RESUMEN
Although enteric helminth infections modulate immunity to mucosal pathogens, their effects on systemic microbes remain less established. Here, we observe increased mortality in mice coinfected with the enteric helminth Heligmosomoides polygyrus bakeri (Hpb) and West Nile virus (WNV). This enhanced susceptibility is associated with altered gut morphology and transit, translocation of commensal bacteria, impaired WNV-specific T cell responses, and increased virus infection in the gastrointestinal tract and central nervous system. These outcomes were due to type 2 immune skewing, because coinfection in Stat6-/- mice rescues mortality, treatment of helminth-free WNV-infected mice with interleukin (IL)-4 mirrors coinfection, and IL-4 receptor signaling in intestinal epithelial cells mediates the susceptibility phenotypes. Moreover, tuft cell-deficient mice show improved outcomes with coinfection, whereas treatment of helminth-free mice with tuft cell-derived cytokine IL-25 or ligand succinate worsens WNV disease. Thus, helminth activation of tuft cell-IL-4-receptor circuits in the gut exacerbates infection and disease of a neurotropic flavivirus.
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Coinfección , Nematospiroides dubius/fisiología , Transducción de Señal , Infecciones por Strongylida/patología , Virus del Nilo Occidental/fisiología , Animales , Linfocitos T CD8-positivos/inmunología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Mucosa Intestinal/parasitología , Mucosa Intestinal/virología , Ratones , Ratones Endogámicos C57BL , Neuronas/parasitología , Neuronas/virología , Receptores de Interleucina-4/metabolismo , Factor de Transcripción STAT6/genética , Índice de Severidad de la Enfermedad , Infecciones por Strongylida/parasitologíaRESUMEN
In response to viral infection, how cells balance translational shutdown to limit viral replication and the induction of antiviral components like interferons (IFNs) is not well understood. Moreover, how distinct isoforms of IFN-induced oligoadenylate synthetase 1 (OAS1) contribute to this antiviral response also requires further elucidation. Here, we show that human, but not mouse, OAS1 inhibits SARS-CoV-2 replication through its canonical enzyme activity via RNase L. In contrast, both mouse and human OAS1 protect against West Nile virus infection by a mechanism distinct from canonical RNase L activation. OAS1 binds AU-rich elements (AREs) of specific mRNAs, including IFNß. This binding leads to the sequestration of IFNß mRNA to the endomembrane regions, resulting in prolonged half-life and continued translation. Thus, OAS1 is an ARE-binding protein with two mechanisms of antiviral activity: driving inhibition of translation but also a broader, non-canonical function of protecting IFN expression from translational shutdown.
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2',5'-Oligoadenilato Sintetasa , Interferones , Oligorribonucleótidos , Virosis , Fiebre del Nilo Occidental , Animales , Humanos , Ratones , 2',5'-Oligoadenilato Sintetasa/genética , 2',5'-Oligoadenilato Sintetasa/metabolismo , Nucleótidos de Adenina , Antivirales/farmacología , Fiebre del Nilo Occidental/genética , Fiebre del Nilo Occidental/metabolismo , Virus del Nilo Occidental/metabolismo , Virus del Nilo Occidental/patogenicidadRESUMEN
Receptor-interacting protein kinase-3 (RIPK3) is an activator of necroptotic cell death, but recent work has implicated additional roles for RIPK3 in inflammatory signaling independent of cell death. However, while necroptosis has been shown to contribute to antiviral immunity, death-independent roles for RIPK3 in host defense have not been demonstrated. Using a mouse model of West Nile virus (WNV) encephalitis, we show that RIPK3 restricts WNV pathogenesis independently of cell death. Ripk3-/- mice exhibited enhanced mortality compared to wild-type (WT) controls, while mice lacking the necroptotic effector MLKL, or both MLKL and caspase-8, were unaffected. The enhanced susceptibility of Ripk3-/- mice arose from suppressed neuronal chemokine expression and decreased central nervous system (CNS) recruitment of T lymphocytes and inflammatory myeloid cells, while peripheral immunity remained intact. These data identify pleiotropic functions for RIPK3 in the restriction of viral pathogenesis and implicate RIPK3 as a key coordinator of immune responses within the CNS.
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Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Fiebre del Nilo Occidental/inmunología , Virus del Nilo Occidental/fisiología , Animales , Sistema Nervioso Central/metabolismo , Quimiocinas/inmunología , Leucocitos/inmunología , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Necrosis , Neuronas/metabolismoRESUMEN
The signaling adaptor TRAF3 is a highly versatile regulator of both innate immunity and adaptive immunity, but how its phosphorylation is regulated is still unknown. Here we report that deficiency in or inhibition of the conserved serine-threonine kinase CK1É suppressed the production of type I interferon in response to viral infection. CK1É interacted with and phosphorylated TRAF3 at Ser349, which thereby promoted the Lys63 (K63)-linked ubiquitination of TRAF3 and subsequent recruitment of the kinase TBK1 to TRAF3. Consequently, CK1É-deficient mice were more susceptible to viral infection. Our findings establish CK1É as a regulator of antiviral innate immune responses and indicate a novel mechanism of immunoregulation that involves CK1É-mediated phosphorylation of TRAF3.
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Caseína Cinasa 1 épsilon/inmunología , Inmunidad Innata/inmunología , Interferón beta/inmunología , Factor 3 Asociado a Receptor de TNF/inmunología , Animales , Caseína Cinasa 1 épsilon/antagonistas & inhibidores , Caseína Cinasa 1 épsilon/genética , Ensayo de Inmunoadsorción Enzimática , Células HEK293 , Células HeLa , Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Humanos , Interferón Tipo I/biosíntesis , Interferón Tipo I/inmunología , Interferón beta/biosíntesis , Espectrometría de Masas , Ratones , Ratones Noqueados , Fosforilación , Proteínas Serina-Treonina Quinasas , Reacción en Cadena en Tiempo Real de la Polimerasa , Infecciones por Rhabdoviridae/inmunología , Factor 3 Asociado a Receptor de TNF/genética , Ubiquitinación , Vesiculovirus/inmunología , Fiebre del Nilo Occidental/inmunología , Virus del Nilo Occidental/inmunologíaRESUMEN
The human helicase senataxin (SETX) has been linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS4) and ataxia with oculomotor apraxia (AOA2). Here we identified a role for SETX in controlling the antiviral response. Cells that had undergone depletion of SETX and SETX-deficient cells derived from patients with AOA2 had higher expression of antiviral mediators in response to infection than did wild-type cells. Mechanistically, we propose a model whereby SETX attenuates the activity of RNA polymerase II (RNAPII) at genes stimulated after a virus is sensed and thus controls the magnitude of the host response to pathogens and the biogenesis of various RNA viruses (e.g., influenza A virus and West Nile virus). Our data indicate a potentially causal link among inborn errors in SETX, susceptibility to infection and the development of neurologic disorders.
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Esclerosis Amiotrófica Lateral/genética , Gripe Humana/inmunología , Orthomyxoviridae/fisiología , ARN Helicasas/metabolismo , ARN Polimerasa II/metabolismo , Degeneraciones Espinocerebelosas/genética , Fiebre del Nilo Occidental/inmunología , Virus del Nilo Occidental/fisiología , Animales , Línea Celular Tumoral , Chlorocebus aethiops , Citocinas/metabolismo , ADN Helicasas , Perros , Regulación hacia Abajo , Humanos , Inmunidad Innata/genética , Factor 3 Regulador del Interferón/metabolismo , Células de Riñón Canino Madin Darby , Ratones , Ratones Noqueados , Análisis por Micromatrices , Enzimas Multifuncionales , ARN Helicasas/genética , ARN Polimerasa II/genética , ARN Interferente Pequeño/genética , Ataxias Espinocerebelosas/congénito , Células Vero , Replicación Viral/genéticaRESUMEN
West Nile virus (WNV) is an arthropod-borne, positive-sense RNA virus that poses an increasing global threat due to warming climates and lack of effective therapeutics. Like other enzootic viruses, little is known about how host context affects the structure of the full-length RNA genome. Here, we report a complete secondary structure of the entire WNV genome within infected mammalian and arthropod cell lines. Our analysis affords structural insights into multiple, conserved aspects of flaviviral biology. We show that the WNV genome folds with minimal host dependence, and we prioritize well-folded regions for functional validation using structural homology between hosts as a guide. Using structure-disrupting, antisense locked nucleic acids, we then demonstrate that the WNV genome contains riboregulatory structures with conserved and host-specific functional roles. These results reveal promising RNA drug targets within flaviviral genomes, and they highlight the therapeutic potential of ASO-LNAs as both WNV-specific and pan-flaviviral therapeutic agents.
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Genoma Viral , ARN Viral , Virus del Nilo Occidental , Virus del Nilo Occidental/genética , Animales , ARN Viral/genética , ARN Viral/metabolismo , Humanos , Línea Celular , Conformación de Ácido Nucleico , Fiebre del Nilo Occidental/virología , Especificidad del Huésped/genética , Interacciones Huésped-Patógeno/genéticaRESUMEN
BACKGROUND: West Nile virus (WNV) outbreaks in birds, humans, and livestock have occurred in multiple areas in Europe and have had a significant impact on animal and human health. The patterns of emergence and spread of WNV in Europe are very different from those in the US and understanding these are important for guiding preparedness activities. METHODS: We mapped the evolution and spread history of WNV in Europe by incorporating viral genome sequences and epidemiological data into phylodynamic models. Spatially explicit phylogeographic models were developed to explore the possible contribution of different drivers to viral dispersal direction and velocity. A "skygrid-GLM" approach was used to identify how changes in environments would predict viral genetic diversity variations over time. FINDINGS: Among the six lineages found in Europe, WNV-2a (a sub-lineage of WNV-2) has been predominant (accounting for 73% of all sequences obtained in Europe that have been shared in the public domain) and has spread to at least 14 countries. In the past two decades, WNV-2a has evolved into two major co-circulating clusters, both originating from Central Europe, but with distinct dynamic history and transmission patterns. WNV-2a spreads at a high dispersal velocity (88km/yr-215 km/yr) which is correlated to bird movements. Notably, amongst multiple drivers that could affect the spread of WNV, factors related to land use were found to strongly influence the spread of WNV. Specifically, the intensity of agricultural activities (defined by factors related to crops and livestock production, such as coverage of cropland, pasture, cultivated and managed vegetation, livestock density) were positively associated with both spread direction and velocity. In addition, WNV spread direction was associated with high coverage of wetlands and migratory bird flyways. CONCLUSION: Our results suggest that-in addition to ecological conditions favouring bird- and mosquito- presence-agricultural land use may be a significant driver of WNV emergence and spread. Our study also identified significant gaps in data and the need to strengthen virological surveillance in countries of Central Europe from where WNV outbreaks are likely seeded. Enhanced monitoring for early detection of further dispersal could be targeted to areas with high agricultural activities and habitats of migratory birds.
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Fiebre del Nilo Occidental , Virus del Nilo Occidental , Animales , Humanos , Virus del Nilo Occidental/genética , Fiebre del Nilo Occidental/epidemiología , Fiebre del Nilo Occidental/veterinaria , Filogeografía , Europa (Continente)/epidemiología , Brotes de EnfermedadesRESUMEN
Anti-Dengue virus (DENV) antibodies can be either protective or pathogenic in humans with prior DENV infection. In a recent issue of Science, Bardina et al. (2017) demonstrated that passive transfer of immune plasma against DENV and West Nile virus (WNV) can enhance Zika virus (ZIKV) infection and pathogenesis in mice.
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Virus del Dengue/inmunología , Dengue/virología , Animales , Anticuerpos Antivirales/inmunología , Humanos , Ratones , Virus del Nilo Occidental/inmunología , Infección por el Virus ZikaRESUMEN
The Orthoflavivirus NS3 helicase (NS3h) is crucial in virus replication, representing a potential drug target for pathogenesis. NS3h utilizes nucleotide triphosphate (ATP) for hydrolysis energy to translocate on single-stranded nucleic acids, which is an important step in the unwinding of double-stranded nucleic acids. Intermediate states along the ATP hydrolysis cycle and conformational changes between these states, represent important yet difficult-to-identify targets for potential inhibitors. Extensive molecular dynamics simulations of West Nile virus NS3h+ssRNA in the apo, ATP, ADP+Pi and ADP bound states were used to model the conformational ensembles along this cycle. Energetic and structural clustering analyses depict a clear trend of differential enthalpic affinity of NS3h with ADP, demonstrating a probable mechanism of hydrolysis turnover regulated by the motif-VI loop (MVIL). Based on these results, MVIL mutants (D471L, D471N and D471E) were found to have a substantial reduction in ATPase activity and RNA replication compared to the wild-type. Simulations of the mutants in the apo state indicate a shift in MVIL populations favoring either a closed or open 'valve' conformation, affecting ATP entry or stabilization, respectively. Combining our molecular modeling with experimental evidence highlights a conformation-dependent role for MVIL as a 'valve' for the ATP-pocket, presenting a promising target for antiviral development.
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Adenosina Trifosfato , Simulación de Dinámica Molecular , ARN Helicasas , Proteínas no Estructurales Virales , Virus del Nilo Occidental , Proteínas no Estructurales Virales/metabolismo , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/genética , Virus del Nilo Occidental/enzimología , Virus del Nilo Occidental/genética , ARN Helicasas/metabolismo , ARN Helicasas/química , ARN Helicasas/genética , Adenosina Trifosfato/metabolismo , Adenosina Difosfato/metabolismo , Adenosina Difosfato/química , Secuencias de Aminoácidos , Mutación , Nucleótidos/metabolismo , Nucleótidos/química , Hidrólisis , Replicación Viral/genética , Conformación Proteica , Proteasas Virales , Serina Endopeptidasas , Nucleósido-Trifosfatasa , ARN Helicasas DEAD-boxRESUMEN
Usutu virus (USUV) and West Nile virus (WNV) are closely related emerging arboviruses belonging to the Flavivirus genus and posing global public health concerns. Although human infection by these viruses is mainly asymptomatic, both have been associated with neurological disorders such as encephalitis and meningoencephalitis. Since USUV and WNV are transmitted through the bite of an infected mosquito, the skin represents the initial site of virus inoculation and provides the first line of host defense. Although some data on the early stages of WNV skin infection are available, very little is known about USUV. Herein, USUV-skin resident cell interactions were characterized. Using primary human keratinocytes and fibroblasts, an early replication of USUV during the first 24 hours was shown in both skin cells. In human skin explants, a high viral tropism for keratinocytes was observed. USUV infection of these models induced type I and III interferon responses associated with upregulated expression of various interferon-stimulated genes as well as pro-inflammatory cytokine and chemokine genes. Among the four USUV lineages studied, the Europe 2 strain replicated more efficiently in skin cells and induced a higher innate immune response. In vivo, USUV and WNV disseminated quickly from the inoculation site to distal cutaneous tissues. In addition, viral replication and persistence in skin cells were associated with an antiviral response. Taken together, these results provide a better understanding of the pathophysiology of the early steps of USUV infection and suggest that the skin constitutes a major amplifying organ for USUV and WNV infection.IMPORTANCEUsutu virus (USUV) and West Nile virus (WNV) are closely related emerging Flaviviruses transmitted through the bite of an infected mosquito. Since they are directly inoculated within the upper skin layers, the interactions between the virus and skin cells are critical in the pathophysiology of USUV and WNV infection. Here, during the early steps of infection, we showed that USUV can efficiently infect two human resident skin cell types at the inoculation site: the epidermal keratinocytes and the dermal fibroblasts, leading to the induction of an antiviral innate immune response. Moreover, following cutaneous inoculation, we demonstrated that both viruses can rapidly spread, replicate, and persist in all distal cutaneous tissues in mice, a phenomenon associated with a generalized skin inflammatory response. These results highlight the key amplifying and immunological role of the skin during USUV and WNV infection.
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Infecciones por Flavivirus , Flavivirus , Tropismo Viral , Fiebre del Nilo Occidental , Virus del Nilo Occidental , Animales , Humanos , Ratones , Antivirales , Culicidae , Infecciones por Flavivirus/virología , Interferones , Fiebre del Nilo Occidental/virología , Piel/inmunología , Piel/patología , Piel/virología , Técnicas In VitroRESUMEN
Induction of type I interferon is a central event of innate immunity, essential for host defense. Here we report that the transcription factor ELF4 is induced by type I interferon and upregulates interferon expression in a feed-forward loop. ELF4 deficiency leads to reduced interferon production, resulting in enhanced susceptibility to West Nile virus encephalitis in mice. After viral infection, ELF4 is recruited by STING, interacts with and is activated by the MAVS-TBK1 complex, and translocates into the nucleus to bind interferon promoters. Cooperative binding with ELF4 increases the binding affinity of interferon regulatory factors IRF3 and IRF7, which is mediated by EICE elements. Thus, in addition to identifying a regulator of innate immune signaling, we uncovered a role for EICE elements in interferon transactivation.
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Proteínas de Unión al ADN/inmunología , Interferón beta/inmunología , Factores de Transcripción/inmunología , Fiebre del Nilo Occidental/inmunología , Virus del Nilo Occidental/inmunología , Animales , Línea Celular , Células Cultivadas , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Células HEK293 , Células HeLa , Interacciones Huésped-Patógeno/inmunología , Humanos , Immunoblotting , Factor 3 Regulador del Interferón/genética , Factor 3 Regulador del Interferón/inmunología , Factor 3 Regulador del Interferón/metabolismo , Factor 7 Regulador del Interferón/genética , Factor 7 Regulador del Interferón/inmunología , Factor 7 Regulador del Interferón/metabolismo , Interferón beta/genética , Interferón beta/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Unión Proteica/inmunología , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/inmunología , Análisis de Supervivencia , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Activación Transcripcional/inmunología , Fiebre del Nilo Occidental/virología , Virus del Nilo Occidental/fisiologíaRESUMEN
Arthropod-borne viruses (arboviruses) pose significant threats to global public health by causing a spectrum of diseases ranging from mild febrile illnesses to severe neurological complications. Understanding the intricate interplay between arboviruses and the immune system within the central nervous system is crucial for developing effective strategies to combat these infections and mitigate their neurological sequelae. This review comprehensively explores the mechanisms by which arboviruses such as Zika virus, West Nile virus, and Dengue virus manipulate immune responses within the CNS, leading to diverse clinical manifestations.
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Virus del Dengue , Virus del Nilo Occidental , Infección por el Virus Zika , Virus Zika , Humanos , Sistema Nervioso Central , Inmunidad , Infección por el Virus Zika/complicacionesRESUMEN
West Nile virus (WNV) is the most common arthropod-borne flavivirus in the United States; however, the vector ligand(s) that participate in infection are not known. We now show that an Aedes aegypti C-type lectin, mosGCTL-1, is induced by WNV, interacts with WNV in a calcium-dependent manner, and facilitates infection in vivo and in vitro. A mosquito homolog of human CD45 in A. aegypti, designated mosPTP-1, recruits mosGCTL-1 to enable viral attachment to cells and to enhance viral entry. In vivo experiments show that mosGCTL-1 and mosPTP-1 function as part of the same pathway and are critical for WNV infection of mosquitoes. A similar phenomenon was also observed in Culex quinquefasciatus, a natural vector of WNV, further demonstrating that these genes participate in WNV infection. During the mosquito blood-feeding process, WNV infection was blocked in vivo with mosGCTL-1 antibodies. A molecular understanding of flaviviral-arthropod interactions may lead to strategies to control viral dissemination in nature.
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Aedes/virología , Culex/virología , Proteínas de Insectos/metabolismo , Lectinas Tipo C/metabolismo , Antígenos Comunes de Leucocito/metabolismo , Internalización del Virus , Virus del Nilo Occidental/fisiología , Animales , Humanos , Antígenos Comunes de Leucocito/químicaRESUMEN
Disease transmission prediction across wildlife is crucial for risk assessment of emerging infectious diseases. Susceptibility of host species to pathogens is influenced by the geographic, environmental, and phylogenetic context of the specific system under study. We used machine learning to analyze how such variables influence pathogen incidence for multihost pathogen assemblages, including one of direct transmission (coronaviruses and bats) and two vector-borne systems (West Nile Virus [WNV] and birds, and malaria and birds). Here we show that this methodology is able to provide reliable global spatial susceptibility predictions for the studied host-pathogen systems, even when using a small amount of incidence information (i.e., [Formula: see text] of information in a database). We found that avian malaria was mostly affected by environmental factors and by an interaction between phylogeny and geography, and WNV susceptibility was mostly influenced by phylogeny and by the interaction between geographic and environmental distances, whereas coronavirus susceptibility was mostly affected by geography. This approach will help to direct surveillance and field efforts providing cost-effective decisions on where to invest limited resources.
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Animales Salvajes , Enfermedades Transmisibles Emergentes , Susceptibilidad a Enfermedades , Animales , Animales Salvajes/parasitología , Animales Salvajes/virología , Enfermedades de las Aves/epidemiología , Enfermedades de las Aves/transmisión , Quirópteros/virología , Enfermedades Transmisibles Emergentes/epidemiología , Enfermedades Transmisibles Emergentes/transmisión , Enfermedades Transmisibles Emergentes/veterinaria , Coronavirus , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/transmisión , Infecciones por Coronavirus/veterinaria , Bases de Datos Factuales , Ambiente , Monitoreo Epidemiológico , Geografía , Interacciones Huésped-Patógeno , Incidencia , Aprendizaje Automático , Malaria/epidemiología , Malaria/transmisión , Malaria/veterinaria , Filogenia , Medición de Riesgo , Fiebre del Nilo Occidental/epidemiología , Fiebre del Nilo Occidental/transmisión , Fiebre del Nilo Occidental/veterinaria , Virus del Nilo OccidentalRESUMEN
West Nile virus (WNV), an arthropod-borne flavivirus, can cause severe symptoms, including encephalitis, and death, posing a threat to public health and the economy. However, there is still no approved treatment or vaccine available for humans. Here, we developed a novel vaccine platform based on a classical insect-specific flavivirus (cISF) YN15-283-02, which was derived from Culicoides. The cISF-WNV chimera was constructed by replacing prME structural genes of the infectious YN15-283-02 cDNA clone with those of WNV and successfully rescued in Aedes albopictus cells. cISF-WNV was nonreplicable in vertebrate cells and nonpathogenic in type I interferon receptor (IFNAR)-deficient mice. A single-dose immunization of cISF-WNV elicited considerable Th1-biased antibody responses in C57BL/6 mice, which was sufficient to offer complete protection against lethal WNV challenge with no symptoms. Our studies demonstrated the potential of the insect-specific cISF-WNV as a prophylactic vaccine candidate to prevent infection with WNV.
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Aedes , Flavivirus , Vacunas , Fiebre del Nilo Occidental , Virus del Nilo Occidental , Animales , Ratones , Humanos , Virus del Nilo Occidental/genética , Flavivirus/genética , Fiebre del Nilo Occidental/prevención & control , Anticuerpos Antivirales , Ratones Endogámicos C57BLRESUMEN
We analyzed West Nile Virus (WNV) exposure from 1,222 blood donors during 2017-2018 from an area of south-central Spain. Results revealed WNV seroprevalence of 0.08% (95% CI 0.004%-0.4%) in this population. Our findings underscore the need for continued surveillance and research to manage WNV infection in this region.
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Anticuerpos Antivirales , Donantes de Sangre , Fiebre del Nilo Occidental , Virus del Nilo Occidental , Humanos , España/epidemiología , Fiebre del Nilo Occidental/epidemiología , Virus del Nilo Occidental/inmunología , Estudios Seroepidemiológicos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anticuerpos Antivirales/sangre , Adulto Joven , Adolescente , AncianoRESUMEN
Natural killer (NK) cells are cytotoxic lymphocytes important for viral defense. West Nile virus (WNV) infection of the central nervous system (CNS) causes marked recruitment of bone marrow (BM)-derived monocytes, T cells and NK cells, resulting in severe neuroinflammation and brain damage. Despite substantial numbers of NK cells in the CNS, their function and phenotype remain largely unexplored. Here, we demonstrate that NK cells mature from the BM to the brain, upregulate inhibitory receptors and show reduced cytokine production and degranulation, likely due to the increased expression of the inhibitory NK cell molecule, MHC-I. Intriguingly, this correlated with a reduction in metabolism associated with cytotoxicity in brain-infiltrating NK cells. Importantly, the degranulation and killing capability were restored in NK cells isolated from WNV-infected tissue, suggesting that WNV-induced NK cell inhibition occurs in the CNS. Overall, this work identifies a potential link between MHC-I inhibition of NK cells and metabolic reduction of their cytotoxicity during infection.
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Fiebre del Nilo Occidental , Virus del Nilo Occidental , Humanos , Virus del Nilo Occidental/genética , Fiebre del Nilo Occidental/genética , Encéfalo , Células Asesinas Naturales , Linfocitos TRESUMEN
Mathematical models within the Ross-Macdonald framework increasingly play a role in our understanding of vector-borne disease dynamics and as tools for assessing scenarios to respond to emerging threats. These threats are typically characterized by a high degree of heterogeneity, introducing a range of possible complexities in models and challenges to maintain the link with empirical evidence. We systematically identified and analysed a total of 77 published papers presenting compartmental West Nile virus (WNV) models that use parameter values derived from empirical studies. Using a set of 15 criteria, we measured the dissimilarity compared with the Ross-Macdonald framework. We also retrieved the purpose and type of models and traced the empirical sources of their parameters. Our review highlights the increasing refinements in WNV models. Models for prediction included the highest number of refinements. We found uneven distributions of refinements and of evidence for parameter values. We identified several challenges in parametrizing such increasingly complex models. For parameters common to most models, we also synthesize the empirical evidence for their values and ranges. The study highlights the potential to improve the quality of WNV models and their applicability for policy by establishing closer collaboration between mathematical modelling and empirical work.
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Fiebre del Nilo Occidental , Virus del Nilo Occidental , Humanos , Modelos Teóricos , Fiebre del Nilo Occidental/transmisiónRESUMEN
IMPORTANCE: Arboviruses, particularly those transmitted by mosquitoes, pose a significant threat to humans and are an increasing concern because of climate change, human activity, and expanding vector-competent populations. West Nile virus is of significant concern as the most frequent mosquito-borne disease transmitted annually within the continental United States. Here, we identify a previously uncharacterized signaling pathway that impacts West Nile virus infection, namely endothelin signaling. Additionally, we demonstrate that we can successfully translate results obtained from D. melanogaster into the more relevant human system. Our results add to the growing field of insulin-mediated antiviral immunity and identify potential biomarkers or intervention targets to better address West Nile virus infection and severe disease.
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Endotelinas , Insulina , Fiebre del Nilo Occidental , Animales , Humanos , Drosophila melanogaster/inmunología , Drosophila melanogaster/metabolismo , Drosophila melanogaster/virología , Insulina/metabolismo , Transducción de Señal , Fiebre del Nilo Occidental/inmunología , Fiebre del Nilo Occidental/metabolismo , Fiebre del Nilo Occidental/virología , Virus del Nilo Occidental/inmunología , Virus del Nilo Occidental/fisiología , Endotelinas/inmunología , Endotelinas/metabolismoRESUMEN
Powassan virus (POWV) is an emerging tick-borne flavivirus that causes neuroinvasive diseases, including encephalitis, meningitis, and paralysis. Similar to other neuroinvasive flaviviruses, such as West Nile virus (WNV) and Japanese encephalitis virus (JEV), POWV disease presentation is heterogeneous, and the factors influencing disease outcome are not fully understood. We used Collaborative Cross (CC) mice to assess the impact of host genetic factors on POWV pathogenesis. We infected a panel of Oas1b-null CC lines with POWV and observed a range of susceptibility, indicating that host factors other than the well-characterized flavivirus restriction factor Oas1b modulate POWV pathogenesis in CC mice. Among the Oas1b-null CC lines, we identified multiple highly susceptible lines (0% survival), including CC071 and CC015, and two resistant lines, CC045 and CC057 (>75% survival). The susceptibility phenotypes generally were concordant among neuroinvasive flaviviruses, although we did identify one line, CC006, that was specifically resistant to JEV, suggesting that both pan-flavivirus and virus-specific mechanisms contribute to susceptibility phenotypes in CC mice. We found that POWV replication was restricted in bone marrow-derived macrophages from CC045 and CC057 mice, suggesting that resistance could result from cell-intrinsic restriction of viral replication. Although serum viral loads at 2 days postinfection were equivalent between resistant and susceptible CC lines, clearance of POWV from the serum was significantly enhanced in CC045 mice. Furthermore, CC045 mice had significantly lower viral loads in the brain at 7 days postinfection than did CC071 mice, suggesting that reduced central nervous system (CNS) infection contributes to the resistant phenotype of CC045 mice. IMPORTANCE Neuroinvasive flaviviruses, such as WNV, JEV, and POWV, are transmitted to humans by mosquitoes or ticks and can cause neurologic diseases, such as encephalitis, meningitis, and paralysis, and they can result in death or long-term sequelae. Although potentially severe, neuroinvasive disease is a rare outcome of flavivirus infection. The factors that determine whether someone develops severe disease after a flavivirus infection are not fully understood, but host genetic differences in polymorphic antiviral response genes likely contribute to the outcome of infection. We evaluated a panel of genetically diverse mice and identified lines with distinct outcomes following infection with POWV. We found that resistance to POWV pathogenesis corresponded to reduced viral replication in macrophages, more rapid clearance of virus in peripheral tissues, and reduced viral infection in the brain. These susceptible and resistant mouse lines will provide a system for investigating the pathogenic mechanisms of POWV and identifying polymorphic host genes that contribute to resistance.