Vertical transmission (VT) and horizontal transmission (HT) of pathogens refer to parental and non-parental chains of host-to-host transmission. Combining HT with VT enlarges considerably the range ...of ecological conditions in which a pathogen can persist, but the factors governing the relative frequency of each transmission mode are poorly understood for pathogens with mixed-mode transmission. Elucidating these factors is particularly important for understanding the epidemiology of arthropod-borne viruses (arboviruses) of public health significance. Arboviruses are primarily maintained by HT between arthropod vectors and vertebrate hosts in nature, but are occasionally transmitted vertically in the vector population from an infected female to her offspring, which is a proposed maintenance mechanism during adverse conditions for HT. Here, we review over a century of published primary literature on natural and experimental VT, which we previously assembled into large databases, to identify biological factors associated with the efficiency of arbovirus VT in mosquito vectors. Using a robust statistical framework, we highlight a suite of environmental, taxonomic, and physiological predictors of arbovirus VT. These novel insights contribute to refine our understanding of strategies employed by arboviruses to persist in the environment and cause substantial public health concern. They also provide hypotheses on the biological processes underlying the relative VT frequency for pathogens with mixed-mode transmission that can be tested empirically.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•The extent and epidemiological importance of arbovirus VT are still debated.•Arboviral emergence events have stimulated VT research.•More recent laboratory assays are associated with enhanced VT ...detection.•Typically <0.1% of mosquitoes are vertically infected in nature.•The outcome of VT studies is context- and method-dependent.
Arthropod-borne viruses (arboviruses) are mainly transmitted horizontally among vertebrate hosts by blood-feeding invertebrate vectors, but can also be transmitted vertically in the vector from an infected female to its offspring. Vertical transmission (VT) is considered a possible mechanism for the persistence of arboviruses during periods unfavorable for horizontal transmission, but the extent and epidemiological significance of this phenomenon have remained controversial. To help resolve this question, we reviewed over a century of published literature on VT to analyze historical trends of scientific investigations on experimental and natural occurrence of VT in mosquitoes. Our synthesis highlights the influence of major events of public health significance in arbovirology on the number of VT publications. Epidemiological landmarks such as emergence events have significantly stimulated VT research. Our analysis also reveals the association between the evolution of virological assays and the probability of VT detection. Increased sensitivity and higher-throughput of modern laboratory assays resulted in enhanced VT detection. In general, VT contribution to arbovirus persistence is likely modest because vertically infected mosquitoes are rarely observed in nature. Taken together, however, our results call for caution when interpreting VT studies because their conclusions are context- and method-dependent.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Due to their error-prone replication, RNA viruses typically exist as a diverse population of closely related genomes, which is considered critical for their fitness and adaptive potential. Intra-host ...demographic fluctuations that stochastically reduce the effective size of viral populations are a challenge to maintaining genetic diversity during systemic host infection. Arthropod-borne viruses (arboviruses) traverse several anatomical barriers during infection of their arthropod vectors that are believed to impose population bottlenecks. These anatomical barriers have been associated with both maintenance of arboviral genetic diversity and alteration of the variant repertoire. Whether these patterns result from stochastic sampling (genetic drift) rather than natural selection, and/or from the influence of vector genetic heterogeneity has not been elucidated. Here, we used deep sequencing of full-length viral genomes to monitor the intra-host evolution of a wild-type dengue virus isolate during infection of several mosquito genetic backgrounds. We estimated a bottleneck size ranging from 5 to 42 founding viral genomes at initial midgut infection, irrespective of mosquito genotype, resulting in stochastic reshuffling of the variant repertoire. The observed level of genetic diversity increased following initial midgut infection but significantly differed between mosquito genetic backgrounds despite a similar initial bottleneck size. Natural selection was predominantly negative (purifying) during viral population expansion. Taken together, our results indicate that dengue virus intra-host genetic diversity in the mosquito vector is shaped by genetic drift and purifying selection, and point to a novel role for vector genetic factors in the genetic breadth of virus populations during infection. Identifying the evolutionary forces acting on arboviral populations within their arthropod vector provides novel insights into arbovirus evolution.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Computational analyses of pathogen genomes are increasingly used to unravel the dispersal history and transmission dynamics of epidemics. Here, we show how to go beyond historical reconstructions and ...use spatially-explicit phylogeographic and phylodynamic approaches to formally test epidemiological hypotheses. We illustrate our approach by focusing on the West Nile virus (WNV) spread in North America that has substantially impacted public, veterinary, and wildlife health. We apply an analytical workflow to a comprehensive WNV genome collection to test the impact of environmental factors on the dispersal of viral lineages and on viral population genetic diversity through time. We find that WNV lineages tend to disperse faster in areas with higher temperatures and we identify temporal variation in temperature as a main predictor of viral genetic diversity through time. By contrasting inference with simulation, we find no evidence for viral lineages to preferentially circulate within the same migratory bird flyway, suggesting a substantial role for non-migratory birds or mosquito dispersal along the longitudinal gradient.
Many infectious diseases are thought to have emerged in humans after the Neolithic revolution. Although it is broadly accepted that this also applies to measles, the exact date of emergence for this ...disease is controversial. We sequenced the genome of a 1912 measles virus and used selection-aware molecular clock modeling to determine the divergence date of measles virus and rinderpest virus. This divergence date represents the earliest possible date for the establishment of measles in human populations. Our analyses show that the measles virus potentially arose as early as the sixth century BCE, possibly coinciding with the rise of large cities.
The global emergence of Zika virus (ZIKV) revealed the unprecedented ability for a mosquito-borne virus to cause congenital birth defects. A puzzling aspect of ZIKV emergence is that all human ...outbreaks and birth defects to date have been exclusively associated with the Asian ZIKV lineage, despite a growing body of laboratory evidence pointing towards higher transmissibility and pathogenicity of the African ZIKV lineage. Whether this apparent paradox reflects the use of relatively old African ZIKV strains in most laboratory studies is unclear. Here, we experimentally compare seven low-passage ZIKV strains representing the recently circulating viral genetic diversity. We find that recent African ZIKV strains display higher transmissibility in mosquitoes and higher lethality in both adult and fetal mice than their Asian counterparts. We emphasize the high epidemic potential of African ZIKV strains and suggest that they could more easily go unnoticed by public health surveillance systems than Asian strains due to their propensity to cause fetal loss rather than birth defects.
The kinetics of arthropod-borne virus (arbovirus) transmission by their vectors have long been recognized as a powerful determinant of arbovirus epidemiology. The time interval between virus ...acquisition and transmission by the vector, termed extrinsic incubation period (EIP), combines with vector mortality rate and vector competence to determine the proportion of infected vectors that eventually become infectious. However, the dynamic nature of this process, and the amount of natural variation in transmission kinetics among arbovirus strains, are poorly documented empirically and are rarely considered in epidemiological models. Here, we combine newly generated empirical measurements in vivo and outbreak simulations in silico to assess the epidemiological significance of genetic variation in dengue virus (DENV) transmission kinetics by Aedes aegypti mosquitoes. We found significant variation in the dynamics of systemic mosquito infection, a proxy for EIP, among eight field-derived DENV isolates representing the worldwide diversity of recently circulating type 1 strains. Using a stochastic agent-based model to compute time-dependent individual transmission probabilities, we predict that the observed variation in systemic mosquito infection kinetics may drive significant differences in the probability of dengue outbreak and the number of human infections. Our results demonstrate that infection dynamics in mosquitoes vary among wild-type DENV isolates and that this variation potentially affects the risk and magnitude of dengue outbreaks. Our quantitative assessment of DENV genetic variation in transmission kinetics contributes to improve our understanding of heterogeneities in arbovirus epidemiological dynamics.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The exogenous small interfering RNA (exo-siRNA) pathway is a key antiviral mechanism in the Aedes aegypti mosquito, a widely distributed vector of human-pathogenic arboviruses. This pathway is ...induced by virus-derived double-stranded RNAs (dsRNA) that are cleaved by the ribonuclease Dicer 2 (Dcr2) into predominantly 21 nucleotide (nt) virus-derived small interfering RNAs (vsiRNAs). These vsiRNAs are used by the effector protein Argonaute 2 within the RNA-induced silencing complex to cleave target viral RNA. Dcr2 contains several domains crucial for its activities, including helicase and RNase III domains. In Drosophila melanogaster Dcr2, the helicase domain has been associated with binding to dsRNA with blunt-ended termini and a processive siRNA production mechanism, while the platform-PAZ domains bind dsRNA with 3' overhangs and subsequent distributive siRNA production. Here we analyzed the contributions of the helicase and RNase III domains in Ae. aegypti Dcr2 to antiviral activity and to the exo-siRNA pathway. Conserved amino acids in the helicase and RNase III domains were identified to investigate Dcr2 antiviral activity in an Ae. aegypti-derived Dcr2 knockout cell line by reporter assays and infection with mosquito-borne Semliki Forest virus (Togaviridae, Alphavirus). Functionally relevant amino acids were found to be conserved in haplotype Dcr2 sequences from field-derived Ae. aegypti across different continents. The helicase and RNase III domains were critical for silencing activity and 21 nt vsiRNA production, with RNase III domain activity alone determined to be insufficient for antiviral activity. Analysis of 21 nt vsiRNA sequences (produced by functional Dcr2) to assess the distribution and phasing along the viral genome revealed diverse yet highly consistent vsiRNA pools, with predominantly short or long sequence overlaps including 19 nt overlaps (the latter representing most likely true Dcr2 cleavage products). Combined with the importance of the Dcr2 helicase domain, this suggests that the majority of 21 nt vsiRNAs originate by processive cleavage. This study sheds new light on Ae. aegypti Dcr2 functions and properties in this important arbovirus vector species.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The 1918 influenza pandemic was the deadliest respiratory pandemic of the 20th century and determined the genomic make-up of subsequent human influenza A viruses (IAV). Here, we analyze both the ...first 1918 IAV genomes from Europe and the first from samples prior to the autumn peak. 1918 IAV genomic diversity is consistent with a combination of local transmission and long-distance dispersal events. Comparison of genomes before and during the pandemic peak shows variation at two sites in the nucleoprotein gene associated with resistance to host antiviral response, pointing at a possible adaptation of 1918 IAV to humans. Finally, local molecular clock modeling suggests a pure pandemic descent of seasonal H1N1 IAV as an alternative to the hypothesis of origination through an intrasubtype reassortment.
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