NC State University Microbiology- Scholle laboratory: Flavivirus pathogenesis and host interactions

FLAVIVIRUS PATHOGENESIS

NC STATE UNIVERSITY


FRANK SCHOLLE, PhD.

 


Flavivirus background


The family Flaviviridae contains numerous important human and animal pathogens that cause diverse pathologies including febrile illness, hemorrhagic fever, and encephalitis. Most members of the Flavivirus genus are transmitted by arthropod vectors, such as mosquitoes in case of yellow fever virus (YFV), dengue virus (DENV), Japanese encephalitis virus (JEV) and West Nile virus (WNV) and ticks in case of tick-borne encephalitis virus (TBEV).


    Dengue includes a spectrum of illnesses caused by infection with one of four serotypes of dengue virus (DENV) that occur in more than 100 countries in many tropical and subtropical regions of the world. DENV causes an estimated 100 million infections per year and 100s of thousands of cases of severe dengue. DENV causes a febrile illness, dengue fever, that is rarely fatal, but a portion of DENV-infected patients develops a more severe disease known as dengue hemorrhagic fever.


JEV is the arbovirus thought to be responsible for the largest number of human fatalities. There are 10,000 lethal cases every year of an estimated 50,000 cases of JE. Many JE survivors develop permanent neurological sequelae. JEV is also an important pathogen in horses and pigs, with infections of the latter producing a public health problem in some regions of the world, since pigs amplify the virus peri-domestically, facilitating spread to humans.


YFV has a significant effect on tropical public health in Africa and the Western Hemisphere, despite the existence of an effective vaccine. The WHO estimates that the number of cases reaches 200,000 per year even though only a few hundred are reported each year. YF epidemics caused significant morbidity and mortality in the US until mosquito control was used to prevent YFV transmission.


WNV was first isolated in Africa in the late 1930s but was not considered to be as important a public health problem as other flaviviruses. Since its introduction into the US in 1999, WNV has been responsible for thousands of cases of encephalitis and hundreds of deaths. The disease it causes is similar to that produced by JEV infection, but WNV infections are more likely to be severe in the elderly, whereas severe JEV infections are most often seen in children.



West Nile virus transmission cycle. WNV is maintained in an infection cycle involving birds and mosquito. Once a bird is infected, the virus replicates to high titers to allow reinfection of a feeding mosquito. After initiating infection in the gut of the mosquito, the virus eventually spreads to the salivary glands and can be retransmitted to a new host. Occasionally mosquitos will of course feed on species other than birds. Often, as is the case for humans and horses, the virus can cause severe disease in these species but does not replicate to titers high enough to allow reinfection of a feeding mosquito. These hosts are therefore also referred to as dead-end hosts.

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Contact


Frank Scholle

Department of Microbiology

CB 7615

NCSU

Raleigh, NC, 27695-7615


frank_scholle@ncsu.edu


  1. (919)513-7574 (phone)

(919) 513-7644 (lab)

Research Interests:

My research focuses on interactions of flaviviruses and West Nile virus in particular with the innate immune response of the host. Flaviviruses are positive-strand RNA viruses that are predominantly transmitted through arthropod vectors. Some prominent members of the family Flaviviridae include Yellow fever virus, the dengue viruses and West Nile virus. The innate immune system is the first line of defense against invading pathogens and includes the recognition of a pathogen, the stimulation of proinflammatory cytokine production and ultimately influences the activation and orientation of the adaptive immune response. West Nile virus has evolved mechanisms to interfere with several aspects of this first response, namely by inhibiting signal transduction from the interferon receptor and by blocking signaling through Toll-like receptors,  molecules involved in the recognition of pathogen specific molecular patterns. TLR engagement leads to activation of specific transcription factors and production of cytokines and/or type I interferons. These processes are inhibited in WNV-infected cells. Our research has shown that the WNV nonstructural protein NS1 can inhibit TLR signal transduction. We are currently investigating the mechanism of this inhibition as well as the potential roles of TLRs in WNV pathogenesis and induction of an adaptive response. A variety of different approaches are used in my laboratory to investigate these issues including  classical molecular virology, molecular cell biology, mouse pathogenesis studies and immunological studies.

NCSU Links:

Scholle lab page links:

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