Flaviviruses

Morphology:

Genome:

Single-stranded, (+)sense RNA, ~10.5kb. The genome has a 5' cap but is not polyadenylated at the 3' end. The genetic organization differs from Togaviruses - structural proteins at 5' end of genome, N.S. at 3' end:

Replication:

The initial stages are similar to Togavirus replication (occurring in cytoplasm), but there are significant differences:

1. The entire flavivirus genome is translated as a single polyprotein which is then cleaved into the mature proteins (as in Picornaviruses, c.f. Togaviruses).
2. Complementary (-)strand RNA is synthesized by NS proteins, used as a template for genomic progeny RNA synthesis:
   Filomatori CV, et al. A 5' RNA element promotes dengue virus RNA synthesis on a circular genome. Genes Dev. 2006 20: 2238-2249: The mechanisms of RNA replication of plus-strand RNA viruses are still unclear. Here, we identified the first promoter element for RNA synthesis described in a flavivirus. Using dengue virus as a model, we found that the viral RdRp discriminates the viral RNA by specific recognition of a 5' element named SLA. We demonstrated that RNA-RNA interactions between 5' and 3' end sequences of the viral genome enhance dengue virus RNA synthesis only in the presence of an intact SLA. We propose a novel mechanism for minus-strand RNA synthesis in which the viral polymerase binds SLA at the 5' end of the genome and reaches the site of initiation at the 3' end via long-range RNA-RNA interactions. These findings provide an explanation for the strict requirement of dengue virus genome cyclization during viral replication.
3. Assembly occurs during budding, characteristically into cytoplasmic vacuoles rather than at the cell surface. Release occurs when cell lyses.

Pathogenesis:

Host Range: Many species can replicate in both mammalian and insect cells. Can survive for long periods in hosts such as ticks by replicating in this host (without damage to the insect).

Pathogenesis: Produce a wide range of diseases - fever; arthralgia; rash; haemorrhagic fever; encephalitis). The outcome of infection is influenced by both virus and host-specific factors (age, sex, genetic susceptibility, pre-exposure to same or related agent).

Yellow Fever

(Latin 'flavus' = yellow). One virus, of invariant serotype, first recognized by Walter Reed, 1900 (Panama Canal). Transmitted by mosquitoes.
Pathogenesis: After an incubation period of 3 to 6 days, 5% to 50% of infected people develop disease, beginning with a nonspecific 1- to 3-day febrile illness, followed by a brief remission, and then by a life-threatening "toxic" syndrome accompanied by epistaxis, other hemorrhagic phenomena, jaundice, and disseminated intravascular coagulation. Mortality rates for yellow fever are approximately 20%. Diagnosis of the disease is established by cultivation of the virus from blood (serum) or tissue, antigen detection by immunofluorescence or immunohistochemistry, RNA detection by RT-PCR (reverse transcriptase polymerase chain reaction), or by specific antibody detection. Transient viraemia, primary multiplication in lymph nodes; secondary multiplication occurs in liver (jaundice), spleen, kidneys, heart and bone marrow with much tissue damage. Genetic variation between different human populations results in various severity of disease, but genes involved are not known.
Epidemiology: Yellow fever endemic zones are located between 15° N and 10° S latitude in Africa and South America. It is estimated that the global incidence of yellow fever is around 200,000 cases annually. Urban yellow fever is responsible for most cases, and this form of the disease has been increasing dramatically in Africa over the past 15 years (see Emerging Viral Diseases). Yellow fever is reported by 33 countries worldwide, but 90% of cases occur in Africa, and only 10% in South America. In the Americas, jungle yellow fever remains the dominant type due to the growing importance of epizootic disease, which occurs at the interface between jungle and urbanized areas. Imported yellow fever is a threat to all countries - in 1996, 15 million Americans traveled to and from yellow fever endemic regions.
17D - live attenuated vaccine strain (Theiler 1937) - very effective. This has eradicated yellow fever from USA - much more difficult to tackle in central and S. America where mosquito control is less effective. With greater vaccine usage among elderly travelers, a previously unknown vaccine-associated complication is being recognized: viremia and systemic disease resembling yellow fever. This complication is 12-fold more likely in persons older than 45 years.

Tutorial on Yellow Fever

UK Department of Health current vaccination guidelines

MicrobiologyBytes: Yellow Fever - Out of Africa

Dengue Fever

Epidemiology: This disease was first described 1780, and the virus was isolated by Sabin 1944. Dengue virus infection is the most common arthropod-borne disease worldwide with an increasing incidence in the tropical regions of Asia, Africa, and Central and South America. There are four serotypes of the virus. All are transmitted by mosquitoes, which are not affected by the disease, although an infected mosquito may infect others (not via man). The global prevalence of dengue has grown dramatically in recent decades. The disease is now endemic in more than 100 countries in Africa, the Americas, the Eastern Mediterranean, South-east Asia and the Western Pacific. South-East Asia and the Western Pacific are most seriously affected. Some 2,500 million people - two fifths of the world's population - are now at risk from dengue. It is estimated that there may be 50 million cases of dengue infection worldwide every year. Pathogenesis: Primary infection may be asymptomatic or may result in dengue fever. This is generally a self-limiting febrile illness which occurs after a 4-8 day incubation period. It has symptoms such as fever, aches and arthralgia (pain in the joints) which can progress to arthritis (inflammation of the joints), myositis (inflammation of muscle tissue) and a discrete macular or maculopapular rash. In this situation clinical differentiation from other viral illnesses may not be possible, recovery is rapid, and need for supportive treatment is minimal. Mongkolsapaya J, et al. Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nature Med. 2003 9: 921-927

Dengue haemorrhagic fever (DHF) is a potentially deadly complication. The incubation period is unknown but is likely to be similar to that of dengue fever. Dengue hemorrhagic fever commences with high fever and many of the symptoms of dengue fever, but with extreme lethargy and drowsiness. The patient has increased vascular permeability and abnormal homeostasis (homeostasis is the maintenance of equilibrium, or constant conditions, in a biological system) that can lead to hypovolemia (abnormal decrease in blood volume) and hypotension (drop in blood pressure), and in severe cases, result in hypovolemic shock (Shock due to a decrease in blood volume) often complicated by severe internal bleeding.

Dengue shock syndrome (DSS) results from leakage of plasma into the extravascular compartment. Rapid and poor volume pulse, hypotension, cold extremities, and restlessness occur. In addition to the plasma leakage, which is the result of generalized vasculitis, disseminated intravascular coagulation is present. Dengue shock syndrome is usually a progression of dengue haemorrhagic fever and is often fatal.
The four serotypes of dengue virus that have 60-80% homology to each other. Infection with one dengue serotype provides lifelong homologous immunity but limited heterologous immunity. Almost all patients with DHF have had previous experience with at least one of the four serotypes of dengue viruses. Upon infection, the immune response produced specific antibodies to that subtype's surface proteins that prevents the virus from binding to macrophage cells (the target cell that dengue viruses infect) and gaining entry. However, if another subtype of dengue virus infects the same individual, the virus will activate the immune system to attack it as if it was the first subtype. Antibodies are produced to combat the sub type previously encountered. These antibodies bind to the surface proteins but do not inactivate the virus. The immune response attracts numerous macrophages, which the virus proceeds to infect because it has not been inactivated. The hypothesis that heterotypic antibodies from a previous dengue virus infection promote increased viral replication within mononuclear leukocytes by antibody-dependent enhancement, causing the symptoms to be much more serious. The body also releases cytokines that cause the endothelial tissue to become permeable, which results in hemorrhagic fever and fluid loss from the blood vessels
Of cascades and perfect storms: the immunopathogenesis of dengue haemorrhagic fever-dengue shock syndrome (DHF/DSS). Immunol Cell Biol. Nov 28 2006.

Treatment: The management of dengue fever is supportive with bed rest, adequate fluid intake, and control of fever and pain with antipyretics and analgesics (e.g. paracetamol). For the more severe manifestations of dengue virus infection, appropriate management requires early recognition and rapid intravenous fluid replacement. In severe cases blood transfusions may be required.
There is currently no vaccine is available to protect against dengue infection. There are three major concerns in the development of a dengue vaccine. Firstly is the possibility that it could lead to antibody-dependent enhancement of infection and thus produce DHF/DSS. Candidate vaccines based on live attenuated viruses should therefore contain all four serotypes to give comprehensive protection without adverse side effects. Another concern is the possibility of virus evolution through genome recombination. A third concern is that the vaccine may produce adverse reactions, for example, recently a tetravalent live attenuated vaccine was tested in human volunteers and in children, phase I and phase II trails have shown mildly adverse reactions with monovalent vaccines, but more frequent and significantly more severe reactions with the tetravalent vaccine.
The present lack of a successful vaccine against the dengue virus, causes prevention methods to be approached by reducing disease vector population, with Integrated Pest Management (IPM) programs for mosquito control. These utilize a combination of control strategies, including mosquito surveillance, source reduction, eradicating larvae and eradicating adult mosquitoes. Eradicating adult mosquitoes alone is ineffective in controlling mosquito populations because it is difficult to treat the inaccessible habitat of the adults. Mosquito larvae are left to continue their development, and they quickly replace the adults. However, mosquitoes can build up resistance if pesticides are overused.

West Nile Virus

West Nile virus is a member of the Japanese encephalitis antigenic complex of the genus Flavivirus, family Flaviviridae. All known members of this complex (Alfuy, Japanese encephalitis, Kokobera, Koutango, Kunjin, Murray Valley encephalitis, St. Louis encephalitis, Stratford, Usutu, and West Nile viruses) are transmissible by mosquitoes and many of them can cause febrile, sometimes fatal, illnesses in humans. West Nile virus was first isolated in the West Nile district of Uganda in 1937 but is in fact the most widespread of the flaviviruses, with geographic distribution including Africa and Eurasia. Unexpectedly, an outbreak of human arboviral encephalitis attributable to a mosquito-transmitted West Nile-like virus (WNLV) occurred in New York and surrounding states in 1999, resulting (to January 2000) in ~50 cases and 7 deaths. In this case, the virus appears to have been transmitted from wild, domestic and exotic birds by Culex mosquitoes - a classic pattern of arbovirus transmission. West Nile virus RNA has been detected in overwintering mosquitoes in New York city & the geographic range of the virus is increasing in the USA.

• Medscape: West Nile Virus: A Reemerging Global Pathogen
• Dauphin G, Zientara S. West Nile virus: Recent trends in diagnosis and vaccine development. Vaccine 2006

West Nile virus activity - United States, January 1 - September 12, 2006. MMWR 2006 55: 996.

Many Flaviviruses are particularly important in that they are emerging viruses.

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