The continued threat of emerging flaviviruses

Abstract

F laviviruses are single-stranded RNA viruses vectored principally by arthropods that cause severe illnesses in humans. The extensive global spread and epidemic transmission of flaviviruses during the last seven decades has been remarkable. The mosquito-borne dengue viruses (DENV) infect an estimated 400 million humans each year; more than a quarter of the world's population lives in areas where DENV is now endemic 1 . By comparison, only sporadic DENV epidemics were documented before the Second World War 2 . The introductions of West Nile (WNV) and Zika (ZIKV) viruses into the Western Hemisphere was followed by rapid geographical spread, large numbers of human infections and considerable morbidity 3,4 . Ongoing yellow fever virus (YFV) transmission and its encroachment on urban environments, despite the existence of an effective vaccine, poses a serious public health challenge 5-7 . Other flaviviruses present ongoing health risks or are beginning to emerge in different parts of the world, including Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV) and Usutu virus (USUV).The epidemic potential of flaviviruses reflects many factors related to the unique characteristics of their insect vectors, the consequences of poorly planned urbanization that creates ideal arthropod breeding habitats, the geographical expansion of vectors, changing environmental conditions and extensive global travel 8,9 . Beyond arthropods and humans, flaviviruses are also known to infect a wide array of animal species and can be important veterinary pathogens that threaten economically important domesticated animals 10-14 . These vertebrate animal hosts may constitute important stable reservoirs and contribute to defining conditions that support the introduction of new viral species and transmission among humans 15 . The continued threat of flavivirus emergence and re-emergence highlights a need for a detailed fundamental understanding of the biology of these viruses, the immune responses that can contain them and the possible countermeasures that can blunt their impact on public health should new outbreaks occur. Flavivirus structure and replicationFlaviviruses are small (~50 nm) spherical virus particles that incorporate a single genomic RNA of positive-sense polarity encoding three structural and seven non-structural proteins (Fig. 1a). Our knowledge of the biology of flaviviruses has advanced considerably with the availability of high-resolution structures of viral structural proteins and of virions at different stages of the replication cycle or in complex with antibodies or host factors 16 . Crystal structures of the enzymatic non-structural proteins also have been solved, accelerating advances in an understanding of virus replication and pathogenesis [17][18][19] and enabling structure-guided drug discovery, as reviewed elsewhere 20 .Virion structure and morphogenesis. Flaviviruses are assembled using three viral structural proteins (C, prM and E), a host lipid envelope and the viral genomic RNA. The structure of ...

Construction of Stable Reporter Flaviviruses and Their Applications

“…The past two decades have been a lesson in the potential of unknown or unrecognized RNA viruses to emerge from animal reservoirs in new locations to cause local epidemics or widespread pandemics. In 1999, the United States saw the introduction of West Nile virus, which has caused tens of thousands of cases of neurological disease [ 1 ]. Subsequently, 2002 saw the first outbreak caused by a new coronavirus, severe acute respiratory syndrome coronavirus (SARS CoV), which infected thousands of people before control measures ended its spread [ 2 ].…”

“…Collectively, these viruses cause greater than 390 million infections yearly, with the majority of those being from the four serotypes of dengue virus [ 7 ]. Along with the more well-known and studied of the Flaviviruses, come a number of lesser known but emerging family members with outbreak potential [ 1 ]. Discouragingly, current medical countermeasures are restricted to vaccines with limited availability or efficacy and no direct-acting antivirals [ 8 ].…”

Structure-guided paradigm shifts in flavivirus assembly and maturation mechanisms

“…Though there have been many studies aimed at the development and identification of small molecule inhibitors capable of preventing and treating flavivirus infections (reviewed extensively in Pierson and Diamond, 2020 ), there are currently no antiviral therapeutics clinically approved for the treatment of flavivirus infected individuals, nor for use in preventative measures in at risk populations. There exists a significant need to produce therapeutics and vaccines capable of reducing the spread of flaviviruses.…”

A versatile reporter system to monitor virus infected cells and its application to dengue virus and SARS-CoV-2

“…Positive sense single stranded RNA viruses constitute a major fraction of endemic and emerging human viruses (1). Among the positive-strand RNA viruses, flaviviruses such as dengue virus (DENV) and Zika virus (ZIKV) are some of the most prevalent arboviral pathogens and are considered a major public health problem (2,3).…”