Global Health Impacts of Vector-Borne Diseases Workshop Summary (2016) / Chapter Skim
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A10 - Arbovirus Evolution, Vector Competence, and Virulence Models - Changing Patterns of Infection - Corey W. Hecksel and Rebecca Rico-Hesse
A10 - Arbovirus Evolution, Vector Competence, and Virulence Models - Changing Patterns of Infection - Corey W. Hecksel and Rebecca Rico-Hesse
Pages 285-306
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2014. High level of vector competence of Aedes aegypti and Aedes albopictus from ten American countries as a crucial factor in the spread of chikungunya virus.
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Thus, for detecting differences between evolving viruses in humans, we require systems in which to measure virulence, or the effects of viral replication and the damage this causes in different human cells (tropism) , leading to overall pathogenesis and differing degrees of disease; these factors would also have an impact on how often the human viremic host could infect other vectors.
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The importance of these studies is also highlighted by the fact that these data are needed to derive any of the mathematical models of disease dynamics also discussed in this workshop, which depend on accuracy of input for realistic prediction outcomes. Dengue Viruses Disease Characteristics and Viral Genetic Variability Currently, dengue viruses are the most prevalent of all the arboviruses, causing an estimated 400 million human infections per year, in over 100 countries worldwide; however, these infections produce clinical disease, dengue fever (DF)
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and in northern Peru, in 2000 (Cruz et al., 2013) , and the viruses isolated on the Mexican border with Texas, in 2005, are now SE Asian genotype viruses (see top black highlight in Figure A10-1)
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Viruses are grouped into four genotypes, with the Southeast Asian and American genotypes shaded. Each virus is labeled with the first four letters of the country in which it was isolated, followed by the last two digits of the year of isolation, and the strain number or name.
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Our studies with infectious clones and recombinant laboratory techniques have allowed us to pinpoint some parts of the virus that we believe can lead to increases in replication that translate into higher virion production, increased mosquito infectivity and vector competence, and increased human virulence and pathogenesis. Virus replication in target cells Owing to the lack of animal models of disease, and only indirectly, by observation of human clinical presentations (during prospective epidemiologic studies)
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However, when the numbers of viral RNA genomes (DENV are notoriously difficult to measure as infectious particles) were compared across donors, all donor samples produced much higher amounts of SE Asian genotype viruses.
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. NOTE: Within each graph, the white bars represent the mean results of seven American genotype viruses, and the gray bars represent the results from 12 SE Asian genotype viruses.
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was entered and analyzed in RNASTAR software, which uses a processive analysis to estimate RNA folding patterns. SOURCE: Rico-Hesse, 2009.
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These hypotheses are currently being evaluated using novel and complex approaches in cell biology, viral chimeras, and biochemical and physical structure analyses. Our studies with chimeras of SE Asian and American genotype viruses, with substitutions in the 5'UTR, EN390D amino acids, and 3'UTR, demonstrated that all three of these sites are important determinants of virus replication in primary human cell cultures (macrophages and DCs)
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In addition, we performed studies of virus tropism, with a SE Asian genotype virus, demonstrating replication in numerous human cells, by flow cytometry and immunohistochemistry. These studies showed DENV replication in differentiated human B cells and in numerous, unidentified cells in the humanized mouse bone marrow (Mota and Rico-Hesse, 2011)
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Further improvements of this animal model may lead to a better understanding of DENV tropism for human cells, and their contribution to pathogenesis of DF and DHF. DENV determinants of pathogenesis, including mosquito saliva To further develop the humanized mouse model of DENV disease, we initiated studies using only one strain of DENV-2, K0049, from the most virulent, SE Asian genotype, but this time by infecting the CB-hu-mice by the natural route of infection, mosquito bite (Cox et al., 2012)
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There are many factors that remain to be tested in CB-hu-mice, including the role of specific mosquito saliva proteins on the effects to virus and host cells, and the innate immune response, but fortunately, these mice are ready to be used in FIGURE A10-6 Comparison of viremias (measured by RNA equivalents in serum, by quantitative RT-PCR) in CB-hu-mice infected with DENV-2, strain K0049, by each of two routes: by subcutaneous injection of six log PFU equivalents, or by infected mosquito bites (4–5 mosquitoes per mouse)
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, with both SE Asian and American viruses in the same amounts in spiked blood, as a direct competition experiment, the SE Asian viruses were able to disseminate into the salivary glands by day 7 versus day 10 for American genotype viruses, in mosquitoes from varied geographical collection sites (Cologna et al., 2005)
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The probability (P) of these mosquitoes to transmit the SE Asian viruses is up to 60-fold higher than for American genotype viruses, depending on day after mosquito infection (extrinsic incubation)
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tail on the 3′ end. Numerous studies have used comparison of nucleotide sequences from either the E2 or E1 envelope genes to generate phylogenetic trees of evolutionary relationships of CHIKV strains from around the world (Lanciotti et al., 1998; Powers et al., 2000)
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and virulence characteristics. Virus Replication in Target Cells Although numerous reports describe growth of different strains of CHIKV in keratinocytes and fibroblasts in culture, a recent report disputes those results, and concludes that keratinocytes first serve as an antiviral defense on the skin, with specific innate immune factors secreted (Bernard et al., 2014)
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. Cryo electron density map of chikungunya virus-likeparticles, low pass filtered to 10Å and radial colored (green: 220Å to blue: 420Å)
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. FIGURE A10-9 Preparation of humanized mice, using fetal tissues and hematopoietic stem cells (BLT-hu-mice: bone marrow, liver, and thymus)
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However, more recent experiments using over 35 different colonies of Aedes albopictus and Aedes aegypti mosquito strains, and testing CHIKV strains with the E1226A and E1226V mutation in the ECSA genotype backgrounds, and the new, Asian genotype virus that has been introduced recently to the Americas, have not shown consistent statistically significant differences in vector competence for either species of mosquito (three groups showed lower dissemination in albopictus)
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2001. Differential susceptibility of Aedes aegypti to infection by the American and Southeast Asian genotypes of dengue type 2 virus.
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2011. Dengue virus tropism in humanized mice recapitulates human dengue fever.
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