoms last for approximately 8 days, with most individuals mounting a full recovery thereafter. Any second-stage symptoms materializing in doubt 20-30% of affected individuals after about a week of a short-term remission, indicating the virus has successfully spread to the protective layer of tissue that covers the spinal cord, brain, or both. This second round of symptoms are much more likely to cause enduring harm, and are heralded by a sudden spike in temperature with clinical features of meningitis in 50% of cases, encephalitis in 40% of cases, and meningoencephalitis in 10% of cases. Second-stage illness generally will require hospitalization and are gradually alleviated over the course of a few weeks, although it may take anywhere from a few months to several years to make a full recovery of the associated long-term neurologic complications that present themselves in anywhere between 30-60% of second-stage affected cases. Long-term complications can (in some cases) become permanent, and encompass: memory problems, changes in mental state, problems with impulse control, sensitivity to bright light, trouble maintaining concentration for any period of time, seizures, and occasionally paralysis or an inability to speak. Second-stage symptoms in adults over 40 are at an increased risk of meningoencephalitis and meningoencephalomyelitis, along with a much higher mortality rate in affected persons over the age of 60. Advance illness in children is almost always limited to meningitis. The European TBEV sub-type is generally found to be more severe in adults, but Siberian and Far-eastern infections are more dangerous overall and far worse in children. The Siberian strain in particular is widely suggested to be responsible for chronic meningitis in children. Mortality resulting from a European sub-type infection ranges between 1-2% of all cases, with death occurring within 5 to 7 days after the onset of neurological signs, whereas the two other sub-types average a much higher 5-20% mortality.

Diagnosis

Diagnostic confirmation of infection can be determined through the collection of blood or cerebrospinal fluid (CSF). The virus itself can only be isolated from the blood in the first phase of infection, and can also be detected through abnormalities such as a low platelet or white blood cell count, or in some cases by slightly elevated levels of liver enzymes in the serum. Upon the onset of second-stage symptoms diagnosis is typically only possible through testing for specific B cell antibodies in the blood or CSF (depending on how far along the infection is). The second stage is also commonly associated with a sudden increase in white blood cell count in the body.

Structure

TBEV is a viral hemorrhagic fever of the family Flaviviridae, meaning that it's a positive. single-stranded RNA virus. TBE falls under the serocomplex of the same name along with other emerging and re-emerging pathogens, which include all flaviviruses. The TBEV virion is enveloped in a protein capsid, and houses an RNA genome 11kb in length, and is organized as having a large open-reading frame flanked by 5' and 3' non-coding regions. Translation of the genome results in a lone polyprotein that will be cleaved by viral and in-host cellular processes into three structural proteins (C, prM/M, and E), as well as seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5). The capsid (C) protein binds to the RNA strand and catalyses the envelopment of itself within a lipid bilayer peppered with prM and E proteins to form a spherical nucleocapsid. The membrane and precursor membrane (prM/M) protein prevents the E protein from fusing with the newly-derived membrane too early in immature virions. Infected cells will begin secretion of mature virions once the precursor (prM) fragment has been cleaved by C-X-C chemokine receptor type 4 (CXCR-4, also known as fusin) within the host's trans-Golgi network. The envelope (E) protein is known to be integral to receptor binding and membrane fusion. It is also the immunodominant antigen on the capsid to be recognized by the host body's immune response. Per their name, nonstructural proteins are not included in forming the physical composition of the virion, and many of their functions remain as of yet unknown. Their involvement in virus-host interactions remain poorly understood, although NS4B and NS5 have been identified in flaviruses as having selectively immunosuppressant properties. In addition, multiple NS functions have also been found linked to virus replication and the processing of the polyprotein via modification of the endoplasmic reticulum.

Treatment and prevention

TBE has no known drug therapy available to date, but the majority of symptoms experienced by affected individuals should be mild enough not to require attention beyond over the counter painkillers such as ibuprofen or acetaminophen. Access to a vaccine si available in some endemic countries, but adverse reactions in children limit their usefulness, and testing for more effective alternatives is still ongoing. One of the more pervasive vaccines, Ticovac and it's children-specific counterpart Ticovac Jr. (also known as FSME IMMUNE and FSME IMMUN Junior, respectively) may be effective against the far-eastern viral strain, but is specifically meant to prevent against the European sub-type. The optimum window for any TBE vaccination is starting in the winter months preceding the spring in order to ensure protection before the emergence of tick nymphs from diapause. Vaccination is not advisable if the individual is currently presenting a fever, has an auto-immune disease, is an expectant or nursing mother, or has a pre-existing cerebral disorder. Adverse reactions to vaccination is relatively rare, and when present are commonly mild and fleeting. When reported, the most common side effects include pain, and tenderness at the site of injection as well as a more general sense of fatigue and muscle aches. Headaches in particular are more associated with vaccinations in children, in addition to a feeling of restlessness and light fever. TBE immunoglobin treatment was previously administered after tick attachment as a form of post-exposure prophylaxis, but concerns that it may have negative effects on the course of the disease has made it an unpopular course of treatment in present-day.