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Keywords = arbovirus pathogenesis

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17 pages, 10439 KB  
Review
Structural and Functional Hallmarks of Sindbis Virus Proteins: From Virion Architecture to Pathogenesis
by Qibin Geng, Chanakha K. Navaratnarajah and Wei Zhang
Int. J. Mol. Sci. 2025, 26(17), 8323; https://doi.org/10.3390/ijms26178323 - 27 Aug 2025
Viewed by 822
Abstract
Sindbis virus (SINV), a prototype of the Alphavirus genus (family Togaviridae), is a globally distributed arbovirus causing febrile rash and debilitating arthritis in humans. Viral structural proteins—capsid (C), E1, and E2—are fundamental to the virion’s architecture, mediating all stages from assembly to [...] Read more.
Sindbis virus (SINV), a prototype of the Alphavirus genus (family Togaviridae), is a globally distributed arbovirus causing febrile rash and debilitating arthritis in humans. Viral structural proteins—capsid (C), E1, and E2—are fundamental to the virion’s architecture, mediating all stages from assembly to host cell entry and pathogenesis, thus representing critical targets for study. This review consolidates the historical and current understanding of SINV structural biology, tracing progress from early microscopy to recent high-resolution cryo-electron microscopy (cryo-EM) and X-ray crystallography. We detail the virion’s precise T = 4 icosahedral architecture, composed of a nucleocapsid core and an outer glycoprotein shell. Key functional roles tied to protein structure are examined: the capsid’s dual capacity as a serine protease and an RNA-packaging scaffold that interacts with the E2 cytoplasmic tail; the E1 glycoprotein’s function as a class II fusion protein driving membrane fusion; and the E2 glycoprotein’s primary role in receptor binding, which dictates cellular tropism and serves as the main antigenic target. Furthermore, we connect these molecular structures to viral evolution and disease, analyzing how genetic variation among SINV genotypes, particularly in the E2 gene, influences host adaptation, immune evasion, and the clinical expression of arthritogenic and neurovirulent disease. In conclusion, the wealth of structural data on SINV offers a powerful paradigm for understanding alphavirus biology. However, critical gaps persist, including the high-resolution visualization of dynamic conformational states during viral entry and the specific molecular determinants of chronic disease. Addressing these challenges through integrative structural and functional studies is paramount. Such knowledge will be indispensable for the rational design of next-generation antiviral therapies and broadly protective vaccines against the ongoing threat posed by SINV and related pathogenic alphaviruses. Full article
(This article belongs to the Special Issue Advanced Perspectives on Virus–Host Interactions)
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15 pages, 19921 KB  
Article
Ultrastructural Insight into Rift Valley Fever Virus Pathogenesis in Different Human Cell Types
by Daniele Lapa, Maria Anele Romeo, Leonardo Duca, Carlotta Castelli, Eliana Specchiarello, Fabrizio Maggi and Laura Falasca
Int. J. Mol. Sci. 2025, 26(17), 8183; https://doi.org/10.3390/ijms26178183 - 23 Aug 2025
Viewed by 623
Abstract
Rift Valley Fever Virus (RVFV) is an arbovirus that predominantly affects sheep, goats, and cattle, causing epizootics in livestock and epidemics in humans. Infection in pregnant livestock leads to high abortion rates and neonatal mortality. In humans, RVFV usually causes a self-limiting febrile [...] Read more.
Rift Valley Fever Virus (RVFV) is an arbovirus that predominantly affects sheep, goats, and cattle, causing epizootics in livestock and epidemics in humans. Infection in pregnant livestock leads to high abortion rates and neonatal mortality. In humans, RVFV usually causes a self-limiting febrile illness, but severe forms can develop, such as hepatitis, hemorrhage, encephalitis, and death. In addition, the association between RVFV infection during pregnancy and miscarriages or stillbirths has been documented. RVFV is transmitted by a range of mosquito species, and, due to the diffusion of these insects, the virus has spread in several world regions, making possible the risk of a public health emergency. Nevertheless, research remains limited and cellular pathology is still poorly characterized. This work aimed to fill some knowledge gaps on the comprehension of RVFV pathogenesis. For this purpose, transmission electron microscopy (TEM) was used to analyze cellular modifications associated with RVFV morphogenesis in four human cell lines (HuH-7, LAN-5, A549, and HTR-8/SVneo) derived from liver, brain, lung, and placenta. Our results showed that all four cell lines are permissive to RVFV infection and highlighted differences in the cytopathogenesis associated with the cell type. These findings could have important implications in understanding disease mechanisms and developing antiviral strategies. Full article
(This article belongs to the Special Issue Host-Virus Interaction)
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18 pages, 1778 KB  
Review
A Comprehensive Review of the Neglected and Emerging Oropouche Virus
by Fengwei Bai, Prince M. D. Denyoh, Cassandra Urquhart, Sabin Shrestha and Donald A. Yee
Viruses 2025, 17(3), 439; https://doi.org/10.3390/v17030439 - 19 Mar 2025
Cited by 3 | Viewed by 3687
Abstract
Oropouche virus (OROV) is a neglected and emerging arbovirus that infects humans and animals in South and Central America. OROV is primarily transmitted to humans through the bites of infected midges and possibly some mosquitoes. It is the causative agent of Oropouche fever, [...] Read more.
Oropouche virus (OROV) is a neglected and emerging arbovirus that infects humans and animals in South and Central America. OROV is primarily transmitted to humans through the bites of infected midges and possibly some mosquitoes. It is the causative agent of Oropouche fever, which has high morbidity but low mortality rates in humans. The disease manifests in humans as high fever, headache, myalgia, arthralgia, photophobia, and, in some cases, meningitis and encephalitis. Additionally, a recent report suggests that OROV may cause fetal death, miscarriage, and microcephaly in newborns when women are infected during pregnancy, similar to the issues caused by the Zika virus (ZIKV), another mosquito-borne disease in the same regions. OROV was first reported in the mid-20th century in the Amazon basin. Since then, over 30 epidemics and more than 500,000 infection cases have been reported. The actual case numbers may be much higher due to frequent misdiagnosis, as OROV infection presents similar clinical symptoms to other co-circulating viruses, such as dengue virus (DENV), chikungunya virus (CHIKV), ZIKV, and West Nile virus (WNV). Due to climate change, increased travel, and urbanization, OROV infections have occurred at an increasing pace and have spread to new regions, with the potential to reach North America. According to the World Health Organization (WHO), over 10,000 cases were reported in 2024, including in areas where it was not previously detected. There is an urgent need to develop vaccines, antivirals, and specific diagnostic tools for OROV diseases. However, little is known about this surging virus, and no specific treatments or vaccines are available. In this article, we review the most recent progress in understanding virology, transmission, pathogenesis, diagnosis, host–vector dynamics, and antiviral vaccine development for OROV, and provide implications for future research directions. Full article
(This article belongs to the Special Issue Oropouche Virus (OROV): An Emerging Peribunyavirus (Bunyavirus))
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11 pages, 2218 KB  
Article
Acute Chikungunya Virus Infection Triggers a Diverse Range of T Helper Lymphocyte Profiles
by Ramayana Morais de Medeiros Brito, Marília Farias de Melo, José Veríssimo Fernandes, Joanna Gardel Valverde, Paulo Marcos Matta Guedes, Josélio Maria Galvão de Araújo and Manuela Sales Lima Nascimento
Viruses 2024, 16(9), 1387; https://doi.org/10.3390/v16091387 - 30 Aug 2024
Cited by 2 | Viewed by 1605
Abstract
Chikungunya virus (CHIKV) is an arbovirus causing acute febrile illness with severe joint pain, often leading to chronic arthralgia. This study investigated the adaptive immune responses during the early stages of symptomatic acute CHIKV infection, focusing on the transcription factors and cytokines linked [...] Read more.
Chikungunya virus (CHIKV) is an arbovirus causing acute febrile illness with severe joint pain, often leading to chronic arthralgia. This study investigated the adaptive immune responses during the early stages of symptomatic acute CHIKV infection, focusing on the transcription factors and cytokines linked to Th1, Th2, Th17, and Treg cells. Thirty-six individuals were enrolled: nine healthy controls and 27 CHIKV-positive patients confirmed by qRT-PCR. Blood samples were analyzed for the mRNA expression of transcription factors (Tbet, GATA3, FoxP3, STAT3, RORγt) and cytokines (IFN-γ, IL-4, IL-17, IL-22, TGF-β, IL-10). The results showed the significant upregulation of Tbet, GATA3, FoxP3, STAT3, and RORγt in CHIKV-positive patients, with RORγt displaying the highest increase. Correspondingly, cytokines IFN-γ, IL-4, IL-17, and IL-22 were upregulated, while TGF-β was downregulated. Principal component analysis (PCA) confirmed the distinct immune profiles between CHIKV-positive and healthy individuals. A correlation analysis indicated that higher Tbet expression correlated with a lower viral load, whereas FoxP3 and TGF-β were associated with higher viral loads. Our study sheds light on the intricate immune responses during acute CHIKV infection, characterized by a mixed Th1, Th2, Th17, and Treg response profile. These results emphasize the complex interplay between different adaptive immune responses and how they may contribute to the pathogenesis of Chikungunya fever. Full article
(This article belongs to the Special Issue Innate and Adaptive Immune Responses to Arbovirus Infections)
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14 pages, 1013 KB  
Review
Exploring Iguape Virus—A Lesser-Known Orthoflavivirus
by Marielena V. Saivish, Maurício L. Nogueira, Shannan L. Rossi and Nikos Vasilakis
Viruses 2024, 16(6), 960; https://doi.org/10.3390/v16060960 - 14 Jun 2024
Cited by 1 | Viewed by 3324
Abstract
Brazil has earned the moniker “arbovirus hotspot”, providing an ideal breeding ground for a multitude of arboviruses thriving in various zoonotic and urban cycles. As the planet warms and vectors expand their habitat range, a nuanced understanding of lesser-known arboviruses and the factors [...] Read more.
Brazil has earned the moniker “arbovirus hotspot”, providing an ideal breeding ground for a multitude of arboviruses thriving in various zoonotic and urban cycles. As the planet warms and vectors expand their habitat range, a nuanced understanding of lesser-known arboviruses and the factors that could drive their emergence becomes imperative. Among these viruses is the Iguape virus (IGUV), a member of the Orthoflavivirus aroaense species, which was first isolated in 1979 from a sentinel mouse in the municipality of Iguape, within the Vale do Ribeira region of São Paulo State. While evidence suggests that IGUV circulates among birds, wild rodents, marsupials, bats, and domestic birds, there is no information available on its pathogenesis in both humans and animals. The existing literature on IGUV spans decades, is outdated, and is often challenging to access. In this review, we have curated information from the known literature, clarifying its elusive nature and investigating the factors that may influence its emergence. As an orthoflavivirus, IGUV poses a potential threat, which demands our attention and vigilance, considering the serious outbreaks that the Zika virus, another neglected orthoflavivirus, has unleashed in the recent past. Full article
(This article belongs to the Special Issue Zoonotic and Vector-Borne Viral Diseases)
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11 pages, 1114 KB  
Perspective
Beyond Borders: Investigating the Mysteries of Cacipacoré, a Lesser-Studied Arbovirus in Brazil
by Marielena V. Saivish, Maurício L. Nogueira, Shannan L. Rossi and Nikos Vasilakis
Viruses 2024, 16(3), 336; https://doi.org/10.3390/v16030336 - 22 Feb 2024
Cited by 4 | Viewed by 2473
Abstract
Cacipacoré virus (CPCV) was discovered in 1977 deep in the Amazon rainforest from the blood of a black-faced ant thrush (Formicarius analis). As a member of the family Flaviviridae and genus orthoflavivirus, CPCV’s intricate ecological association with vectors and hosts raises [...] Read more.
Cacipacoré virus (CPCV) was discovered in 1977 deep in the Amazon rainforest from the blood of a black-faced ant thrush (Formicarius analis). As a member of the family Flaviviridae and genus orthoflavivirus, CPCV’s intricate ecological association with vectors and hosts raises profound questions. CPCV’s transmission cycle may involve birds, rodents, equids, bovines, marsupials, non-human primates, and bats as potential vertebrate hosts, whereas Culex and Aedes spp. mosquitoes have been implicated as potential vectors of transmission. The virus’ isolation across diverse biomes, including urban settings, suggests its adaptability, as well as presents challenges for its accurate diagnosis, and thus its impact on veterinary and human health. With no specific treatment or vaccine, its prevention hinges on traditional arbovirus control measures. Here, we provide an overview of its ecology, transmission cycles, epidemiology, pathogenesis, and prevention, aiming at improving our ability to better understand this neglected arbovirus. Full article
(This article belongs to the Section Invertebrate Viruses)
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10 pages, 2122 KB  
Article
Exploring the Interactions between Human microRNAs and the Ilheus Virus Genome
by Joyhare Barbosa Souza and Samir Mansour Moraes Casseb
SynBio 2023, 1(3), 194-203; https://doi.org/10.3390/synbio1030014 - 26 Oct 2023
Viewed by 1857
Abstract
MicroRNAs (miRNAs) are small non-coding RNA molecules that play a fundamental role in the regulation of gene expression in humans. There has been a growing interest in investigating the interactions between human miRNAs and viruses to better understand the underlying mechanisms of the [...] Read more.
MicroRNAs (miRNAs) are small non-coding RNA molecules that play a fundamental role in the regulation of gene expression in humans. There has been a growing interest in investigating the interactions between human miRNAs and viruses to better understand the underlying mechanisms of the immune response and viral pathogenesis. The Ilheus virus, an arbovirus transmitted by mosquitoes, is known to cause disease in humans, with symptoms ranging from mild fever to severe neurological complications. This scientific article aims to explore the potential role of human miRNAs in their association with the genome of the Ilheus virus. Previous research has indicated that miRNAs can affect viral replication and the host’s immune response, playing a critical role in modulating the virus–host interaction. Here, we will investigate the possible interactions between specific human miRNAs and regions of the Ilheus virus genome, focusing on identifying miRNAs that may impact viral replication or the host’s immune response. A search for potential human miRNAs associated with the viral genome of ILHV was conducted through database searches such as miRBase. For the elucidation of targets regulated by these miRNAs, the TargetScan program was adopted. Functional enrichment analysis, inferring the function of genes regulated by miRNAs, was provided by the DAVID software. To elucidate the secondary structure, tools hosted in the RNAFold repositories were employed. In summary, our research has identified miRNAs linked to crucial sections of the Ilheus virus genome. These miRNAs can potentially regulate genes associated with neurological and immune functions. This highlights the intricate interplay between human miRNAs and the Ilheus virus genome, suggesting a pivotal role for these molecules in the host’s response to viral infections. Full article
(This article belongs to the Special Issue Feature Paper Collection in Synthetic Biology)
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16 pages, 1455 KB  
Article
In Depth Viral Diversity Analysis in Atypical Neurological and Neonatal Chikungunya Infections in Rio de Janeiro, Brazil
by Maria Celeste Torres, Fatima Di Maio, David Brown, Moira Spyer, Eleni Nastouli, Patrícia Brasil and Ana Maria Bispo de Filippis
Viruses 2022, 14(9), 2006; https://doi.org/10.3390/v14092006 - 10 Sep 2022
Cited by 4 | Viewed by 2504
Abstract
Chikungunya virus (CHIKV) is an arthropod-borne virus (arbovirus) transmitted by Aedes mosquitoes. The human infection usually manifests as a febrile and incapacitating arthritogenic illness, self-limiting and non-lethal. However, since 2013, CHIKV spreading through the tropics and to the Americas was accompanied by an [...] Read more.
Chikungunya virus (CHIKV) is an arthropod-borne virus (arbovirus) transmitted by Aedes mosquitoes. The human infection usually manifests as a febrile and incapacitating arthritogenic illness, self-limiting and non-lethal. However, since 2013, CHIKV spreading through the tropics and to the Americas was accompanied by an increasing number of cases of atypical disease presentation, namely severe neuropathies and neonatal infection due to intrapartum vertical transmission. The pathophysiological mechanisms underlying these conditions have not been fully elucidated. However, arbovirus intrahost genetic diversity is thought to be linked to viral pathogenesis. To determine whether particular viral variants could be somehow associated, we analyzed the intrahost genetic diversity of CHIKV in three infected patients with neurological manifestations and three mothers infected during the intrapartum period, as well as their babies following vertical transmission. No statistically supported differences were observed for the genetic variability (nucleotide substitutions/gene length) along the genome between the groups. However, the newborn and cerebrospinal fluid samples (corresponding to virus passed through the placenta and/or the blood–brain barrier (BBB)) presented a different composition of their intrahost mutant ensembles compared to maternal or patient serum samples, even when concurrent. This finding could be consistent with the unidirectional virus transmission through these barriers, and the effect of selective bottlenecks during the transmission event. In addition, a higher proportion of defective variants (insertions/deletions and stop codons) was detected in the CSF and maternal samples and those were mainly distributed within the viral non-structural genes. Since defective viral genomes in RNA viruses are known to contribute to the outcome of acute viral infections and influence disease severity, their role in these atypical cases should be further investigated. Finally, with the in silico approach adopted, we detected no relevant non-conservative mutational pattern that could provide any hint of the pathophysiological mechanisms underlying these atypical cases. The present analysis represents a unique contribution to our understanding of the transmission events in these cases and generates hypotheses regarding underlying mechanisms, that can be explored further. Full article
(This article belongs to the Special Issue Chikungunya Virus and Emerging Alphaviruses)
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10 pages, 5534 KB  
Article
Factors Involved in the Apoptotic Cell Death Mechanism in Yellow Fever Hepatitis
by Jeferson da Costa Lopes, Luiz Fábio Magno Falcão, Arnaldo Jorge Martins Filho, Marcos Luiz Gaia Carvalho, Caio Cesar Henriques Mendes, Fábio Alves Olímpio, Vanessa do Socorro Cabral Miranda, Lais Carneiro dos Santos, Jannifer Oliveira Chiang, Ana Cecilia Ribeiro Cruz, Vanessa Costa Alves Galúcio, Raimunda do Socorro da Silva Azevedo, Lívia Caricio Martins, Maria Irma Seixas Duarte, Jorge Rodrigues de Sousa, Pedro Fernando da Costa Vasconcelos and Juarez Antônio Simões Quaresma
Viruses 2022, 14(6), 1204; https://doi.org/10.3390/v14061204 - 1 Jun 2022
Cited by 5 | Viewed by 4400
Abstract
Yellow fever (YF), a non-contagious infectious disease, is endemic or enzootic to the tropical regions of the Americas and Africa. Periodic outbreaks or epidemics have a significant impact on public health. Programmed cell death, or apoptosis, is generally characterised by distinct morphological changes [...] Read more.
Yellow fever (YF), a non-contagious infectious disease, is endemic or enzootic to the tropical regions of the Americas and Africa. Periodic outbreaks or epidemics have a significant impact on public health. Programmed cell death, or apoptosis, is generally characterised by distinct morphological changes and energy-dependent biochemical pathways. In this study, we performed immunohistochemistry analysis to identify and quantify proteases and protein targets involved in the cascade that triggers apoptosis in YF virus (YFV)-infected human hepatocytes. Liver tissue samples were collected from 26 individuals, among whom 21 were diagnosed as YF-positive, and five were flavivirus-negative and died due to other causes. The histopathological alterations in YFV-positive cases were characterised by the presence of apoptotic bodies, steatosis, cellular swelling, and extensive necrosis and haemorrhage in the hepatic lobules. Additionally, we observed an abundance of inflammatory infiltrates in the portal tract. The expression of various apoptotic markers in the hepatic parenchyma, including CASPASE 3, CASPASE 8, BAX, FAS, FASL, GRANZYME B, and SURVIVIN, differed between YFV-positive cases and controls. Collectively, this study confirmed the complexity of YFV infection-induced apoptosis in situ. However, our data suggest that apoptosis in liver parenchyma lesions may significantly contribute to the pathogenesis of fatal YF in humans. Full article
(This article belongs to the Special Issue Arboviral Lifecycle)
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17 pages, 1165 KB  
Review
Arboviruses: How Saliva Impacts the Journey from Vector to Host
by Christine A. Schneider, Eric Calvo and Karin E. Peterson
Int. J. Mol. Sci. 2021, 22(17), 9173; https://doi.org/10.3390/ijms22179173 - 25 Aug 2021
Cited by 30 | Viewed by 9823
Abstract
Arthropod-borne viruses, referred to collectively as arboviruses, infect millions of people worldwide each year and have the potential to cause severe disease. They are predominately transmitted to humans through blood-feeding behavior of three main groups of biting arthropods: ticks, mosquitoes, and sandflies. The [...] Read more.
Arthropod-borne viruses, referred to collectively as arboviruses, infect millions of people worldwide each year and have the potential to cause severe disease. They are predominately transmitted to humans through blood-feeding behavior of three main groups of biting arthropods: ticks, mosquitoes, and sandflies. The pathogens harbored by these blood-feeding arthropods (BFA) are transferred to animal hosts through deposition of virus-rich saliva into the skin. Sometimes these infections become systemic and can lead to neuro-invasion and life-threatening viral encephalitis. Factors intrinsic to the arboviral vectors can greatly influence the pathogenicity and virulence of infections, with mounting evidence that BFA saliva and salivary proteins can shift the trajectory of viral infection in the host. This review provides an overview of arbovirus infection and ways in which vectors influence viral pathogenesis. In particular, we focus on how saliva and salivary gland extracts from the three dominant arbovirus vectors impact the trajectory of the cellular immune response to arbovirus infection in the skin. Full article
(This article belongs to the Special Issue Molecular Biology of Disease Vectors)
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19 pages, 6478 KB  
Article
Diagnosis and Pathogenesis of Nairobi Sheep Disease Orthonairovirus Infections in Sheep and Cattle
by Julia Hartlaub, Benjamin Gutjahr, Christine Fast, Ali Mirazimi, Markus Keller and Martin H. Groschup
Viruses 2021, 13(7), 1250; https://doi.org/10.3390/v13071250 - 27 Jun 2021
Cited by 19 | Viewed by 4821
Abstract
Nairobi sheep disease orthonairovirus (NSDV) is a zoonotic tick-borne arbovirus, which causes severe gastroenteritis in small ruminants. To date, the virus is prevalent in East Africa and Asia. However, due to climate change, including the spread of transmitting tick vectors and increased animal [...] Read more.
Nairobi sheep disease orthonairovirus (NSDV) is a zoonotic tick-borne arbovirus, which causes severe gastroenteritis in small ruminants. To date, the virus is prevalent in East Africa and Asia. However, due to climate change, including the spread of transmitting tick vectors and increased animal movements, it is likely that the distribution range of NSDV is enlarging. In this project, sheep and cattle (hitherto classified as resistant to NSDV) were experimentally infected with NSDV for a comparative study of the species-specific pathogenesis. For this purpose, several new diagnostic assays (RT-qPCR, ELISA, iIFA, mVNT, PRNT) were developed, which will also be useful for future epidemiological investigations. All challenged sheep (three different doses groups) developed characteristic clinical signs, transient viremia and virus shedding—almost independent on the applied virus dose. Half of the sheep had to be euthanized due to severe clinical signs, including hemorrhagic diarrhea. In contrast, the course of infection in cattle was only subclinical. However, all ruminants showed seroconversion—implying that, indeed, both species are susceptible for NSDV. Hence, not only sheep but also cattle sera can be included in serological monitoring programs for the surveillance of NSDV occurrence and spread in the future. Full article
(This article belongs to the Special Issue Emerging Zoonotic Viral Diseases)
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27 pages, 4939 KB  
Review
Insights into the Pathogenesis of Viral Haemorrhagic Fever Based on Virus Tropism and Tissue Lesions of Natural Rift Valley Fever
by Lieza Odendaal, A Sally Davis and Estelle H Venter
Viruses 2021, 13(4), 709; https://doi.org/10.3390/v13040709 - 20 Apr 2021
Cited by 27 | Viewed by 5932
Abstract
Rift Valley fever phlebovirus (RVFV) infects humans and a wide range of ungulates and historically has caused devastating epidemics in Africa and the Arabian Peninsula. Lesions of naturally infected cases of Rift Valley fever (RVF) have only been described in detail in sheep [...] Read more.
Rift Valley fever phlebovirus (RVFV) infects humans and a wide range of ungulates and historically has caused devastating epidemics in Africa and the Arabian Peninsula. Lesions of naturally infected cases of Rift Valley fever (RVF) have only been described in detail in sheep with a few reports concerning cattle and humans. The most frequently observed lesion in both ruminants and humans is randomly distributed necrosis, particularly in the liver. Lesions supportive of vascular endothelial injury are also present and include mild hydropericardium, hydrothorax and ascites; marked pulmonary congestion and oedema; lymph node congestion and oedema; and haemorrhages in many tissues. Although a complete understanding of RVF pathogenesis is still lacking, antigen-presenting cells in the skin are likely the early targets of the virus. Following suppression of type I IFN production and necrosis of dermal cells, RVFV spreads systemically, resulting in infection and necrosis of other cells in a variety of organs. Failure of both the innate and adaptive immune responses to control infection is exacerbated by apoptosis of lymphocytes. An excessive pro-inflammatory cytokine and chemokine response leads to microcirculatory dysfunction. Additionally, impairment of the coagulation system results in widespread haemorrhages. Fatal outcomes result from multiorgan failure, oedema in many organs (including the lungs and brain), hypotension, and circulatory shock. Here, we summarize current understanding of RVF cellular tropism as informed by lesions caused by natural infections. We specifically examine how extant knowledge informs current understanding regarding pathogenesis of the haemorrhagic fever form of RVF, identifying opportunities for future research. Full article
(This article belongs to the Special Issue Bunyavirus 2020)
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9 pages, 8622 KB  
Article
La Crosse Virus Shows Strain-Specific Differences in Pathogenesis
by Sarah N. Wilson, Krisangel López, Sheryl Coutermash-Ott, Dawn I. Auguste, Danielle L. Porier, Philip M. Armstrong, Theodore G. Andreadis, Gillian Eastwood and Albert J. Auguste
Pathogens 2021, 10(4), 400; https://doi.org/10.3390/pathogens10040400 - 29 Mar 2021
Cited by 7 | Viewed by 5444
Abstract
La Crosse virus (LACV) is the leading cause of pediatric viral encephalitis in North America, and is an important public health pathogen. Historically, studies involving LACV pathogenesis have focused on lineage I strains, but no former work has explored the pathogenesis between or [...] Read more.
La Crosse virus (LACV) is the leading cause of pediatric viral encephalitis in North America, and is an important public health pathogen. Historically, studies involving LACV pathogenesis have focused on lineage I strains, but no former work has explored the pathogenesis between or within lineages. Given the absence of LACV disease in endemic regions where a robust entomological risk exists, we hypothesize that some LACV strains are attenuated and demonstrate reduced neuroinvasiveness. Herein, we compared four viral strains representing all three lineages to determine differences in neurovirulence or neuroinvasiveness using three murine models. A representative strain from lineage I was shown to be the most lethal, causing >50% mortality in each of the three mouse studies. However, other strains only presented excessive mortality (>50%) within the suckling mouse neurovirulence model. Neurovirulence was comparable among strains, but viruses differed in their neuroinvasive capacities. Our studies also showed that viruses within lineage III vary in pathogenesis with contemporaneous strains, showing reduced neuroinvasiveness compared to an ancestral strain from the same U.S. state (i.e., Connecticut). These findings demonstrate that LACV strains differ markedly in pathogenesis, and that strain selection is important for assessing vaccine and therapeutic efficacies. Full article
(This article belongs to the Collection Feature Papers in Viral Pathogens)
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20 pages, 5269 KB  
Article
Dengue Virus Serotype 2 Intrahost Diversity in Patients with Different Clinical Outcomes
by Maria Celeste Torres, Marcos Cesar Lima de Mendonça, Cintia Damasceno dos Santos Rodrigues, Vagner Fonseca, Mario Sergio Ribeiro, Ana Paula Brandão, Rivaldo Venâncio da Cunha, Ana Isabel Dias, Lucy Santos Vilas Boas, Alvina Clara Felix, Maira Alves Pereira, Luzia Maria de Oliveira Pinto, Anavaj Sakuntabhai, Ana Maria Bispo de Filippis and on behalf of ZikAction Consortium
Viruses 2021, 13(2), 349; https://doi.org/10.3390/v13020349 - 23 Feb 2021
Cited by 18 | Viewed by 4555
Abstract
Intrahost genetic diversity is thought to facilitate arbovirus adaptation to changing environments and hosts, and it might also be linked to viral pathogenesis. Dengue virus serotype 2 (DENV-2) has circulated in Brazil since 1990 and is associated with severe disease and explosive outbreaks. [...] Read more.
Intrahost genetic diversity is thought to facilitate arbovirus adaptation to changing environments and hosts, and it might also be linked to viral pathogenesis. Dengue virus serotype 2 (DENV-2) has circulated in Brazil since 1990 and is associated with severe disease and explosive outbreaks. Intending to shed light on the viral determinants for severe dengue pathogenesis, we sought to analyze the DENV-2 intrahost genetic diversity in 68 patient cases clinically classified as dengue fever (n = 31), dengue with warning signs (n = 19), and severe dengue (n = 18). Unlike previous DENV intrahost diversity studies whose approaches employed PCR, here we performed viral whole-genome deep sequencing from clinical samples with an amplicon-free approach, representing the real intrahost diversity scenario. Striking differences were detected in the viral population structure between the three clinical categories, which appear to be driven mainly by different infection times and selection pressures, rather than being linked with the clinical outcome itself. Diversity in the NS2B gene, however, showed to be constrained, irrespective of clinical outcome and infection time. Finally, 385 non-synonymous intrahost single-nucleotide variants located along the viral polyprotein, plus variants located in the untranslated regions, were consistently identified among the samples. Of them, 124 were exclusively or highly detected among cases with warning signs and among severe cases. However, there was no variant that by itself appeared to characterize the cases of greater severity, either due to its low intrahost frequency or the conservative effect on amino acid substitution. Although further studies are necessary to determine their real effect on viral proteins, this heightens the possibility of epistatic interactions. The present analysis represents an initial effort to correlate DENV-2 genetic diversity to its pathogenic potential and thus contribute to understanding the virus’s dynamics within its human host. Full article
(This article belongs to the Special Issue Endemic Arboviruses)
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23 pages, 2624 KB  
Article
Pathogenicity of West Nile Virus Lineage 1 to German Poultry
by Cora M. Holicki, Friederike Michel, Ana Vasić, Christine Fast, Martin Eiden, Cristian Răileanu, Helge Kampen, Doreen Werner, Martin H. Groschup and Ute Ziegler
Vaccines 2020, 8(3), 507; https://doi.org/10.3390/vaccines8030507 - 5 Sep 2020
Cited by 12 | Viewed by 4908
Abstract
West Nile virus (WNV) is a mosquito-borne virus that originates from Africa and at present causes neurological disease in birds, horses, and humans all around the globe. As West Nile fever is an important zoonosis, the role of free-ranging domestic poultry as a [...] Read more.
West Nile virus (WNV) is a mosquito-borne virus that originates from Africa and at present causes neurological disease in birds, horses, and humans all around the globe. As West Nile fever is an important zoonosis, the role of free-ranging domestic poultry as a source of infection for humans should be evaluated. This study examined the pathogenicity of an Italian WNV lineage 1 strain for domestic poultry (chickens, ducks, and geese) held in Germany. All three species were subcutaneously injected with WNV, and the most susceptible species was also inoculated via mosquito bite. All species developed various degrees of viremia, viral shedding (oropharyngeal and cloacal), virus accumulation, and pathomorphological lesions. Geese were most susceptible, displaying the highest viremia levels. The tested waterfowl, geese, and especially ducks proved to be ideal sentinel species for WNV due to their high antibody levels and relatively low blood viral loads. None of the three poultry species can function as a reservoir/amplifying host for WNV, as their viremia levels most likely do not suffice to infect feeding mosquitoes. Due to the recent appearance of WNV in Germany, future pathogenicity studies should also include local virus strains. Full article
(This article belongs to the Special Issue West Nile Virus Disease)
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