Venezuelan equine encephalitis virus in the mosquito vector Aedes taeniorhynchus: Infection initiated by a small number of susceptible epithelial cells and a population bottleneck

Smith, Darci R.; Adams, Alexandra; Kenney, Joan L.; Wang, Eryu; Weaver, Scott C.

doi:10.1016/j.virol.2007.10.011

Cited by 98 publications

(111 citation statements)

References 40 publications

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“…The MOI differed by several orders of magnitude between the two virus-strain/mosquito-species pairs, as suggested by previous estimates of cell coinfection (6,7). Figure 1 shows the inferred distribution of MOI values among the population of infected cells.…”

supporting

confidence: 60%

Demographics of Natural Oral Infection of Mosquitos by Venezuelan Equine Encephalitis Virus

Gutiérrez

Thébaud

Smith

et al. 2015

J Virol

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The within-host diversity of virus populations can be drastically limited during between-host transmission, with primary infection of hosts representing a major constraint to diversity maintenance. However, there is an extreme paucity of quantitative data on the demographic changes experienced by virus populations during primary infection. Here, the multiplicity of cellular infection (MOI) and population bottlenecks were quantified during primary mosquito infection by Venezuelan equine encephalitis virus, an arbovirus causing neurological disease in humans and equids. RNA viral infections generally generate large and diverse populations within the infected host. This diversity plays a key role in important epidemiological and evolutionary processes (1-3). However, several steps during transmission can constrain the demographics and genetics of the virus population, with host primary infection being one of the main barriers.During primary infection, the number of initially infected cells is not infinite, potentially lowering the size and genetic diversity of the colonizing population compared to that present in the donor host. The multiplicity of cellular infection (MOI) in those cells is thus a fundamental parameter determining the demographics and genetics of the colonizing population. The MOI is the number of genomes of a virus that enter and replicate in a cell (4). This parameter impacts the size of population bottlenecks during primary infection because, for a given number of primary infected cells, the higher the MOI, the larger the colonizing population. Furthermore, the MOI also influences genetic diversity, as it largely defines the intensity of genetic exchange and complementation among genotypes during cell coinfection.Despite the importance of the MOI and population bottlenecks, there is a striking lack of formal estimates of these parameters, not only during primary infections but throughout the virus transmission cycle (reviewed in reference 4). Here, we use available data sets to estimate the demographics of Venezuelan equine encephalitis virus (VEEV), a mosquito-borne arbovirus, during the primary oral infection (i.e., the midgut infection) of its mosquito vectors.VEEV is an alphavirus in the family Togaviridae that periodically causes epidemics and equine epizootics. It circulates in two transmission cycles, the epizootic/epidemic (here called epizootic) and enzootic cycles, with distinct strains and mosquito species associated with each cycle. Enzootic VEEV strains are generally associated with the absence of disease in equids, with the exception of certain subtype IE strains (5), and transmission cycles are associated with forest mosquitos, mainly Culex (Melanoconion) spp., and rodent hosts. Epizootic strains tend to be highly pathogenic to equids and can be transmitted by mosquito species that feed principally on large mammals, like Aedes (Ochlerotatus) taeniorhynchus. Vector susceptibilities vary widely, with enzootic VEEV strains typically exhibiting highly efficient but specific infectivit...

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supporting

confidence: 60%

Demographics of Natural Oral Infection of Mosquitos by Venezuelan Equine Encephalitis Virus

Gutiérrez

Thébaud

Smith

et al. 2015

J Virol

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“…Passage history for virus strains used has been previously published (13,14). Detailed descriptions of the molecular cloning methods used to construct recombinant WEEV.McM reporter viruses are provided below and have been previously published (7).…”

Section: Virusesmentioning

confidence: 99%

“…We also used epifluorescence and confocal microscopy to precisely map sites of virus replication in mice using WEEV.McM expressing DsRed. Recombinant, double-subgenomic WEEV.McM or VEEV.3908 (subtype IC) expressing fLUC (13) and WEEV.McM expressing DsRed (Fig. 1A) were used in this study.…”

mentioning

confidence: 99%

Entry Sites of Venezuelan and Western Equine Encephalitis Viruses in the Mouse Central Nervous System following Peripheral Infection

Phillips

Rico

Stauft

et al. 2016

J Virol

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Venezuelan and western equine encephalitis viruses (VEEV and WEEV; Alphavirus; Togaviridae) are mosquito-borne pathogens causing central nervous system (CNS) disease in humans and equids. Adult CD-1 mice also develop CNS disease after infection with VEEV and WEEV. Adult CD-1 mice infected by the intranasal (i.n.) route, showed that VEEV and WEEV enter the brain through olfactory sensory neurons (OSNs). In this study, we injected the mouse footpad with recombinant WEEV (McMillan) or VEEV (subtype IC strain 3908) expressing firefly luciferase (fLUC) to simulate mosquito infection and examined alphavirus entry in the CNS. Luciferase expression served as a marker of infection detected as bioluminescence (BLM) by in vivo and ex vivo imaging. BLM imaging detected WEEV and VEEV at 12 h postinoculation (hpi) at the injection site (footpad) and as early as 72 hpi in the brain. BLM from WEEV.McM-fLUC and VEEV.3908-fLUC injections was initially detected in the brain's circumventricular organs (CVOs). No BLM activity was detected in the olfactory neuroepithelium or OSNs. Mice were also injected in the footpad with WEEV.McM expressing DsRed (Discosoma sp.) and imaged by confocal fluorescence microscopy. DsRed imaging supported our BLM findings by detecting WEEV in the CVOs prior to spreading along the neuronal axis to other brain regions. Taken together, these findings support our hypothesis that peripherally injected alphaviruses enter the CNS by hematogenous seeding of the CVOs followed by centripetal spread along the neuronal axis. IMPORTANCEVEEV and WEEV are mosquito-borne viruses causing sporadic epidemics in the Americas. Both viruses are associated with CNS disease in horses, humans, and mouse infection models. In this study, we injected VEEV or WEEV, engineered to express bioluminescent or fluorescent reporters (fLUC and DsRed, respectively), into the footpads of outbred CD-1 mice to simulate transmission by a mosquito. Reporter expression serves as detectable bioluminescent and fluorescent markers of VEEV and WEEV replication and infection. Bioluminescence imaging, histological examination, and confocal fluorescence microscopy were used to identify early entry sites of these alphaviruses in the CNS. We observed that specific areas of the brain (circumventricular organs [CVOs]) consistently showed the earliest signs of infection with VEEV and WEEV. Histological examination supported VEEV and WEEV entering the brain of mice at specific sites where the blood-brain barrier is naturally absent. E astern, Venezuelan, and western equine encephalitis viruses (EEEV, VEEV, and WEEV; Alphavirus; Togaviridae) are mosquito-borne viruses in the Americas causing central nervous system (CNS) disease in humans and equids (1). EEEV, VEEV, and WEEV are maintained in nature via transmission cycles between vertebrate hosts and specific mosquito species (2). Historically, these alphaviruses have caused sporadic epizootics and epidemics in horses and humans, respectively (1, 3). Outbreaks have led to significant rates of morbidity...

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“…Epidemic outbreaks of the epizootic strains occur in 10-20-year intervals in the ranch areas in Peru, Venezuela, Colombia and Ecuador after heavy rainfall, which lead to increased mosquito populations (Rivas et al 1997). Enzootic strains are transmitted by Culex species, whereas the main vector of the epizootic strains seems to be Ochlerotatus taeniorhynchus and possibly also Psorophora confinnis, but nearly all mosquito species have been found to be infected during epizootics (Rivas et al 1997;Smith et al 2008;Zacks and Paessler 2010). Weaver et al (1992) list Culex cedeci, Cx.…”

Section: Togaviridaementioning

confidence: 99%

Bats as Potential Reservoir Hosts for Vector-Borne Diseases

Melaun

Werblow

Busch

et al. 2013

Bats (Chiroptera) as Vectors of Diseases and Parasites

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Venezuelan equine encephalitis virus in the mosquito vector Aedes taeniorhynchus: Infection initiated by a small number of susceptible epithelial cells and a population bottleneck

Cited by 98 publications

References 40 publications

Demographics of Natural Oral Infection of Mosquitos by Venezuelan Equine Encephalitis Virus

Demographics of Natural Oral Infection of Mosquitos by Venezuelan Equine Encephalitis Virus

Entry Sites of Venezuelan and Western Equine Encephalitis Viruses in the Mouse Central Nervous System following Peripheral Infection

Bats as Potential Reservoir Hosts for Vector-Borne Diseases

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