RESUMEN
Kyasanur Forest disease virus (KFDV) and the closely related Alkhurma hemorrhagic disease virus (AHFV) are emerging flaviviruses that cause severe viral hemorrhagic fevers in humans. Increasing geographical expansion and case numbers, particularly of KFDV in southwest India, class these viruses as a public health threat. Viral pathogenesis is not well understood and additional vaccines and antivirals are needed to effectively counter the impact of these viruses. However, current animal models of KFDV pathogenesis do not accurately reproduce viral tissue tropism or clinical outcomes observed in humans. Here, we show that pigtailed macaques (Macaca nemestrina) infected with KFDV or AHFV develop viremia that peaks 2 to 4 days following inoculation. Over the course of infection, animals developed lymphocytopenia, thrombocytopenia, and elevated liver enzymes. Infected animals exhibited hallmark signs of human disease characterized by a flushed appearance, piloerection, dehydration, loss of appetite, weakness, and hemorrhagic signs including epistaxis. Virus was commonly present in the gastrointestinal tract, consistent with human disease caused by KFDV and AHFV where gastrointestinal symptoms (hemorrhage, vomiting, diarrhea) are common. Importantly, RNAseq of whole blood revealed that KFDV downregulated gene expression of key clotting factors that was not observed during AHFV infection, consistent with increased severity of KFDV disease observed in this model. This work characterizes a nonhuman primate model for KFDV and AHFV that closely resembles human disease for further utilization in understanding host immunity and development of antiviral countermeasures.
Asunto(s)
Modelos Animales de Enfermedad , Virus de la Encefalitis Transmitidos por Garrapatas/patogenicidad , Encefalitis Transmitida por Garrapatas/virología , Fiebres Hemorrágicas Virales/virología , Macaca nemestrina , Animales , Chlorocebus aethiops , Citocinas/sangre , Virus de la Encefalitis Transmitidos por Garrapatas/genética , Virus de la Encefalitis Transmitidos por Garrapatas/inmunología , Encefalitis Transmitida por Garrapatas/inmunología , Encefalitis Transmitida por Garrapatas/patología , Femenino , Células HEK293 , Fiebres Hemorrágicas Virales/inmunología , Fiebres Hemorrágicas Virales/patología , Humanos , Ganglios Linfáticos/virología , Células Vero , ViremiaRESUMEN
To assess the relationship between the expression of CD38 and the progression of hemorrhagic fever with renal syndrome (HFRS), we determined the levels of CD38 during different phases of HFRS and evaluated the relationship between changes in CD38 expression and the progression of HFRS. The expression of CD38 in 68 patients with HFRS was analyzed by flow cytometry, and this method was also used to determine the levels of CD4+T, CD8+T, and B lymphocytes and NK cells. Furthermore, creatinine (Cr), uric acid (UA), and urea in serum at each stage of HFRS were measured using commercial kits. The basic clinical reference values for leukocytes, platelets (PLT), and red blood cells were determined by conventional methods. The colloidal gold method was used to measure HFRS antibody levels in the patients. A significant change in CD38 expression was observed from the fever phase to the recovery phase in patients with HFRS. Moreover, the expression of CD38 was proportionally correlated with the levels of Cr, UA, and urea in serum. In contrast, there was an inverse correlation between CD38 and PLT. Interestingly, an increase in CD38 expression correlated with an increase in CD8+T lymphocytes, B cells, and NK cells, but with a decrease in CD4+T lymphocytes. The expression of CD38 is associated with the progression of HFRS, suggesting that it may be a potent indicator of the stages of this disorder.
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ADP-Ribosil Ciclasa 1/metabolismo , Fiebre Hemorrágica con Síndrome Renal/inmunología , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Linfocitos B , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Creatinina , Femenino , Citometría de Flujo , Fiebre Hemorrágica con Síndrome Renal/sangre , Fiebre Hemorrágica con Síndrome Renal/orina , Fiebres Hemorrágicas Virales/sangre , Fiebres Hemorrágicas Virales/inmunología , Humanos , Células Asesinas Naturales , Masculino , Persona de Mediana Edad , Ácido ÚricoRESUMEN
For more than 20 years, researchers have used laboratory mice lacking type I or both type I and type II interferon (IFN) responses to study viruses that cause hemorrhagic fever (HF) in humans. Whereas immunocompetent mice do not become ill when infected with Ebola, Lassa, dengue and other HF viruses, IFN-deficient mice typically develop severe or fatal disease when inoculated with these pathogens. The ease of employment of these "mouse models" has led to their extensive use in biocontainment laboratories to assess the efficacy of novel vaccines, often without consideration of whether adaptive immune responses in IFN-deficient mice accurately mirror those in humans. Failure to consider these questions may lead to inappropriate expectations of the predictive value of mouse experiments. In two invited articles, we investigate this question. This paper examines how the lack of type I or both type I and type II IFN signaling may affect the development of adaptive immune responses in mice and the outcome of vaccine studies. A second article reviews the published literature on the use of IFN-deficient mice for the assessment of novel vaccines against HF viruses.
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Inmunidad Adaptativa , Fiebres Hemorrágicas Virales/prevención & control , Interferón Tipo I/deficiencia , Interferón gamma/deficiencia , Vacunas Virales/inmunología , Animales , Modelos Animales de Enfermedad , Fiebres Hemorrágicas Virales/inmunología , Ratones , VacunaciónRESUMEN
For more than 20 years, researchers have used laboratory mice lacking type I or both type I and II interferon (IFN) responses to study high-containment viruses that cause hemorrhagic fevers (HF) in humans. With the exception of Rift Valley fever virus, agents that cause viral HF in humans, such as Ebola and Lassa virus, do not cause disease in mature immunocompetent mice. In contrast, IFN-deficient mice typically develop severe or fatal disease when inoculated with these agents. The sensitivity of IFN-deficient mice to disease has led to their widespread use in biocontainment laboratories to assess the efficacy of novel vaccines against HF viruses, often without considering whether adaptive immune responses in IFN-deficient mice accurately mirror those in immunocompetent humans. Failure to recognize these questions may lead to inappropriate expectations of the predictive value of mouse experiments. In two invited articles, we investigate these questions. The present article reviews the use of IFN-deficient mice for assessing novel vaccines against HF viruses, including Ebola, Lassa, Crimean-Congo hemorrhagic fever and Rift Valley fever viruses. A companion paper examines the general question of how the lack of IFN signaling may affect adaptive immune responses and the outcome of vaccine studies in mice.
Asunto(s)
Modelos Animales de Enfermedad , Fiebres Hemorrágicas Virales/inmunología , Fiebres Hemorrágicas Virales/prevención & control , Interferón Tipo I/deficiencia , Interferón gamma/deficiencia , Vacunas Virales/inmunología , Animales , Anticuerpos Antivirales/sangre , RatonesRESUMEN
Several clade B New World arenaviruses (NWAs) can cause severe and often fatal hemorrhagic fever, for which preventive and therapeutic measures are severely limited. These NWAs use human transferrin receptor 1 (hTfR1) as a host cell receptor for virus entry. The most prevalent of the pathogenic NWAs is Junín virus (JUNV), the etiological agent of Argentine hemorrhagic fever. Small animal models of JUNV infection are limited because most laboratory rodent species are refractory to disease. Only guinea pigs are known to develop disease following JUNV infection, but the underlying mechanisms are not well characterized. In the present study, we demonstrate marked susceptibility of Hartley guinea pigs to uniformly lethal disease when challenged with as few as 4 PFU of the Romero strain of JUNV. In vitro, we show that infection of primary guinea pig macrophages results in greater JUNV replication compared to infection of hamster or mouse macrophages. We provide evidence that the guinea pig TfR1 (gpTfR1) is the principal receptor for JUNV, while hamster and mouse orthologs fail to support viral entry/infection of pseudotyped murine leukemia viruses expressing pathogenic NWA glycoproteins or JUNV. Together, our results indicate that gpTfR1 serves as the primary receptor for pathogenic NWAs, enhancing viral infection in guinea pigs.IMPORTANCE JUNV is one of five known NWAs that cause viral hemorrhagic fever in humans. Countermeasures against JUNV infection are limited to immunization with the Candid#1 vaccine and immune plasma, which are available only in Argentina. The gold standard small animal model for JUNV infection is the guinea pig. Here, we demonstrate high sensitivity of this species to severe JUNV infection and identify gpTfR1 as the primary receptor. Use of hTfR1 for host cell entry is a feature shared by pathogenic NWAs. Our results show that expression of gpTfR1 or hTfR1 comparably enhances JUNV virus entry/infectivity. Our findings shed light on JUNV infection in guinea pigs as a model for human disease and suggest that similar pathophysiological mechanisms related to iron sequestration during infection and regulation of TfR1 expression may be shared between humans and guinea pigs. A better understanding of the underlying disease process will guide development of new therapeutic interventions.
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Virus Junin/inmunología , Virus Junin/patogenicidad , Receptores de Transferrina/metabolismo , Animales , Arenavirus/inmunología , Arenavirus/patogenicidad , Células CHO , Chlorocebus aethiops , Cricetulus , Modelos Animales de Enfermedad , Femenino , Glicoproteínas/metabolismo , Cobayas/inmunología , Cobayas/metabolismo , Células HEK293 , Fiebre Hemorrágica Americana/inmunología , Fiebre Hemorrágica Americana/virología , Fiebres Hemorrágicas Virales/inmunología , Fiebres Hemorrágicas Virales/virología , Humanos , Virus Junin/metabolismo , Macrófagos/virología , Masculino , Receptores de Transferrina/inmunología , Células Vero , Internalización del Virus , Replicación ViralRESUMEN
Hemorrhagic fevers (HF) resulting from pathogenic arenaviral infections have traditionally been neglected as tropical diseases primarily affecting African and South American regions. There are currently no FDA-approved vaccines for arenaviruses, and treatments have been limited to supportive therapy and use of non-specific nucleoside analogs, such as Ribavirin. Outbreaks of arenaviral infections have been limited to certain geographic areas that are endemic but known cases of exportation of arenaviruses from endemic regions and socioeconomic challenges for local control of rodent reservoirs raise serious concerns about the potential for larger outbreaks in the future. This review synthesizes current knowledge about arenaviral evolution, ecology, transmission patterns, life cycle, modulation of host immunity, disease pathogenesis, as well as discusses recent development of preventative and therapeutic pursuits against this group of deadly viral pathogens.
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Infecciones por Arenaviridae , Arenavirus/inmunología , Brotes de Enfermedades , Fiebres Hemorrágicas Virales , Tolerancia Inmunológica , Ribavirina/uso terapéutico , África/epidemiología , Infecciones por Arenaviridae/tratamiento farmacológico , Infecciones por Arenaviridae/epidemiología , Infecciones por Arenaviridae/inmunología , Fiebres Hemorrágicas Virales/tratamiento farmacológico , Fiebres Hemorrágicas Virales/epidemiología , Fiebres Hemorrágicas Virales/inmunología , Humanos , América del Sur/epidemiologíaRESUMEN
Simian hemorrhagic fever virus (SHFV) causes a fulminant and typically lethal viral hemorrhagic fever (VHF) in macaques (Cercopithecinae: Macaca spp.) but causes subclinical infections in patas monkeys (Cercopithecinae: Erythrocebus patas). This difference in disease course offers a unique opportunity to compare host responses to infection by a VHF-causing virus in biologically similar susceptible and refractory animals. Patas and rhesus monkeys were inoculated side-by-side with SHFV. Unlike the severe disease observed in rhesus monkeys, patas monkeys developed a limited clinical disease characterized by changes in complete blood counts, serum chemistries, and development of lymphadenopathy. Viral RNA was measurable in circulating blood 2 days after exposure, and its duration varied by species. Infectious virus was detected in terminal tissues of both patas and rhesus monkeys. Varying degrees of overlap in changes in serum concentrations of interferon (IFN)-γ, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-6 were observed between patas and rhesus monkeys, suggesting the presence of common and species-specific cytokine responses to infection. Similarly, quantitative immunohistochemistry of livers from terminal monkeys and whole blood flow cytometry revealed varying degrees of overlap in changes in macrophages, natural killer cells, and T-cells. The unexpected degree of overlap in host response suggests that relatively small subsets of a host's response to infection may be responsible for driving hemorrhagic fever pathogenesis. Furthermore, comparative SHFV infection in patas and rhesus monkeys offers an experimental model to characterize hostâ»response mechanisms associated with viral hemorrhagic fever and evaluate pan-viral hemorrhagic fever countermeasures.
Asunto(s)
Infecciones por Arterivirus/veterinaria , Arterivirus/patogenicidad , Fiebres Hemorrágicas Virales/veterinaria , Interacciones Huésped-Patógeno , Enfermedades de los Monos/inmunología , Animales , Anticuerpos Antivirales/sangre , Arterivirus/inmunología , Infecciones por Arterivirus/inmunología , Citocinas/sangre , Erythrocebus , Femenino , Fiebres Hemorrágicas Virales/inmunología , Macaca , Macrófagos/virología , Masculino , Enfermedades de los Monos/virología , ARN Viral , Replicación ViralRESUMEN
Several Old World and New World arenaviruses are responsible for severe endemic and epidemic hemorrhagic fevers, whereas other members of the Arenaviridae family are nonpathogenic. To date, no approved vaccines, antivirals, or specific treatments are available, except for Junín virus. However, protection of nonhuman primates against Lassa fever virus (LASV) is possible through the inoculation of the closely related but nonpathogenic Mopeia virus (MOPV) before challenge with LASV. We reasoned that this virus, modified by using reverse genetics, would represent the basis for the generation of a vaccine platform against LASV and other pathogenic arenaviruses. After showing evidence of exoribonuclease (ExoN) activity in NP of MOPV, we found that this activity was essential for multiplication in antigen-presenting cells. The introduction of multiple mutations in the ExoN site of MOPV NP generated a hyperattenuated strain (MOPVExoN6b) that is (i) genetically stable over passages, (ii) has increased immunogenic properties compared to those of MOPV, and (iii) still promotes a strong type I interferon (IFN) response. MOPVExoN6b was further modified to harbor the envelope glycoproteins of heterologous pathogenic arenaviruses, such as LASV or Lujo, Machupo, Guanarito, Chapare, or Sabia virus in order to broaden specific antigenicity while preserving the hyperattenuated characteristics of the parental strain. Our MOPV-based vaccine candidate for LASV, MOPEVACLASV, was used in a one-shot immunization assay in nonhuman primates and fully protected them from a lethal challenge with LASV. Thus, our hyperattenuated strain of MOPV constitutes a promising new live-attenuated vaccine platform to immunize against several, if not all, pathogenic arenaviruses.IMPORTANCE Arenaviruses are emerging pathogens transmitted to humans by rodents and responsible for endemic and epidemic hemorrhagic fevers of global concern. Nonspecific symptoms associated with the onset of infection make these viruses difficult to distinguish from other endemic pathogens. Moreover, the unavailability of rapid diagnosis in the field delays the identification of the virus and early care for treatment and favors spreading. The vaccination of exposed populations would be of great help to decrease morbidity and human-to-human transmission. Using reverse genetics, we generated a vaccine platform for pathogenic arenaviruses based on a modified and hyperattenuated strain of the nonpathogenic Mopeia virus and showed that the Lassa virus candidate fully protected nonhuman primates from a lethal challenge. These results showed that a rationally designed recombinant MOPV-based vaccine is safe, immunogenic, and efficacious in nonhuman primates.
Asunto(s)
Arenaviridae/inmunología , Fiebres Hemorrágicas Virales/inmunología , Fiebre de Lassa/inmunología , Virus Lassa/inmunología , Enfermedades de los Monos/inmunología , Enfermedades de los Monos/prevención & control , Vacunas Atenuadas/inmunología , Vacunas Virales/inmunología , Animales , Arenaviridae/genética , Línea Celular , Chlorocebus aethiops , Cricetinae , Exorribonucleasas/metabolismo , Células HEK293 , Fiebres Hemorrágicas Virales/patología , Fiebres Hemorrágicas Virales/transmisión , Fiebres Hemorrágicas Virales/virología , Humanos , Interferón Tipo I/inmunología , Fiebre de Lassa/prevención & control , Fiebre de Lassa/virología , Macaca fascicularis , Enfermedades de los Monos/virología , Vacunación , Células VeroRESUMEN
Arenaviruses such as Lassa virus (LASV) cause hemorrhagic fever. Terminal shock is associated with a systemic cytokine storm, but the mechanisms are ill defined. Here we used HLA-A2-expressing mice infected with a monkey-pathogenic strain of lymphocytic choriomeningitis virus (LCMV-WE), a close relative of LASV, to investigate the pathophysiology of arenavirus hemorrhagic fever (AHF). AHF manifested as pleural effusions, edematous skin swelling, and serum albumin loss, culminating in hypovolemic shock. A characteristic cytokine storm included numerous pro-inflammatory cytokines and nitric oxide (NO) metabolites. Edema formation and terminal shock were abrogated in mice lacking inducible nitric oxide synthase (iNOS), although the cytokine storm persisted. iNOS was upregulated in the liver in a T cell- and interferon-γ (IFN-γ)-dependent fashion. Accordingly, blockade of IFN-γ or depletion of T cells repressed hepatic iNOS and prevented disease despite unchecked high-level viremia. We identify the IFN-γ-iNOS axis as an essential and potentially druggable molecular pathway to AHF-induced shock.
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Fiebres Hemorrágicas Virales/inmunología , Interferón gamma/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Óxido Nítrico Sintasa de Tipo II/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Fiebres Hemorrágicas Virales/genética , Fiebres Hemorrágicas Virales/virología , Humanos , Interferón gamma/genética , Coriomeningitis Linfocítica/genética , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico/inmunología , Óxido Nítrico Sintasa de Tipo II/genéticaRESUMEN
Surveillance is a valuable tool for understanding prevailing and previously undiagnosed infections in a geographic area. We examined 480 archived serum samples from patients with history of persistent fever (>40°C, 60-72h) who were referred to hospitals in Rawalpindi/Islamabad, Lahore, and Faisalabad districts for dengue antibody detection in 2014-15. Each sample was processed for detection of antigens and seroconversion, using real-time polymerase chain reaction and enzyme linked immunosorbent assay, respectively, against dengue haemorrhagic fever (DHF) virus serotypes 1-4, West Nile virus fever (WNVF), Crimean-Congo haemorrhagic fever (CCHF), and Chikungunya virus (CGV). The presence of antigens and antibodies to at least one of the studied viral haemorrhagic fevers (VHFs) was detected in 465 (96.8%, 95% CI: 94.9-98.1) and 442 samples (92.1%, 95% CI: 89.3-94.2), respectively. No sera were found positive to CCHF. There was a significant association between gender and positivity to at least one of the VHFs (χ2=8.12, df=1, p<0.005). Except for DHF serotype 2 and 3 (ττ=0.41), Goodman and Kruskal's Tau statistic revealed no significant association for occurrence of different viruses within the studied population (ττ=0-0.06). Cosinor analysis confirmed significant seasonality, with a higher number of cases of persistent fever in August through November, peaking in October. The study suggests circulation of multiple arthropod-borne viral infections and, in addition to DHF, ascertain the needs for screening patients for CGV and WNVF too. It also demonstrates the necessity of well-integrated disease surveillance in several geographic regions and at-risk populations in Pakistan to develop appropriate disease and vector control strategies.
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Anticuerpos Antivirales/sangre , Antígenos Virales/sangre , Fiebres Hemorrágicas Virales/inmunología , Adulto , Ensayo de Inmunoadsorción Enzimática , Femenino , Fiebres Hemorrágicas Virales/genética , Humanos , Masculino , Persona de Mediana Edad , Pakistán/epidemiología , Vigilancia de la Población , Reacción en Cadena en Tiempo Real de la Polimerasa , Estaciones del Año , Factores Sexuales , Adulto JovenRESUMEN
The clinical syndrome referred to as viral hemorrhagic fever (VHF) can be caused by several different families of RNA viruses, including select members of the arenaviruses, bunyaviruses, filoviruses, and flaviviruses. VHF is characterized by malaise, fever, vascular permeability, decreased plasma volume, coagulation abnormalities, and varying degrees of hemorrhage. Study of the filovirus Ebola virus has demonstrated a critical role for suppression of innate antiviral defenses in viral pathogenesis. Additionally, antigen-presenting cells are targets of productive infection and immune dysregulation. Among these cell populations, monocytes and macrophages are proposed to produce damaging inflammatory cytokines, while infected dendritic cells fail to undergo proper maturation, potentially impairing adaptive immunity. Uncontrolled virus replication and accompanying inflammatory responses are thought to promote vascular leakage and coagulopathy. However, the specific molecular pathways that underlie these features of VHF remain poorly understood. The arenavirus Lassa virus and the flavivirus yellow fever virus exhibit similar molecular pathogenesis suggesting common underlying mechanisms. Because non-human primate models that closely mimic VHF are available for Ebola, Lassa, and yellow fever viruses, we propose that comparative molecular studies using these models will yield new insights into the molecular underpinnings of VHF and suggest new therapeutic approaches.
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Fiebres Hemorrágicas Virales/inmunología , Fiebres Hemorrágicas Virales/metabolismo , Fiebres Hemorrágicas Virales/virología , Inmunidad Adaptativa , Animales , Biomarcadores , Coagulación Sanguínea/inmunología , Permeabilidad Capilar/inmunología , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Innata , Mediadores de Inflamación/metabolismoRESUMEN
UNLABELLED: Simian hemorrhagic fever (SHF) is a highly lethal disease in captive macaques. Three distinct arteriviruses are known etiological agents of past SHF epizootics, but only one, simian hemorrhagic fever virus (SHFV), has been isolated in cell culture. The natural reservoir(s) of the three viruses have yet to be identified, but African nonhuman primates are suspected. Eleven additional divergent simian arteriviruses have been detected recently in diverse and apparently healthy African cercopithecid monkeys. Here, we report the successful isolation in MARC-145 cell culture of one of these viruses, Kibale red colobus virus 1 (KRCV-1), from serum of a naturally infected red colobus (Procolobus [Piliocolobus] rufomitratus tephrosceles) sampled in Kibale National Park, Uganda. Intramuscular (i.m.) injection of KRCV-1 into four cynomolgus macaques (Macaca fascicularis) resulted in a self-limiting nonlethal disease characterized by depressive behavioral changes, disturbance in coagulation parameters, and liver enzyme elevations. In contrast, i.m. injection of SHFV resulted in typical lethal SHF characterized by mild fever, lethargy, lymphoid depletion, lymphoid and hepatocellular necrosis, low platelet counts, increased liver enzyme concentrations, coagulation abnormalities, and increasing viral loads. As hypothesized based on the genetic and presumed antigenic distance between KRCV-1 and SHFV, all four macaques that had survived KRCV-1 injection died of SHF after subsequent SHFV injection, indicating a lack of protective heterotypic immunity. Our data indicate that SHF is a disease of macaques that in all likelihood can be caused by a number of distinct simian arteriviruses, although with different severity depending on the specific arterivirus involved. Consequently, we recommend that current screening procedures for SHFV in primate-holding facilities be modified to detect all known simian arteriviruses. IMPORTANCE: Outbreaks of simian hemorrhagic fever (SHF) have devastated captive Asian macaque colonies in the past. SHF is caused by at least three viruses of the family Arteriviridae: simian hemorrhagic fever virus (SHFV), simian hemorrhagic encephalitis virus (SHEV), and Pebjah virus (PBJV). Nine additional distant relatives of these three viruses were recently discovered in apparently healthy African nonhuman primates. We hypothesized that all simian arteriviruses are potential causes of SHF. To test this hypothesis, we inoculated cynomolgus macaques with a highly divergent simian arterivirus (Kibale red colobus virus 1 [KRCV-1]) from a wild Ugandan red colobus. Despite being only distantly related to red colobuses, all of the macaques developed disease. In contrast to SHFV-infected animals, KRCV-1-infected animals survived after a mild disease presentation. Our study advances the understanding of an important primate disease. Furthermore, our data indicate a need to include the full diversity of simian arteriviruses in nonhuman primate SHF screening assays.
Asunto(s)
Infecciones por Arterivirus/veterinaria , Arterivirus/aislamiento & purificación , Arterivirus/patogenicidad , Colobus/virología , Fiebres Hemorrágicas Virales/veterinaria , Macaca fascicularis/virología , Enfermedades de los Monos/virología , Animales , Arterivirus/genética , Arterivirus/crecimiento & desarrollo , Infecciones por Arterivirus/inmunología , Infecciones por Arterivirus/fisiopatología , Infecciones por Arterivirus/virología , Línea Celular , Fiebres Hemorrágicas Virales/inmunología , Fiebres Hemorrágicas Virales/fisiopatología , Fiebres Hemorrágicas Virales/virología , Hígado/química , Hígado/enzimología , Masculino , Enfermedades de los Monos/inmunología , Enfermedades de los Monos/fisiopatología , Uganda , Carga ViralRESUMEN
Mammalian arenaviruses are zoonotic viruses that cause asymptomatic, persistent infections in their rodent hosts but can lead to severe and lethal hemorrhagic fever with bleeding and multiorgan failure in human patients. Lassa virus (LASV), for example, is endemic in several West African countries, where it is responsible for an estimated 500,000 infections and 5,000 deaths annually. There are currently no FDA-licensed therapeutics or vaccines available to combat arenavirus infection. A hallmark of arenavirus infection (e.g., LASV) is general immunosuppression that contributes to high viremia. Here, we discuss the early host immune responses to arenavirus infection and the recently discovered molecular mechanisms that enable pathogenic viruses to suppress host immune recognition and to contribute to the high degree of virulence. We also directly compare the innate immune evasion mechanisms between arenaviruses and other hemorrhagic fever-causing viruses, such as Ebola, Marburg, Dengue, and hantaviruses. A better understanding of the immunosuppression and immune evasion strategies of these deadly viruses may guide the development of novel preventative and therapeutic options.
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Infecciones por Arenaviridae/inmunología , Arenavirus/inmunología , Arenavirus/patogenicidad , Inmunidad Innata , Animales , Fiebres Hemorrágicas Virales/inmunología , Fiebres Hemorrágicas Virales/virología , Humanos , Evasión Inmune , Interferones/antagonistas & inhibidores , Dedos de ZincRESUMEN
Dengue virus infection is one of the most prevalent mosquito-borne illnesses worldwide, affecting as many as 400 million persons annually. Most people experience a self-limited viral illness, but some experience life-threatening disease. Subsequent infection with other dengue virus serotypes increases the risk of development of severe dengue disease with plasma leakage with or without hemorrhage and end organ impairment. Antibody-dependent enhancement of dengue virus infection has been implicated in the development of severe dengue disease, previously referred to as dengue hemorrhagic fever and dengue shock syndrome. We propose a structural explanation for the role of non-neutralizing antibodies in the development of antibody-dependent enhancement of dengue virus infection via complement fixation or binding to Fcγ receptors facilitating entry into target cells.
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Anticuerpos Antivirales/inmunología , Virus del Dengue/inmunología , Dengue/inmunología , Fiebres Hemorrágicas Virales/inmunología , Anticuerpos Neutralizantes/inmunología , Acrecentamiento Dependiente de Anticuerpo , Proteínas del Sistema Complemento/inmunología , Dengue/complicaciones , Dengue/virología , Epítopos/química , Fiebres Hemorrágicas Virales/complicaciones , Fiebres Hemorrágicas Virales/virología , Humanos , Modelos Teóricos , Dominios Proteicos , Receptores de IgG/metabolismo , Serogrupo , Choque/complicaciones , Choque/inmunologíaAsunto(s)
Arenaviridae/inmunología , Filoviridae/inmunología , Flaviviridae/inmunología , Fiebres Hemorrágicas Virales/inmunología , Fiebres Hemorrágicas Virales/virología , Tolerancia Inmunológica , Inmunidad Innata , Orthobunyavirus/inmunología , Animales , Arenaviridae/metabolismo , Filoviridae/metabolismo , Flaviviridae/metabolismo , Fiebres Hemorrágicas Virales/metabolismo , Interacciones Huésped-Patógeno , Humanos , Orthobunyavirus/metabolismo , Transducción de SeñalRESUMEN
Arenaviruses such as Lassa virus (LASV) can cause severe hemorrhagic fever in humans. As a major impediment to vaccine development, delayed and weak neutralizing antibody (nAb) responses represent a unifying characteristic of both natural infection and all vaccine candidates tested to date. To investigate the mechanisms underlying arenavirus nAb evasion we engineered several arenavirus envelope-chimeric viruses and glycan-deficient variants thereof. We performed neutralization tests with sera from experimentally infected mice and from LASV-convalescent human patients. NAb response kinetics in mice correlated inversely with the N-linked glycan density in the arenavirus envelope protein's globular head. Additionally and most intriguingly, infection with fully glycosylated viruses elicited antibodies, which neutralized predominantly their glycan-deficient variants, both in mice and humans. Binding studies with monoclonal antibodies indicated that envelope glycans reduced nAb on-rate, occupancy and thereby counteracted virus neutralization. In infected mice, the envelope glycan shield promoted protracted viral infection by preventing its timely elimination by the ensuing antibody response. Thus, arenavirus envelope glycosylation impairs the protective efficacy rather than the induction of nAbs, and thereby prevents efficient antibody-mediated virus control. This immune evasion mechanism imposes limitations on antibody-based vaccination and convalescent serum therapy.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Arenavirus/inmunología , Fiebres Hemorrágicas Virales/inmunología , Polisacáridos/inmunología , Animales , Anticuerpos Anti-VIH/inmunología , VIH-1/inmunología , Humanos , Ratones Endogámicos C57BL , Datos de Secuencia MolecularRESUMEN
The status of the various recombinant DNA and RNA-derived candidate vaccines, as well as the Venezuelan equine encephalomyelitis virus (VEEV) replicon vaccine system against extremely hazardous viral hemorrhagic fevers, were reviewed. The VEEV-based replication-incompetent vectors offer attractive features in terms of safety, high expression levels of the heterologous viral antigen, tropism to dendritic cells, robust immune responses, protection efficacy, low potential for pre-existing anti-vector immunity and possibility of engineering multivalent vaccines were tested. These features of the VEEV replicon system hold much promise for the development of new generation vaccine candidates against viral hemorrhagic fevers.
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Anticuerpos Antivirales/biosíntesis , Antígenos Virales/inmunología , Virus de la Encefalitis Equina Venezolana/inmunología , Encefalomielitis Equina Venezolana/prevención & control , Fiebres Hemorrágicas Virales/prevención & control , Vacunas Virales/inmunología , Animales , Antígenos Virales/genética , Protección Cruzada , Células Dendríticas/inmunología , Células Dendríticas/virología , Virus de la Encefalitis Equina Venezolana/patogenicidad , Encefalomielitis Equina Venezolana/inmunología , Encefalomielitis Equina Venezolana/virología , Fiebres Hemorrágicas Virales/inmunología , Fiebres Hemorrágicas Virales/virología , Caballos , Humanos , Replicón , Vacunación , Vacunas Atenuadas , Vacunas Sintéticas , Vacunas Virales/administración & dosificación , Vacunas Virales/biosíntesisRESUMEN
Several enveloped RNA viruses of the arenavirus, bunyavirus, filovirus and flavivirus families are associated with a syndrome known as viral hemorrhagic fever (VHF). VHF is characterized by fever, vascular leakage, coagulation defects and multi organ system failure. VHF is currently viewed as a disease precipitated by viral suppression of innate immunity, which promotes systemic virus replication and excessive proinflammatory cytokine responses that trigger the manifestations of severe disease. However, the mechanisms by which immune dysregulation contributes to disease remain poorly understood. Infection of nonhuman primates closely recapitulates human VHF, notably Ebola and yellow fever, thereby providing excellent models to better define the immunological basis for this syndrome. Here we review the current state of our knowledge and suggest future directions that will better define the immunological mechanisms underlying VHF.
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Fiebres Hemorrágicas Virales/inmunología , Fiebres Hemorrágicas Virales/virología , Interacciones Huésped-Patógeno/inmunología , Animales , Ebolavirus/fisiología , Fiebre Hemorrágica Ebola/inmunología , Fiebre Hemorrágica Ebola/transmisión , Fiebre Hemorrágica Ebola/virología , Fiebres Hemorrágicas Virales/transmisión , Humanos , Evasión Inmune , Membrana Mucosa/inmunología , Membrana Mucosa/metabolismo , Membrana Mucosa/patología , Membrana Mucosa/virología , Fiebre Amarilla/inmunología , Fiebre Amarilla/transmisión , Fiebre Amarilla/virología , Virus de la Fiebre Amarilla/fisiologíaRESUMEN
UNLABELLED: To identify host factors associated with arenavirus virulence, we used a cynomolgus macaque model to evaluate the pathogenesis of Lujo virus (LUJV), a recently emerged arenavirus that caused an outbreak of severe viral hemorrhagic fever in southern Africa. In contrast to human cases, LUJV caused mild, nonlethal illness in macaques. We then compared this to contrasting clinical outcomes during arenavirus infection, specifically to samples obtained from macaques infected with three highly pathogenic lines of Lassa virus (LASV), the causative agent of Lassa fever (LF). We assessed gene expression in peripheral blood mononuclear cells (PBMC) and determined genes that significantly changed expression relative to that in uninfected animals over the course of infection. We detected a 72-h delay in the induction of host responses to infection during LUJV infection compared to that of the animals infected with LASV. This included genes associated with inflammatory and antiviral responses and was particularly apparent among groups of genes promoting cell death. We also observed early differential expression of a subset of genes specific to LUJV infection that accounts for the delayed inflammatory response. Cell type enrichment analysis suggested that host response induction delay and an LUJV-specific profile are due to a different proportion of natural killer cells responding in LUJV infection than that in the LASV-infected animals. Together, these data indicate that delayed proinflammatory and proapoptotic host responses to arenavirus infection could ameliorate disease severity. This conclusion provides insight into the cellular and molecular mechanisms of arenaviral hemorrhagic fever and suggests potential strategies for therapeutic development. IMPORTANCE: Old World arenaviruses are significant human pathogens that often are associated with high mortality. However, mechanisms underlying disease severity and virulence in arenavirus hemorrhagic fever are largely unknown, particularly regarding host responses that contribute to pathogenicity. This study describes a comparison between Lujo and Lassa virus infection in cynomolgus macaques. Lujo virus-infected macaques developed only mild illness, while Lassa virus-infected macaques developed severe illness consistent with Lassa fever. We determined that mild disease is associated with a delay in host expression of genes linked to virulence, such as those causing inflammation and cell death, and with distinct cell types that may mediate this delay. This is the first study to associate the timing and directionality of gene expression with arenaviral pathogenicity and disease outcome and evokes new potential approaches for developing effective therapeutics for treating these deadly emerging pathogens.
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Infecciones por Arenaviridae/patología , Infecciones por Arenaviridae/virología , Fiebres Hemorrágicas Virales/patología , Fiebres Hemorrágicas Virales/virología , Lujo virus/patogenicidad , Animales , Infecciones por Arenaviridae/inmunología , Muerte Celular , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Fiebres Hemorrágicas Virales/inmunología , Inflamación/patología , Células Asesinas Naturales/inmunología , Fiebre de Lassa/patología , Fiebre de Lassa/virología , Virus Lassa/patogenicidad , Leucocitos Mononucleares/inmunología , Macaca fascicularis , Factores de TiempoRESUMEN
BACKGROUND: Rift Valley fever (RVF) is endemic to the tropical regions of eastern and southern Africa. The seroprevalence of RVF was investigated among the human population in Borno State, Nigeria to determine the occurrence of the disease in the study area in comparison with that of Lassa fever and Crimean-Congo Hemorrhagic fever. METHODS: Recombinant nucleoprotein (rNP)-based IgG-ELISAs for the detection of serum antibodies against RVF virus (RVFV), Lassa fever virus (LASV), and Crimean-Congo hemorrhagic fever virus (CCHFV) were used to test human sera in Borno State, Nigeria. The presence of neutralizing antibody against the RVFV-glycoprotein-bearing vesicular stomatitis virus pseudotype (RVFVpv) was also determined in the human sera. RESULTS: Of the 297 serum samples tested, 42 (14.1%) were positive for the presence of RVFV-IgG and 22 (7.4%) and 7 (2.4%) of the serum samples were positive for antibodies against LASV and CCHFV, respectively. There was a positive correlation between the titers of neutralizing antibodies obtained using RVFVpv and those obtained using the conventional neutralization assay with the attenuated RVFV-MP12 strain. CONCLUSIONS: The seroprevalence of RVF was significantly higher than that of LASV and CCHF in Borno State, Nigeria. The RVFVpv-based neutralization assay developed in this study has the potential to replace the traditional assays based on live viruses for the diagnosis and seroepidemiological studies of RVF.