RESUMEN
Viral hemorrhagic fevers (HF) are a group of acute febrile diseases with high mortality rates. Although hemostatic dysfunction appears to be a major determinant of the severity of the disease, it is still unclear what pathogenic mechanisms lead to it. In clinical studies it is found that arenaviruses, such as Lassa, Machupo, and Guanarito viruses cause HF that vary in symptoms and biological alterations. In this study we aimed to characterize the hemostatic dysfunction induced by arenaviral HF to determine its implication in the severity of the disease and to elucidate the origin of this syndrome. We found that lethal infection with Machupo, Guanarito, and Lassa viruses is associated with cutaneomucosal, cerebral, digestive, and pulmonary hemorrhages. The affected animals developed a severe alteration of the coagulation system, which was concomitant with acute hepatitis, minor deficit of hepatic factor synthesis, presence of a plasmatic inhibitor of coagulation, and dysfunction of the fibrinolytic system. Despite signs of increased vascular permeability, endothelial cell infection was not a determinant factor of the hemorrhagic syndrome. There were also alterations of the primary hemostasis during lethal infection, with moderate to severe thrombocytopenia and platelet dysfunction. Finally, we show that lethal infection is accompanied by a reduced hematopoietic potential of the bone marrow. This study provides an unprecedented characterization of the hemostasis defects induced by several highly pathogenic arenaviruses.
Asunto(s)
Arenaviridae , Arenavirus , Fiebres Hemorrágicas Virales , Hemostáticos , Animales , Fiebres Hemorrágicas Virales/patología , Hemorragia/etiología , Hemostasis , MacacaRESUMEN
Monocytes are important target cells of various hemorrhagic fever viruses. In viral hemorrhagic fevers (VHFs), monocytes can be infected by viruses and produce different kinds of cytokines, which contribute to the antiviral immune response and participation in the immunopathogenesis of VHFs. During the pathogenesis of various VHFs (early stage), monocytes change in cell counting, subpopulation distribution and expression of surface molecules with an activated phenotype. Several hemorrhagic fever viruses can infect monocytes and induce immune response, which may play an important role in immunopathological injury. Monocytes and the cytokines they produce may interact with platelets and vascular endothelial cells, contributing to disease progression.
Asunto(s)
Fiebres Hemorrágicas Virales , Monocitos , Humanos , Células Endoteliales , Fiebres Hemorrágicas Virales/patología , Inmunidad , CitocinasRESUMEN
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
Viral haemorrhagic fever can be caused by one of a diverse group of viruses that come from four different families of RNA viruses. Disease severity can vary from mild self-limiting febrile illness to severe disease characterized by high fever, high-level viraemia, increased vascular permeability that can progress to shock, multi-organ failure and death. Despite the urgent need, effective treatments and preventative vaccines are currently lacking for the majority of these viruses. A number of factors preclude the effective study of these diseases in humans including the high virulence of the agents involved, the sporadic nature of outbreaks of these viruses, which are typically in geographically isolated areas with underserviced diagnostic capabilities, and the requirements for high level bio-containment. As a result, animal models that accurately mimic human disease are essential for advancing our understanding of the pathogenesis of viral haemorrhagic fevers. Moreover, animal models for viral haemorrhagic fevers are necessary to test vaccines and therapeutic intervention strategies. Here, we present an overview of the animal models that have been established for each of the haemorrhagic fever viruses and identify which aspects of human disease are modelled. Furthermore, we discuss how experimental design considerations, such as choice of species and virus strain as well as route and dose of inoculation, have an influence on animal model development. We also bring attention to some of the pitfalls that need to be avoided when extrapolating results from animal models.
Asunto(s)
Modelos Animales de Enfermedad , Fiebres Hemorrágicas Virales/patología , Fiebres Hemorrágicas Virales/virología , Animales , Arenaviridae/clasificación , Arenaviridae/patogenicidad , Bunyaviridae/clasificación , Bunyaviridae/patogenicidad , Filoviridae/clasificación , Filoviridae/patogenicidad , Flaviviridae/clasificación , Flaviviridae/patogenicidad , Fiebres Hemorrágicas Virales/fisiopatología , HumanosRESUMEN
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
Lymphocytic choriomeningitis virus strain WE (LCMV-WE), a Risk Group 3 virus, causes a disease in rhesus monkeys that closely resembles human infection with Lassa fever virus, a Risk Group 4 agent. Three stages of disease progression have been defined and profiled in this model: pre-viremic, viremic, and terminal. The earliest or pre-viremic stage reveals changes in the blood profile predictive of the later stages of disease. In order to identify whether specific changes are pathognomonic, it was necessary to perform a parallel infection with an attenuated virus (LCMV-Armstrong). Here we review the use of nonhuman primates to model viral hemorrhagic fever and offer a step-by-step guide to using a rhesus macaque model for Lassa fever.
Asunto(s)
Fiebres Hemorrágicas Virales/patología , Fiebres Hemorrágicas Virales/virología , Animales , Modelos Animales de Enfermedad , Humanos , Fiebre de Lassa/patología , Fiebre de Lassa/veterinaria , Macaca mulattaRESUMEN
Viral hemorrhagic fevers (VHFs) refer to a group of illnesses caused by several distinct families of viruses. In general, the term "viral hemorrhagic fever" is used to describe a severe multisystem syndrome (multisystem in that multiple organ systems in the bpdy are affected). Characteristically, the overall vascular system is damaged, and the body's ability to regulate itself is impaired. These symptoms are often accompanied by hemorrhage (bleeding); however, the bleeding is it rarely life-threatening. While some types of hemorrhagic fever viruses can cause relatively mild illnesses, many of these viruses cause severe, life-threatening disease. The selected disaster diseases for this study included: 1-Crimean-Congo hemorrhagic Fever, 2-Dengue Fever, 3-Ebola Fever, 4-Hem-orrhagic Fever with renal syndrome (HFRS), 5-Hantavirus Pulmonary Syndrome, 6-Lassa Fever, 7-Marburg Fever, 8-Rift Valley Fever and 9-Yellow Fever. The educational training program was given over ten sessions to a group of Staff Nurses. The results showed that the program succeeded in enhancing nurse' knowledge, awareness, responsibility, and obligations toward patients with the Viral Hemorrhagic Fevers The results showed a significant impact of training sessions illuminated in the follow-up test on the knowledge score of nurses in all types of diseases except for the Congo hemorrhagic fever, while, statistical significance varied in some diseases in the study when it comes to the comparison between pretest and post-test. All results confirmed on the positive impact of the training program in enhancing the knowledge of nurses toward VHFs patients and their relevant. There was a significant positive impact of the training sessions on changing the attitude of nurses toward patients with VHFs. This result was confirmed on the collective level since the total scores on tests revealed significant positive impact of the study on changing the attitude of nurses toward relevant patients. The relationship included personal data (age, sex, level of education, & years of experiences) and main variables (knowledge scores & attitude change to patients) with the disease in question. This part revealed a significant relationship between all personal data and total knowledge score among nurses except for the level of education, while all results were insignificant for the relationship between the personal data and the nurses' attitude. Difference between the total nurses' attitude change and the total knowledge scores was significant on the three tests' levels; pre, post, and the follow-up. The overall evaluation showed that six criteria were adopted, regarding the educator, the length of presentations, the evaluation of the studied groups regarding the training facilities, the subject matters, the overall training program, and the importance of diseases in question to their practical working environment. The frequency distribution showed that the educator met nurses' expectations; the material tools were plausible enough to satisfy trainees and presentations were fairly short. But, the training facilities were just excellent by the vast majority of trainees. The entire material met specific needs of relevant health care organizations, but about 43% reported that it was difficult. The vast majority of trainees favored the program under almost all criteria studied in the final questionnaire. Above 50% of trainees were not confident enough toward their ability in applying their knowledge acquired practically. The final evaluation showed that the most important were Rift Valley fever, Ebola fever, Hanta virus pulmonary syndrome, Crimean Congo fever and lastly Dengue fever. Lassa and Marburg fevers were of less interest to nurses.
Asunto(s)
Educación en Enfermería/organización & administración , Fiebres Hemorrágicas Virales/enfermería , Hospitales Militares/organización & administración , Enfermeras y Enfermeros/normas , Adulto , Educación en Enfermería/métodos , Femenino , Fiebres Hemorrágicas Virales/diagnóstico , Fiebres Hemorrágicas Virales/patología , Humanos , Masculino , Personal Militar , Adulto JovenRESUMEN
Human pathogenic hantaviruses and arenaviruses are maintained in nature by persistent infection of rodent carrier populations. Several members of these virus groups can cause significant disease in humans that is generically termed viral hemorrhagic fever (HF) and is characterized as a febrile illness with an increased propensity to cause acute inflammation. Human interaction with rodent carrier populations leads to infection. Arenaviruses are also viewed as potential biological weapons threat agents. There is an increased interest in studying these viruses in animal models to gain a deeper understating not only of viral pathogenesis, but also for the evaluation of medical countermeasures (MCM) to mitigate disease threats. In this review, we examine current knowledge regarding animal models employed in the study of these viruses. We include analysis of infection models in natural reservoirs and also discuss the impact of strain heterogeneity on the susceptibility of animals to infection. This information should provide a comprehensive reference for those interested in the study of arenaviruses and hantaviruses not only for MCM development but also in the study of viral pathogenesis and the biology of these viruses in their natural reservoirs.
Asunto(s)
Arenavirus/patogenicidad , Infecciones por Hantavirus/virología , Fiebres Hemorrágicas Virales/virología , Orthohantavirus/patogenicidad , Animales , Reservorios de Enfermedades , Infecciones por Hantavirus/epidemiología , Infecciones por Hantavirus/patología , Fiebres Hemorrágicas Virales/epidemiología , Fiebres Hemorrágicas Virales/patología , Humanos , Modelos Animales , Roedores/virologíaRESUMEN
Lassa fever (LF) is a severe viral hemorrhagic fever caused by Lassa virus (LASV). The LF program at the Kenema Government Hospital (KGH) in Eastern Sierra Leone currently provides diagnostic services and clinical care for more than 500 suspected LF cases per year. Nearly two-thirds of suspected LF patients presenting to the LF Ward test negative for either LASV antigen or anti-LASV immunoglobulin M (IgM), and therefore are considered to have a non-Lassa febrile illness (NLFI). The NLFI patients in this study were generally severely ill, which accounts for their high case fatality rate of 36%. The current studies were aimed at determining possible causes of severe febrile illnesses in non-LF cases presenting to the KGH, including possible involvement of filoviruses. A seroprevalence survey employing commercial enzyme-linked immunosorbent assay tests revealed significant IgM and IgG reactivity against dengue virus, chikungunya virus, West Nile virus (WNV), Leptospira, and typhus. A polymerase chain reaction-based survey using sera from subjects with acute LF, evidence of prior LASV exposure, or NLFI revealed widespread infection with Plasmodium falciparum malaria in febrile patients. WNV RNA was detected in a subset of patients, and a 419 nt amplicon specific to filoviral L segment RNA was detected at low levels in a single patient. However, 22% of the patients presenting at the KGH between 2011 and 2014 who were included in this survey registered anti-Ebola virus (EBOV) IgG or IgM, suggesting prior exposure to this agent. The 2014 Ebola virus disease (EVD) outbreak is already the deadliest and most widely dispersed outbreak of its kind on record. Serological evidence reported here for possible human exposure to filoviruses in Sierra Leone prior to the current EVD outbreak supports genetic analysis that EBOV may have been present in West Africa for some time prior to the 2014 outbreak.
Asunto(s)
Brotes de Enfermedades , Fiebres Hemorrágicas Virales/epidemiología , Fiebres Hemorrágicas Virales/etiología , Anticuerpos Antibacterianos/sangre , Anticuerpos Antivirales/sangre , ADN Protozoario/sangre , Ensayo de Inmunoadsorción Enzimática , Fiebres Hemorrágicas Virales/patología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Reacción en Cadena de la Polimerasa , ARN Viral/sangre , Estudios Retrospectivos , Estudios Seroepidemiológicos , Sierra Leona/epidemiologíaRESUMEN
Simian hemorrhagic fever virus is an arterivirus that naturally infects species of African nonhuman primates causing acute or persistent asymptomatic infections. Although it was previously estimated that 1% of baboons are SHFV-positive, more than 10% of wild-caught and captive-bred baboons tested were SHFV positive and the infections persisted for more than 10 years with detectable virus in the blood (100-1000 genomes/ml). The sequences of two baboon SHFV isolates that were amplified by a single passage in primary macaque macrophages had a high degree of identity to each other as well as to the genome of SHFV-LVR, a laboratory strain isolated in the 1960s. Infection of Japanese macaques with 100PFU of a baboon isolate consistently produced high level viremia, pro-inflammatory cytokines, elevated tissue factor levels and clinical signs indicating coagulation defects. The baboon virus isolate provides a reliable BSL2 model of viral hemorrhagic fever disease in macaques.
Asunto(s)
Infecciones por Arterivirus/veterinaria , Arterivirus/aislamiento & purificación , Arterivirus/patogenicidad , Fiebres Hemorrágicas Virales/veterinaria , Enfermedades de los Monos/virología , Papio/virología , Animales , Arterivirus/genética , Infecciones por Arterivirus/patología , Infecciones por Arterivirus/virología , Citocinas/sangre , Genoma Viral , Fiebres Hemorrágicas Virales/patología , Fiebres Hemorrágicas Virales/virología , Interacciones Huésped-Patógeno , Macaca , Enfermedades de los Monos/inmunología , Enfermedades de los Monos/patología , Especificidad de Órganos , Viremia/veterinaria , Viremia/virologíaRESUMEN
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.
Asunto(s)
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
The term "viral hemorrhagic fever" (VHF) designates a syndrome of acute febrile illness, increased vascular permeability and coagulation defects which often progresses to bleeding and shock and may be fatal in a significant percentage of cases. The causative agents are some 20 different RNA viruses in the families Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae, which are maintained in a variety of animal species and are transferred to humans through direct or indirect contact or by an arthropod vector. Except for dengue, which is transmitted among humans by mosquitoes, the geographic distribution of each type of VHF is determined by the range of its animal reservoir. Treatments are available for Argentine HF and Lassa fever, but no approved countermeasures have been developed against other types of VHF. The development of effective interventions is hindered by the sporadic nature of most infections and their occurrence in geographic regions with limited medical resources. Laboratory animal models that faithfully reproduce human disease are therefore essential for the evaluation of potential vaccines and therapeutics. The goal of this review is to highlight the current status of animal models that can be used to study the pathogenesis of VHF and test new countermeasures.
Asunto(s)
Modelos Animales de Enfermedad , Fiebres Hemorrágicas Virales/patología , Fiebres Hemorrágicas Virales/virología , Animales , Antivirales/aislamiento & purificación , Antivirales/uso terapéutico , Arenaviridae/fisiología , Bunyaviridae/fisiología , Filoviridae/fisiología , Flaviviridae/fisiología , Fiebres Hemorrágicas Virales/tratamiento farmacológico , Fiebres Hemorrágicas Virales/prevención & control , Humanos , Vacunas Virales/inmunología , Vacunas Virales/aislamiento & purificaciónRESUMEN
BACKGROUND: In 2008 a nosocomial outbreak of five cases of viral hemorrhagic fever due to a novel arenavirus, Lujo virus, occurred in Johannesburg, South Africa. Lujo virus is only the second pathogenic arenavirus, after Lassa virus, to be recognized in Africa and the first in over 40 years. Because of the remote, resource-poor, and often politically unstable regions where Lassa fever and other viral hemorrhagic fevers typically occur, there have been few opportunities to undertake in-depth study of their clinical manifestations, transmission dynamics, pathogenesis, or response to treatment options typically available in industrialized countries. METHODS AND FINDINGS: We describe the clinical features of five cases of Lujo hemorrhagic fever and summarize their clinical management, as well as providing additional epidemiologic detail regarding the 2008 outbreak. Illness typically began with the abrupt onset of fever, malaise, headache, and myalgias followed successively by sore throat, chest pain, gastrointestinal symptoms, rash, minor hemorrhage, subconjunctival injection, and neck and facial swelling over the first week of illness. No major hemorrhage was noted. Neurological signs were sometimes seen in the late stages. Shock and multi-organ system failure, often with evidence of disseminated intravascular coagulopathy, ensued in the second week, with death in four of the five cases. Distinctive treatment components of the one surviving patient included rapid commencement of the antiviral drug ribavirin and administration of HMG-CoA reductase inhibitors (statins), N-acetylcysteine, and recombinant factor VIIa. CONCLUSIONS: Lujo virus causes a clinical syndrome remarkably similar to Lassa fever. Considering the high case-fatality and significant logistical impediments to controlled treatment efficacy trials for viral hemorrhagic fever, it is both logical and ethical to explore the use of the various compounds used in the treatment of the surviving case reported here in future outbreaks. Clinical observations should be systematically recorded to facilitate objective evaluation of treatment efficacy. Due to the risk of secondary transmission, viral hemorrhagic fever precautions should be implemented for all cases of Lujo virus infection, with specialized precautions to protect against aerosols when performing enhanced-risk procedures such as endotracheal intubation.
Asunto(s)
Antivirales/uso terapéutico , Infecciones por Arenaviridae/patología , Infección Hospitalaria/patología , Brotes de Enfermedades , Fiebres Hemorrágicas Virales/patología , Lujo virus/aislamiento & purificación , Acetilcisteína/uso terapéutico , Adulto , Infecciones por Arenaviridae/tratamiento farmacológico , Infecciones por Arenaviridae/epidemiología , Infecciones por Arenaviridae/virología , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/epidemiología , Infección Hospitalaria/virología , Factor VIIa/uso terapéutico , Resultado Fatal , Femenino , Fiebres Hemorrágicas Virales/tratamiento farmacológico , Fiebres Hemorrágicas Virales/epidemiología , Fiebres Hemorrágicas Virales/virología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Fiebre de Lassa/patología , Virus Lassa/aislamiento & purificación , Lujo virus/efectos de los fármacos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/uso terapéutico , Ribavirina/uso terapéutico , Sudáfrica/epidemiologíaRESUMEN
Viral hemorrhagic diseases are a group of systemic viral infections with worldwide distribution and are significant causes of global mortality and morbidity. The hallmarks of viral hemorrhagic fevers are plasma leakage, thrombocytopenia, coagulopathy and hemorrhagic manifestations. The molecular mechanisms leading to plasma leakage in viral hemorrhagic fevers are not well understood. A common theme has emerged in which a complex interplay between pathogens, host immune response, and endothelial cells leads to the activation of endothelial cells and perturbation of barrier integrity. In this article, two clinically distinct viral hemorrhagic fevers caused by dengue viruses and hantaviruses are discussed to highlight their similarities and differences that may provide insights into the pathogenesis and therapeutic approach.
Asunto(s)
Virus del Dengue/aislamiento & purificación , Células Endoteliales/patología , Endotelio Vascular/patología , Fiebres Hemorrágicas Virales/patología , Fiebres Hemorrágicas Virales/virología , Orthohantavirus/aislamiento & purificación , Animales , HumanosRESUMEN
Severe fever with thrombocytopenia syndrome (SFTS) was firstly discovered in China in 2010, followed by several reports from many other countries worldwide. SFTS virus (SFTSV) has been identified as the causative agent of the disease and has been recognized as a public health threat. This novel Bunyavirus belongs to the Phlebovirus genus in the family Bunyaviridae. This review also describes the different aspects of virology, pathogenesis, epidemiology, and clinical symptoms on the basis of the published article surveillance data and phylogenetic analyses of viral sequences of large, medium, and small segments retrieved from database using mega 5.05, simplot 3.5.1, network 4.611, and epi information system 3.5.3 software. SFTS presents with fever, thrombocytopenia, leukocytopenia, and considerable changes in several serum biomarkers. The disease has 10~15% mortality rate, commonly because of multiorgan dysfunction. SFTSV is mainly reported in the rural areas of Central and North-Eastern China, with seasonal occurrence from May to September, mainly targeting those of ≥50 years of age. A wide range of domesticated animals, including sheep, goats, cattle, pigs, dogs, and chickens have been proven seropositive for SFTSV. Ticks, especially Haemaphysalis longicornis, are suspected to be the potential vector, which have a broad animal host range in the world. More studies are needed to elucidate the vector-animal-human ecological cycle, the pathogenic mechanisms in high level animal models and vaccine development.
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Fiebres Hemorrágicas Virales/epidemiología , Fiebres Hemorrágicas Virales/virología , Orthobunyavirus/aislamiento & purificación , Trombocitopenia/etiología , Factores de Edad , Animales , China/epidemiología , Reservorios de Enfermedades , Vectores de Enfermedades , Fiebres Hemorrágicas Virales/patología , Humanos , Orthobunyavirus/clasificación , Orthobunyavirus/genética , Filogenia , Estaciones del Año , Análisis de Supervivencia , Topografía MédicaRESUMEN
Arenaviruses can cause fatal human haemorrhagic fever (HF) diseases for which vaccines and therapies are extremely limited. Both the New World (NW) and Old World (OW) groups of arenaviruses contain HF-causing pathogens. Although these two groups share many similarities, important differences with regard to pathogenicity and molecular mechanisms of virus infection exist. These closely related pathogens share many characteristics, including genome structure, viral assembly, natural host selection and the ability to interfere with innate immune signalling. However, members of the NW and OW viruses appear to use different receptors for cellular entry, as well as different mechanisms of virus internalization. General differences in disease signs and symptoms and pathological lesions in patients infected with either NW or OW arenaviruses are also noted and discussed herein. Whilst both the OW Lassa virus (LASV) and the NW Junin virus (JUNV) can cause disruption of the vascular endothelium, which is an important pathological feature of HF, the immune responses to these related pathogens seem to be quite distinct. Whereas LASV infection results in an overall generalized immune suppression, patients infected with JUNV seem to develop a cytokine storm. Additionally, the type of immune response required for recovery and clearance of the virus is different between NW and OW infections. These differences may be important to allow the viruses to evade host immune detection. Understanding these differences will aid the development of new vaccines and treatment strategies against deadly HF viral infections.
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Infecciones por Arenaviridae/patología , Infecciones por Arenaviridae/virología , Arenavirus del Nuevo Mundo/genética , Arenavirus del Viejo Mundo/genética , Fiebres Hemorrágicas Virales/patología , Fiebres Hemorrágicas Virales/virología , Animales , Infecciones por Arenaviridae/inmunología , Arenavirus del Nuevo Mundo/clasificación , Arenavirus del Nuevo Mundo/inmunología , Arenavirus del Nuevo Mundo/patogenicidad , Arenavirus del Viejo Mundo/clasificación , Arenavirus del Viejo Mundo/inmunología , Arenavirus del Viejo Mundo/patogenicidad , Fiebres Hemorrágicas Virales/inmunología , HumanosRESUMEN
Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly discovered Phlebovirus causing an emerging hemorrhagic fever in East Asia, with reported case fatality rates up to 30%. Despite the high case fatality rate and large number of persons at risk of infection, the pathobiology of the disease is unknown, and no effective animal model has been available for investigating its pathogenesis. We have studied mice and hamsters as potential small-animal models of SFTSV infection following subcutaneous, intraperitoneal, or intracerebral inoculation. Animal tissues were processed for viral load determination, histopathology, immunohistochemistry, and confocal microscopic studies. We found that immunocompetent adult mice and hamsters did not become ill after SFTSV infection. However, alpha/beta interferon receptor knockout (IFNAR(-/-)) mice were highly susceptible to SFTSV infection, and all mice died within 3 to 4 days after subcutaneous inoculation of 10(6) focus-forming units of SFTSV. Histologic examination of tissues of IFNAR(-/-) mice infected with SFTSV showed no detectable lesions. In contrast, by immunohistochemistry virus antigen was found in liver, intestine, kidney, spleen, lymphoid tissue, and brain, but not in the lungs. Mesenteric lymph nodes and spleen were the most heavily infected tissues. Quantitative reverse transcription-PCR (RT-PCR) confirmed the presence of virus in these tissues. Confocal microscopy showed that SFTSV colocalized with reticular cells but did not colocalize with dendritic cells, monocytes/macrophages, neutrophils, or endothelium. Our results indicate that SFTSV multiplied in all organs except for lungs and that mesenteric lymph nodes and spleen were the most heavily infected tissues. The major target cells of SFTSV appear to be reticular cells in lymphoid tissues of intestine and spleen.
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Infecciones por Bunyaviridae/virología , Modelos Animales de Enfermedad , Fiebres Hemorrágicas Virales/virología , Ratones , Phlebovirus/patogenicidad , Receptor de Interferón alfa y beta/deficiencia , Animales , Infecciones por Bunyaviridae/mortalidad , Infecciones por Bunyaviridae/patología , Cricetinae , Femenino , Fiebres Hemorrágicas Virales/mortalidad , Fiebres Hemorrágicas Virales/patología , Humanos , Mesocricetus , Ratones Noqueados , Phlebovirus/genética , Phlebovirus/fisiología , Receptor de Interferón alfa y beta/genética , VirulenciaAsunto(s)
Fiebres Hemorrágicas Virales/epidemiología , Fiebres Hemorrágicas Virales/virología , Infecciones por Rhabdoviridae/epidemiología , Infecciones por Rhabdoviridae/virología , Rhabdoviridae/clasificación , Rhabdoviridae/patogenicidad , República Democrática del Congo/epidemiología , Fiebres Hemorrágicas Virales/patología , Humanos , Rhabdoviridae/aislamiento & purificación , Infecciones por Rhabdoviridae/patología , VirulenciaRESUMEN
Four families of enveloped RNA viruses, filoviruses, flaviviruses, arenaviruses, and bunyaviruses, cause hemorrhagic fevers. These viruses are maintained in specific natural cycles involving nonhuman primates, bats, rodents, domestic ruminants, humans, mosquitoes, and ticks. Vascular instability varies from mild to fatal shock, and hemorrhage ranges from none to life threatening. The pathogenic mechanisms are extremely diverse and include deficiency of hepatic synthesis of coagulation factors owing to hepatocellular necrosis, cytokine storm, increased permeability by vascular endothelial growth factor, complement activation, and disseminated intravascular coagulation in one or more hemorrhagic fevers. The severity of disease caused by these agents varies tremendously; there are extremely high fatality rates in Ebola and Marburg hemorrhagic fevers, and asymptomatic infection predominates in yellow fever and dengue viral infections. Although ineffective immunity and high viral loads are characteristic of several viral hemorrhagic fevers, severe plasma leakage occurs at the time of viral clearance and defervescence in dengue hemorrhagic fever.
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Fiebres Hemorrágicas Virales/virología , Virus ARN/fisiología , Animales , Fiebres Hemorrágicas Virales/patología , HumanosRESUMEN
Lujo virus (LUJV) is a novel member of the Arenaviridae family that was first identified in 2008 after an outbreak of severe hemorrhagic fever (HF). In what was a small but rapidly progressing outbreak, this previously unknown virus was transmitted from the critically ill index patient to 4 attending healthcare workers. Four persons died during this outbreak, for a total case fatality of 80% (4/5). The suspected rodent source of the initial exposure to LUJV remains a mystery. Because of the ease of transmission, high case fatality, and novel nature of LUJV, we sought to establish an animal model of LUJV HF. Initial attempts in mice failed, but infection of inbred strain 13/N guinea pigs resulted in lethal disease. A total of 41 adult strain 13/N guinea pigs were infected with either wild-type LUJV or a full-length recombinant LUJV. Results demonstrated that strain 13/N guinea pigs provide an excellent model of severe and lethal LUJV HF that closely resembles what is known of the human disease. All infected animals experienced consistent weight loss (3-5% per day) and clinical illness characterized by ocular discharge, ruffled fur, hunched posture, and lethargy. Uniform lethality occurred by 11-16 days post-infection. All animals developed disseminated LUJV infection in various organs (liver, spleen, lung, and kidney), and leukopenia, lymphopenia, thrombocytopenia, coagulopathy, and elevated transaminase levels. Serial euthanasia studies revealed a temporal pattern of virus dissemination and increasing severity of disease, primarily targeting the liver, spleen, lungs, and lower gastrointestinal tract. Establishing an animal LUJV model is an important first step towards understanding the high pathogenicity of LUJV and developing vaccines and antiviral therapeutic drugs for this highly transmissible and lethal emerging pathogen.