Ecological and environmental factors affecting transmission of sylvatic yellow fever in the 2017–2019 outbreak in the Atlantic Forest, Brazil

Abstract Background Yellow fever virus (YFV) is an arbovirus that, despite the existence of a safe and effective vaccine, continues to cause outbreaks of varying dimensions in the Americas and Africa. Between 2017 and 2019, Brazil registered un unprecedented sylvatic YFV outbreak whose severity was the result of its spread into zones of the Atlantic Forest with no signals of viral circulation for nearly 80 years. Methods To investigate the influence of climatic, environmental, and ecological factors governing the dispersion and force of infection of YFV in a naïve area such as the landscape mosaic of Rio de Janeiro (RJ), we combined the analyses of a large set of data including entomological sampling performed before and during the 2017–2019 outbreak, with the geolocation of human and nonhuman primates (NHP) and mosquito infections. Results A greater abundance of Haemagogus mosquitoes combined with lower richness and diversity of mosquito fauna increased the probability of finding a YFV-infected mosquito. Furthermore, the analysis of functional traits showed that certain functional groups, composed mainly of Aedini mosquitoes which includes Aedes and Haemagogus mosquitoes, are also more representative in areas where infected mosquitoes were found. Human and NHP infections were more common in two types of landscapes: large and continuous forest, capable of harboring many YFV hosts, and patches of small forest fragments, where environmental imbalance can lead to a greater density of the primary vectors and high human exposure. In both, we show that most human infections (~ 62%) occurred within an 11-km radius of the finding of an infected NHP, which is in line with the flight range of the primary vectors. Conclusions Together, our data suggest that entomological data and landscape composition analyses may help to predict areas permissive to yellow fever outbreaks, allowing protective measures to be taken to avoid human cases. Graphical Abstract

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Mapping environmental suitability of Haemagogus and Sabethes spp. mosquitoes to understand sylvatic transmission risk of yellow fever virus in Brazil

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0010019 ◽

2022 ◽

Vol 16 (1) ◽

pp. e0010019

Author(s):

Sabrina L. Li ◽

André L. Acosta ◽

Sarah C. Hill ◽

Oliver J. Brady ◽

Marco A. B. de Almeida ◽

...

Keyword(s):

Yellow Fever ◽

Yellow Fever Virus ◽

Boosted Regression Trees ◽

Transmission Risk ◽

Infected Mosquito ◽

Effective Vaccine ◽

Human Populations ◽

Vector Surveillance ◽

Transmission Cycle ◽

Environmental Suitability

Background Yellow fever (YF) is an arboviral disease which is endemic to Brazil due to a sylvatic transmission cycle maintained by infected mosquito vectors, non-human primate (NHP) hosts, and humans. Despite the existence of an effective vaccine, recent sporadic YF epidemics have underscored concerns about sylvatic vector surveillance, as very little is known about their spatial distribution. Here, we model and map the environmental suitability of YF’s main vectors in Brazil, Haemagogus spp. and Sabethes spp., and use human population and NHP data to identify locations prone to transmission and spillover risk. Methodology/Principal findings We compiled a comprehensive set of occurrence records on Hg. janthinomys, Hg. leucocelaenus, and Sabethes spp. from 1991–2019 using primary and secondary data sources. Linking these data with selected environmental and land-cover variables, we adopted a stacked regression ensemble modelling approach (elastic-net regularized GLM, extreme gradient boosted regression trees, and random forest) to predict the environmental suitability of these species across Brazil at a 1x1 km resolution. We show that while suitability for each species varies spatially, high suitability for all species was predicted in the Southeastern region where recent outbreaks have occurred. By integrating data on NHP host reservoirs and human populations, our risk maps further highlight municipalities within the region that are prone to transmission and spillover. Conclusions/Significance Our maps of sylvatic vector suitability can help elucidate potential locations of sylvatic reservoirs and be used as a tool to help mitigate risk of future YF outbreaks and assist in vector surveillance. Furthermore, at-risk regions identified from our work could help disease control and elucidate gaps in vaccination coverage and NHP host surveillance.

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Yellow Fever Outbreak in Eastern Senegal, 2020–2021

Viruses ◽

10.3390/v13081475 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1475

Author(s):

Moussa Moïse Diagne ◽

Marie Henriette Dior Ndione ◽

Alioune Gaye ◽

Mamadou Aliou Barry ◽

Diawo Diallo ◽

...

Keyword(s):

Yellow Fever ◽

Yellow Fever Virus ◽

Mosquito Species ◽

Virus Transmission ◽

Genomic Analysis ◽

Hemorrhagic Fever ◽

Fever Virus ◽

World Health ◽

Effective Vaccine ◽

Ministry Of Health

Yellow fever virus remains a major threat in low resource countries in South America and Africa despite the existence of an effective vaccine. In Senegal and particularly in the eastern part of the country, periodic sylvatic circulation has been demonstrated with varying degrees of impact on populations in perpetual renewal. We report an outbreak that occurred from October 2020 to February 2021 in eastern Senegal, notified and managed through the synergistic effort yellow fever national surveillance implemented by the Senegalese Ministry of Health in collaboration with the World Health Organization, the countrywide 4S network set up by the Ministry of Health, the Institut Pasteur de Dakar, and the surveillance of arboviruses and hemorrhagic fever viruses in human and vector populations implemented since mid 2020 in eastern Senegal. Virological analyses highlighted the implication of sylvatic mosquito species in virus transmission. Genomic analysis showed a close relationship between the circulating strain in eastern Senegal, 2020, and another one from the West African lineage previously detected and sequenced two years ago from an unvaccinated Dutch traveler who visited the Gambia and Senegal before developing signs after returning to Europe. Moreover, genome analysis identified a 6-nucleotide deletion in the variable domain of the 3′UTR with potential impact on the biology of the viral strain that merits further investigations. Integrated surveillance of yellow fever virus but also of other arboviruses of public health interest is crucial in an ecosystem such as eastern Senegal.

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Yellow Fever Virus Down-Regulates mRNA Expression of SOCS1 in the Initial Phase of Infection in Human Cell Lines

Viruses ◽

10.3390/v12080802 ◽

2020 ◽

Vol 12 (8) ◽

pp. 802

Author(s):

Michael B. Yakass ◽

David Franco ◽

Osbourne Quaye

Keyword(s):

Mrna Expression ◽

Yellow Fever ◽

Yellow Fever Virus ◽

Expression Patterns ◽

Fever Virus ◽

Effective Vaccine ◽

Interferon Β ◽

Infected Cells ◽

Insight Into

Flaviviruses are constantly evolving diverse immune evasion strategies, and the exploitation of the functions of suppressors of cytokine signalling (SOCS) and protein inhibitors of activated STATs (PIAS) to favour virus replication has been described for Dengue and Japanese encephalitis viruses but not for yellow fever virus (YFV), which is still of global importance despite the existence of an effective vaccine. Some mechanisms that YFV employs to evade host immune defence has been reported, but the expression patterns of SOCS and PIAS in infected cells is yet to be determined. Here, we show that SOCS1 is down-regulated early in YFV-infected HeLa and HEK 293T cells, while SOCS3 and SOCS5 are not significantly altered, and PIAS mRNA expression appears to follow a rise-dip pattern akin to circadian-controlled genes. We also demonstrate that YFV evades interferon-β application to produce comparable viral titres. This report provides initial insight into the in vitro expression dynamics of SOCS and PIAS upon YFV infection and a basis for further investigation into SOCS/PIAS expression and how these modulate the immune response in animal models.

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AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model

10.1101/2021.10.25.465665 ◽

2021 ◽

Author(s):

Kai Lin ◽

Steven S Good ◽

Justin G. Julander ◽

Abbie Weight ◽

Adel Moussa

Keyword(s):

Yellow Fever ◽

Yellow Fever Virus ◽

Limit Of Detection ◽

Virus Titer ◽

Fever Virus ◽

Effective Vaccine ◽

Hamster Model ◽

Nucleotide Analog

Yellow fever virus (YFV) is a zoonotic pathogen re-emerging in parts of the world, causing a viral hemorrhagic fever associated with high mortality rates. While an effective vaccine is available, having an effective antiviral against YFV is critical against unexpected outbreaks, or when vaccination is not recommended. We have previously identified AT-281, the free base of AT-752, an orally available double prodrug of a guanosine nucleotide analog, as a potent inhibitor of YFV in vitro , with a 50% effective concentration (EC 50 ) of 0.31 µM. In hamsters infected with YFV (Jimenez strain), viremia rose about 4 log 10 -fold and serum alanine aminotransferase (ALT) 2-fold compared to sham-infected animals. Treatment with 1000 mg/kg AT-752 for 7 days, initiated 4 h prior to viral challenge, reduced viremia to below the limit of detection by day 4 post infection (pi) and returned ALT to normal levels by day 6 pi. When treatment with AT-752 was initiated 2 days pi, the virus titer and ALT dropped >2 log 10 and 53% by day 4 and 6 pi, respectively. In addition, at 21 days pi, 70 – 100% of the infected animals in the treatment groups survived compared to 0% of the untreated group (p<0.001). Moreover, in vivo formation of the active triphosphate metabolite AT-9010 was measured in the animal tissues, with the highest concentrations in liver and kidney, organs that are vulnerable to the virus. The demonstrated in vivo activity of AT-752 suggests that it is a promising compound for clinical development in the treatment of YFV infection.

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A community-level investigation following a yellow fever virus outbreak in South Omo Zone, South-West Ethiopia

PeerJ ◽

10.7717/peerj.6466 ◽

2019 ◽

Vol 7 ◽

pp. e6466 ◽

Cited By ~ 3

Author(s):

Ranya Mulchandani ◽

Fekadu Massebo ◽

Fekadu Bocho ◽

Claire L. Jeffries ◽

Thomas Walker ◽

...

Keyword(s):

Yellow Fever ◽

Yellow Fever Virus ◽

Case Fatality ◽

Public Health Problem ◽

Fever Virus ◽

World Health ◽

Effective Vaccine ◽

Breeding Sites ◽

Study Results ◽

South Omo

Background Despite the availability of a highly effective vaccine, yellow fever virus (YFV) remains an important public health problem across Africa and South America due to its high case-fatality rate. This study investigated the historical epidemiology and contemporary entomological and social determinants of a YFV outbreak in South Omo Zone (SOZ), Ethiopia. Methods A YFV outbreak occurred in SOZ, Ethiopia in 2012–2014. Historical epidemiological data were retrieved from the SOZ Health Department and analyzed. Entomological sampling was undertaken in 2017, including mosquito species identification and molecular screening for arboviruses to understand mosquito habitat distribution, and finally current knowledge, attitudes and preventative practices within the affected communities were assessed. Results From October 2012 to March 2014, 165 suspected cases and 62 deaths were reported, principally in rural areas of South Ari region (83.6%). The majority of patients were 15–44 years old (75.8%) and most case deaths were males (76%). Between June and August 2017, 688 containers were sampled across 180 households to identify key breeding sites for Aedes mosquitoes. Ensete ventricosum (“false banana”) and clay pots outside the home were the most productive natural and artificial breeding sites, respectively. Entomological risk indices classified most sites as “high risk” for future outbreaks under current World Health Organization criteria. Adult mosquitoes in houses were identified as members of the Aedes simpsoni complex but no YFV or other arboviruses were detected by PCR. The majority of community members had heard of YFV, however few activities were undertaken to actively reduce mosquito breeding sites. Discussion Study results highlight the potential role vector control could play in mitigating local disease transmission and emphasize the urgent need to strengthen disease surveillance systems and in-country laboratory capacity to facilitate more rapid responses to future YFV outbreaks.

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An RNA Pseudoknot Is Required for Production of Yellow Fever Virus Subgenomic RNA by the Host Nuclease XRN1

Journal of Virology ◽

10.1128/jvi.01047-10 ◽

2010 ◽

Vol 84 (21) ◽

pp. 11395-11406 ◽

Cited By ~ 119

Author(s):

Patrícia A. G. C. Silva ◽

Carina F. Pereira ◽

Tim J. Dalebout ◽

Willy J. M. Spaan ◽

Peter J. Bredenbeek

Keyword(s):

Yellow Fever ◽

Rna Structure ◽

Mammalian Cells ◽

Yellow Fever Virus ◽

Fever Virus ◽

Infected Mosquito ◽

Molecular Characteristics ◽

Subgenomic Rna ◽

Rna Pseudoknot

ABSTRACT Cells and mice infected with arthropod-borne flaviviruses produce a small subgenomic RNA that is colinear with the distal part of the viral 3′-untranslated region (UTR). This small subgenomic flavivirus RNA (sfRNA) results from the incomplete degradation of the viral genome by the host 5′-3′ exonuclease XRN1. Production of the sfRNA is important for the pathogenicity of the virus. This study not only presents a detailed description of the yellow fever virus (YFV) sfRNA but, more importantly, describes for the first time the molecular characteristics of the stalling site for XRN1 in the flavivirus genome. Similar to the case for West Nile virus, the YFV sfRNA was produced by XRN1. However, in contrast to the case for other arthropod-borne flaviviruses, not one but two sfRNAs were detected in YFV-infected mammalian cells. The smaller of these two sfRNAs was not observed in infected mosquito cells. The larger sfRNA could also be produced in vitro by incubation with purified XRN1. These two YFV sfRNAs formed a 5′-nested set. The 5′ ends of the YFV sfRNAs were found to be just upstream of the previously predicted RNA pseudoknot PSK3. RNA structure probing and mutagenesis studies provided strong evidence that this pseudoknot structure was formed and served as the molecular signal to stall XRN1. The sequence involved in PSK3 formation was cloned into the Sinrep5 expression vector and shown to direct the production of an sfRNA-like RNA. These results underscore the importance of the RNA pseudoknot in stalling XRN1 and also demonstrate that it is the sole viral requirement for sfRNA production.

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Restricted replication and lysosomal trafficking of yellow fever 17D vaccine virus in human dendritic cells

Journal of General Virology ◽

10.1099/vir.0.82272-0 ◽

2007 ◽

Vol 88 (1) ◽

pp. 148-156 ◽

Cited By ~ 28

Author(s):

Dupeh R. Palmer ◽

Stefan Fernandez ◽

John Bisbing ◽

Kristina K. Peachman ◽

Mangala Rao ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Yellow Fever ◽

Virus Replication ◽

Yellow Fever Virus ◽

Vaccine Virus ◽

Yellow Fever Vaccine ◽

Effective Vaccine ◽

Contributing Factors

The yellow fever virus attenuated 17D vaccine strain is a safe and effective vaccine and a valuable model system for evaluating immune responses against attenuated viral variants. This study compared the in vitro interactions of the commercially available yellow fever vaccine (YF-VAX), Dengue virus and the live-attenuated dengue vaccine PDK50 with dendritic cells (DCs), the main antigen-presenting cells at the initiation of immune responses. Similar to PDK50, infection with YF-VAX generated activated DCs; however, for YF-VAX, activation occurred with limited intracellular virus replication. The majority of internalized virus co-localized with endolysosomal markers within 90 min, suggesting that YF-VAX is processed rapidly in DCs. These results indicate that restricted virus replication and lysosomal compartmentalization may be important contributing factors to the success of the YF-VAX vaccine.

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Evolutionary and ecological factors underlying the tempo and distribution of yellow fever virus activity

Infection Genetics and Evolution ◽

10.1016/j.meegid.2012.08.015 ◽

2013 ◽

Vol 13 ◽

pp. 198-210 ◽

Cited By ~ 29

Author(s):

Christine V.F. Carrington ◽

Albert J. Auguste

Keyword(s):

Yellow Fever ◽

Yellow Fever Virus ◽

Ecological Factors ◽

Fever Virus ◽

Virus Activity

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Yellow Fever Virus: Diagnostics for a Persistent Arboviral Threat

Journal of Clinical Microbiology ◽

10.1128/jcm.00827-18 ◽

2018 ◽

Vol 56 (10) ◽

Cited By ~ 9

Author(s):

Jesse J. Waggoner ◽

Alejandra Rojas ◽

Benjamin A. Pinsky

Keyword(s):

Yellow Fever ◽

Yellow Fever Virus ◽

Current Knowledge ◽

Hemorrhagic Fever ◽

Clinical Diagnostics ◽

Fever Virus ◽

Diagnostic Methods ◽

Effective Vaccine ◽

Molecular Testing ◽

Viral Culture

ABSTRACTYellow fever (YF) is the prototypical hemorrhagic fever and results from infection with yellow fever virus (YFV), which is endemic to regions of Africa and South America. Despite the availability of an effective vaccine, YFV continues to cause disease throughout regions where it is endemic, including intermittent large outbreaks among undervaccinated populations. A number of diagnostic methods and assays have been described for the detection of YFV infection, including viral culture, molecular testing, serology, and antigen detection. Commercial diagnostics are not widely available, and testing is generally performed at a small number of reference laboratories. The goal of this article, therefore, is to review available clinical diagnostics for YFV, which may not be familiar to many practitioners outside areas where it is endemic. Additionally, we identify gaps in our current knowledge about YF that pertain to diagnosis and describe interventions that may improve YFV detection.

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