Arboviruses

Arboviruses (arthropod-borne virus) are transmitted by arthropods, primarily mosquitoes and ticks. It is a collective term for a large group of diverse viruses, more than 400.

*Family*	Genus	Genome	Viruses of Medical Interest in USA
Togavirus	Alphavirus	ss (+) RNA	Western, Eastern, and Venezuelan encephalitis viruses, Chikungunya; rubella virus (respir. secretions)
Flavivirus	Flavivirus	ss (+) RNA	Yellow Fever, Dengue, St. Louis Encephalitis, Japanese B encephalitis viruses, hepatitis C^*
Bunyavirus	Bunyavirus	3 segments of (-) RNA H-bonded to each other	California encephalitis virus
Reovirus	Orbivirus	10-11 segmented ds RNA	Colorado tick fever virus

Hepatitis C is not transmitted by arthropods

Important Properties

Morphology – enveloped icosahedral nucleocapsid (exception: Reovirus have a naked double-layered capsid).

Transmission – arboviruses multiply in both the vertebrate host (frequently birds and rodents) and the bloodsucking vector. Viruses are distributed from vector to host to vector to host. As such humans are usually "dead-end" hosts because the [virus] in human blood is too low and the duration of viremia too brief for the next bite to transmit the virus.

Findings – Hemorrhagic fevers kill by causing shock, hepatitis and encephalitis may involve destruction of host cells by the infecting virus.

Proteins – Structural proteins: Capsid or Nucleoproteins coat the genomic RNA.

Flavivurses: Matrix protein that is membrane associated and a glycosylated envelope protein.

Togaviruses: Envelope proteins E1 and E2.

Both: non-structural proteins for replication including polymerase and proteases.
(Dengue Virus: NS-5 and NS-3 cooperate to form the RNA dependent RNA polymerase)

Replication of Flavivirus and Togavirus

Flavivirus and Togavirus Replication Cycle

(1) viral attachment to envelope glycoproteins

(2) entry via receptor mediated endocytosis Þ break through endosome

(3) genome replication occurs in the cytoplasm

(4) see ‘replication schemes’ below, flavivirus and togavirus differ.

(5) Viral assembly at the plasma membrane and release by budding (no lysis)

Replication Schemes

Flavivirus:

(1) translation of: capsid or nucleocapsid protein (N), surface glycoproteins (E), surface protein structures (M), and non-structural replication proteins.
(2) proteolytic processing
(3) synthesis of (-) mRNA
(4) synthesis of full length mRNA

Other characteristics: no poly (A) tail, rather uses 3’ hair-pin loop as primer for (-) mRNA strand. Has 5’ cap.

Togavirus:

(1) translation and processing of replication proteins
(2) synthesis of (-) strand mRNA
(3) synthesis of full-length mRNA and subgenomic mRNA
(4) translation of non-structural (C=capsid, E1 and E2=glycoproteins) and structural proteins; proteolytic processing
(5) assembly and release at membrane

Other characteristics: poly (A) tail is present, also has 5’ cap.

Dengue and Dengue Hemorrhagic Fever (DHF)

Etiology: ss (+) RNA flavivirus, see above for replication characteristics.

Serotypes: 4 closely related serotypes (Dengue 1-4). Can have infection with more than one of these at a time.

Occasionally can develop cross-reactive antibodies.

Vector: Aedes aegypti most common vector. Aedes albopicturs potential vector in temperate climates.

Epidemiology: Tropics, particularly coastal, urban areas. 100,000,000 cases/year. DHF often seen in SE Asia, Caribbean, Central and South America.

Pathogenesis: DHF is most severe in kids experiencing their 2^nd episode of infection with a different serotype from the 1^st virus infection, or infants losing passive maternal Abs – the reason for this is immune enhancement

Immune enhancement: Patient recovers from classic dengue and now has Abs against one of the serotypes. Once infected with another serotype the old antibodies act in a cross-reactive manner and bind the new virus! Immune complexes composed of virus and Ab are formed, activate complement, and cause Ý vascular permeability and thrombocytopenia. Shock and Hemorrhage result. Further, macrophages get hyperinfected and get eliminated by T cells. These destroyed macrophages release thromboplastin stimulating the clotting cascade and causing disseminated intravascular coagulation (DIC).

Clinical Presentation

Adults: symptomatic with fever, join and muscle pain ("breakbone fever", "7-day fever"), maculopapular rash and photophobia.

Children: usually asymptomatic or with limited fever, but 1-5% progress to DHF. Bleeding occurs on the 2^nd-3^rd day; shock on the 4^th day. Shock may come and go throughout 24h, therefore, patients require constant surveillance.

Stages of Dengue Syndromes:

(1) Fever, malaise
(2) Hemorrhagic manifestations (+ tourniquet test = petechiae)
(3) Thrombocytopenia (<100,000/mL), circulatory failure, hypotension, shock
(4) Hemoconcentration: hematocrit increased by > 20%. Profound Shock.

Future vaccine and control strategies:

Antiviral vaccines – any vaccine must address the problem of immune enhancement.
Vector competence – genetically engineered resistance to viral infection in mosquitos.