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1.
Curr Top Microbiol Immunol ; 439: 265-303, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36592249

RESUMO

Members of the family Arenaviridae are classified into four genera: Antennavirus, Hartmanivirus, Mammarenavirus, and Reptarenavirus. Reptarenaviruses and hartmaniviruses infect (captive) snakes and have been shown to cause boid inclusion body disease (BIBD). Antennaviruses have genomes consisting of 3, rather than 2, segments, and were discovered in actinopterygian fish by next-generation sequencing but no biological isolate has been reported yet. The hosts of mammarenaviruses are mainly rodents and infections are generally asymptomatic. Current knowledge about the biology of reptarenaviruses, hartmaniviruses, and antennaviruses is very limited and their zoonotic potential is unknown. In contrast, some mammarenaviruses are associated with zoonotic events that pose a threat to human health. This review will focus on mammarenavirus genetic diversity and its biological implications. Some mammarenaviruses including lymphocytic choriomeningitis virus (LCMV) are excellent experimental model systems for the investigation of acute and persistent viral infections, whereas others including Lassa (LASV) and Junin (JUNV) viruses, the causative agents of Lassa fever (LF) and Argentine hemorrhagic fever (AHF), respectively, are important human pathogens. Mammarenaviruses were thought to have high degree of intra-and inter-species amino acid sequence identities, but recent evidence has revealed a high degree of mammarenavirus genetic diversity in the field. Moreover, closely related mammarenavirus can display dramatic phenotypic differences in vivo. These findings support a role of genetic variability in mammarenavirus adaptability and pathogenesis. Here, we will review the molecular biology of mammarenaviruses, phylogeny, and evolution, as well as the quasispecies dynamics of mammarenavirus populations and their biological implications.


Assuntos
Arenaviridae , Animais , Humanos , Arenaviridae/genética , Arenaviridae/metabolismo , Roedores , Variação Genética
2.
Viruses ; 14(12)2022 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-36560653

RESUMO

Lassa virus (LASV) is a highly pathogenic virus that is categorized as a biosafety level-4 pathogen. Currently, there are no approved drugs or vaccines specific to LASV. In this study, high-throughput screening of a fragment-based drug discovery library was performed against LASV entry using a pseudotype virus bearing the LASV envelope glycoprotein complex (GPC). Two compounds, F1920 and F1965, were identified as LASV entry inhibitors that block GPC-mediated membrane fusion. Analysis of adaptive mutants demonstrated that the transient mutants L442F and I445S, as well as the constant mutant F446L, were located on the same side on the transmembrane domain of the subunit GP2 of GPC, and all the mutants conferred resistance to both F1920 and F1965. Furthermore, F1920 antiviral activity extended to other highly pathogenic mammarenaviruses, whereas F1965 was LASV-specific. Our study showed that both F1920 and F1965 provide a potential backbone for the development of lead drugs for preventing LASV infection.


Assuntos
Arenaviridae , Inibidores da Fusão de HIV , Febre Lassa , Humanos , Vírus Lassa , Antivirais/farmacologia , Antivirais/uso terapêutico , Descoberta de Drogas , Inibidores da Fusão de HIV/uso terapêutico
3.
Front Immunol ; 13: 1010635, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36248895

RESUMO

Viral hemorrhagic fever (VHF) is a term referring to a group of life-threatening infections caused by several virus families (Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae). Depending on the virus, the infection can be mild and can be also characterized by an acute course with fever accompanied by hypervolemia and coagulopathy, resulting in bleeding and shock. It has been suggested that the course of the disease is strongly influenced by the activation of signaling pathways leading to RIG-I-like receptor-dependent interferon production. RIG-I-like receptors (RLRs) are one of two major receptor families that detect viral nucleic acid. RLR receptor activation is influenced by a number of factors that may have a key role in the differences that occur during the antiviral immune response in VHF. In the present study, we collected data on RLR receptors in viral hemorrhagic fevers and described factors that may influence the activation of the antiviral response. RLR receptors seem to be a good target for VHF research, which may contribute to better therapeutic and diagnostic strategies. However, due to the difficulty of conducting such studies in humans, we suggest using Lagovirus europaeus as an animal model for VHF.


Assuntos
Arenaviridae , RNA Helicases DEAD-box/metabolismo , Febres Hemorrágicas Virais , Ácidos Nucleicos , Animais , Antivirais , Humanos , Interferons
4.
Antiviral Res ; 208: 105444, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36243175

RESUMO

Infections by pathogenic New World mammarenaviruses (NWM)s, including Junín virus (JUNV), can result in a severe life-threatening viral hemorrhagic fever syndrome. In the absence of FDA-licensed vaccines or antivirals, these viruses are considered high priority pathogens. The mammarenavirus envelope glycoprotein complex (GPC) mediates pH-dependent fusion between viral and cellular membranes, which is essential to viral entry and may be vulnerable to small-molecule inhibitors that disrupt this process. ARN-75039 is a potent fusion inhibitor of a broad spectrum of pseudotyped and native mammarenaviruses in cell culture and Tacaribe virus infection in mice. In the present study, we evaluated ARN-75039 against pathogenic JUNV in the rigorous guinea pig infection model. The compound was well-tolerated and had favorable pharmacokinetics supporting once-per-day oral dosing in guinea pigs. Importantly, significant protection against JUNV challenge was observed even when ARN-75039 was withheld until 6 days after the viral challenge when clinical signs of disease are starting to develop. We also show that ARN-75039 combination treatment with favipiravir, a viral polymerase inhibitor, results in synergistic activity in vitro and improves survival outcomes in JUNV-challenged guinea pigs. Our findings support the continued development of ARN-75039 as an attractive therapeutic candidate for treating mammarenaviral hemorrhagic fevers, including those associated with NWM infection.


Assuntos
Arenaviridae , Febre Hemorrágica Americana , Febres Hemorrágicas Virais , Vírus Junin , Cobaias , Camundongos , Animais , Febre Hemorrágica Americana/tratamento farmacológico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Amidas/farmacologia , Amidas/uso terapêutico , Antirretrovirais/farmacologia
5.
Virology ; 576: 83-95, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36183499

RESUMO

The mammarenavirus Lassa virus (LASV) causes a life-threatening acute febrile disease, Lassa fever (LF). To date, no US Food and Drug Administration (FDA)-licensed medical countermeasures against LASV are available. This underscores the need for the development of novel anti-LASV drugs. Here, we screen an FDA-approved drug library to identify novel anti-LASV drug candidates using an infectious-free cell line expressing a functional LASV ribonucleoprotein (vRNP), where levels of vRNP-directed reporter gene expression serve as a surrogate for vRNP activity. Our screen identified the pan-ErbB tyrosine kinase inhibitor afatinib as a potent inhibitor of LASV vRNP activity. Afatinib inhibited multiplication of lymphocytic choriomeningitis virus (LCMV) a mammarenavirus closely related to LASV. Cell-based assays revealed that afatinib inhibited multiple steps of the LASV and LCMV life cycles. Afatinib also inhibited multiplication of Junín virus vaccine strain Candid#1, indicating that afatinib can have antiviral activity against a broad range of human pathogenic mammarenaviruses.


Assuntos
Arenaviridae , Febre Lassa , Vacinas , Chlorocebus aethiops , Animais , Humanos , Afatinib , Células Vero , Vírus Lassa/genética , Vírus da Coriomeningite Linfocítica , Antivirais/farmacologia , Ribonucleoproteínas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Estágios do Ciclo de Vida
6.
Microbiol Spectr ; 10(5): e0170522, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36094085

RESUMO

Reptarenaviruses cause boid inclusion body disease (BIBD), a potentially fatal disease, occurring in captive constrictor snakes boas and pythons worldwide. Classical BIBD, characterized by the formation of pathognomonic cytoplasmic inclusion bodies (IBs), occurs mainly in boas, whereas in pythons, for example, reptarenavirus infection most often manifests as central nervous system signs with limited IB formation. The natural hosts of reptarenaviruses are unknown, although free-ranging/wild constrictor snakes are among the suspects. Here, we report BIBD with reptarenavirus infection in indigenous captive and wild boid snakes in Costa Rica using histology, immunohistology, transmission electron microscopy, and next-generation sequencing (NGS). The snakes studied represented diagnostic postmortem cases of captive and wild-caught snakes since 1989. The results from NGS on archival paraffin blocks confirm that reptarenaviruses were already present in wild boa constrictors in Costa Rica in the 1980s. Continuous sequences that were de novo assembled from the low-quality RNA obtained from paraffin-embedded tissue allowed the identification of a distinct pair of reptarenavirus S and L segments in all studied animals; in most cases, reference assembly could recover almost complete segments. Sampling of three prospective cases in 2018 allowed an examination of fresh blood or tissues and resulted in the identification of additional reptarenavirus segments and hartmanivirus coinfection. Our results show that BIBD is not only a disease of captive snakes but also occurs in indigenous wild constrictor snakes in Costa Rica, suggesting boa constrictors to play a role in natural reptarenavirus circulation. IMPORTANCE The literature describes cases of boid inclusion body disease (BIBD) in captive snakes since the 1970s, and in the 2010s, others and ourselves identified reptarenaviruses as the causative agent. BIBD affects captive snakes globally, but the origin and the natural host of reptarenaviruses remain unknown. In this report, we show BIBD and reptarenavirus infections in two native Costa Rican constrictor snake species, and by studying archival samples, we show that both the viruses and the disease have been present in free-ranging/wild snakes in Costa Rica at least since the 1980s. The diagnosis of BIBD in wild boa constrictors suggests that this species plays a role in the circulation of reptarenaviruses. Additional sample collection and analysis would help to clarify this role further and the possibility of, e.g., vector transmission from an arthropod host.


Assuntos
Infecções por Arenaviridae , Arenaviridae , Boidae , Doenças Transmissíveis , Animais , Boidae/genética , Infecções por Arenaviridae/veterinária , Parafina , Arenaviridae/genética , Corpos de Inclusão , RNA
7.
Viruses ; 14(9)2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-36146676

RESUMO

Highly pathogenic Arenaviruses, like the Lassa Virus (LASV), pose a serious public health threat in affected countries. Research and development of vaccines and therapeutics are urgently needed but hampered by the necessity to handle these pathogens under biosafety level 4 conditions. These containment restrictions make large-scale screens of antiviral compounds difficult. Therefore, the Mopeia virus (MOPV), closely related to LASV, is often used as an apathogenic surrogate virus. We established for the first time trisegmented MOPVs (r3MOPV) with duplicated S segments, in which one of the viral genes was replaced by the reporter genes ZsGreen (ZsG) or Renilla Luciferase (Rluc), respectively. In vitro characterization of the two trisegmented viruses (r3MOPV ZsG/Rluc and r3MOPV Rluc/ZsG), showed comparable growth behavior to the wild type virus and the expression of the reporter genes correlated well with viral titer. We used the reporter viruses in a proof-of-principle in vitro study to evaluate the antiviral activity of two well characterized drugs. IC50 values obtained by Rluc measurement were similar to those obtained by virus titers. ZsG expression was also suitable to evaluate antiviral effects. The trisegmented MOPVs described here provide a versatile and valuable basis for rapid high throughput screening of broadly reactive antiviral compounds against arenaviruses under BSL-2 conditions.


Assuntos
Arenaviridae , Orthopoxvirus , Antivirais/farmacologia , Arenaviridae/genética , Genes Reporter , Vírus Lassa , Luciferases de Renilla/genética , Orthopoxvirus/genética , Pesquisa
8.
Microb Pathog ; 172: 105793, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36165863

RESUMO

Mammarena viruses are emerging pathogenic agents and cause hemorrhagic fevers in humans. These viruses accomplish host immune system evasion to replicate and spread in the host. There are only few available therapeutic options developed for Mammarena Virus (also called MMV). Currently, only a single candidate vaccine called Candid#1 is available against Junin virus. Similarly, the effective treatment Ribavirin is used only in Lassa fever treatments. Herein, immune-informatics pipeline has been used to annotate whole proteome of the seven human infecting Mammarena strains. The extensive immune based analysis reveals specie specific epitopes with a crucial role in immune response induction. This was achieved by construction of immunogenic epitopes (CTL "Cytotoxic T-Lymphocytes", HTL "Helper T-Lymphocytes", and B cell "B-Lymphocytes") based vaccine designs against seven different Mammarena virus species. Furthermore, validation of the vaccine constructs through exploring physiochemical properties was performed to confirm experimental feasibility. Additionally, in-silico cloning and receptor based immune simulation was performed to ensure induction of primary and secondary immune response. This was confirmed through expression of immune factors such as IL, cytokines, and antibodies. The current study provides with novel vaccine designs which needs further demonstrations through potential processing against MMVs. Future studies may be directed towards advanced evaluations to determine the efficacy and safety of the designed vaccines through further experimental procedures.


Assuntos
Arenaviridae , Vacinas Virais , Humanos , Vacinologia/métodos , Arenaviridae/genética , Epitopos de Linfócito B , Epitopos de Linfócito T , Proteoma , Ribavirina , Vacinas de Subunidades , Citocinas , Simulação de Acoplamento Molecular , Biologia Computacional
9.
Microbiol Spectr ; 10(4): e0158522, 2022 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-35862992

RESUMO

Mammarenaviruses establish a persistent infection in their rodent and bat hosts, and the evidence suggests that reptarenaviruses and hartmaniviruses found in captive snakes act similarly. In snakes, reptarenaviruses cause boid inclusion body disease (BIBD), which is often associated with secondary infections. Snakes with BIBD usually carry more than a single pair of reptarenavirus S and L segments and occasionally demonstrate hartmanivirus coinfection. Here, we reported the generation of cell lines persistently infected with a single or two reptarenavirus(es) and a cell line with persistent reptarenavirus-hartmanivirus coinfection. By RT-PCR we demonstrated that the amount of viral RNA within the persistently infected cells remains at levels similar to those observed following initial infection. Using antibodies against the glycoproteins (GPs) and nucleoprotein (NP) of reptarenaviruses, we studied the levels of viral protein in cells passaged 10 times after the original inoculation and observed that the expression of GPs declines dramatically during persistent infection, unlike the expression of NP. Immunofluorescence (IF) staining served to demonstrate differences in the distribution of NP within the persistently infected compared to freshly infected cells. IF staining of cells inoculated with the viruses secreted from the persistently infected cell lines produced similar NP staining compared to cells infected with a traditionally passaged virus, suggesting that the altered NP expression pattern of persistently infected cells does not relate to changes in the virus. The cell cultures described herein can serve as tools for studying the coinfection and superinfection interplay between reptarenaviruses and studying the BIBD pathogenesis mechanisms. IMPORTANCE Mammarenaviruses cause a persistent infection in their natural rodent and bat hosts. Reptarenaviruses cause boid inclusion body disease (BIBD) in constrictor snakes, but it is unclear whether snakes are the natural host of these viruses. In this study, we showed that reptarenaviruses established a persistent infection in cultured Boa constrictor cells and that the persistently infected cells continued to produce infectious virus. Our results showed that persistent infection results from subsequent passaging of cells inoculated with a single reptarenavirus, two reptarenaviruses, or even when inoculating the cells with reptarenavirus and hartmanivirus (another arenavirus genus). The results further suggested that coinfection would not result in overt competition between the different reptarenaviruses, thus helping to explain the frequent reptarenavirus coinfections in snakes with BIBD. The established cell culture models of persistent infection could help to elucidate the role of coinfection and superinfection and potential immunosuppression as the pathogenic mechanisms behind BIBD.


Assuntos
Arenaviridae , Boidae , Quirópteros , Coinfecção , Superinfecção , Animais , Arenaviridae/genética , Linhagem Celular
10.
Viruses ; 14(7)2022 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-35891543

RESUMO

Replication-competent reporter-expressing viruses are crucial tools in molecular virology with applications that range from antiviral screening to live-cell imaging of protein spatiotemporal dynamics. However, there is currently little information available regarding viable strategies to develop reporter-expressing arenaviruses. To address this, we used Tacaribe virus (TCRV), an apathogenic BSL2 arenavirus, to assess the feasibility of different reporter expression approaches. We first generated trisegmented TCRV viruses with either the glycoprotein (GP) or nucleoprotein (NP) replaced by a reporter (GFP, mCherry, or nanoluciferase). These viruses were all viable, but showed marked differences in brightness and attenuation. Next, we generated terminal fusions with each of the TCRV proteins (i.e., NP, GP, polymerase (L), matrix protein (Z)) either with or without a T2A self-cleavage site. We tested both the function of the reporter-fused proteins alone, and the viability of corresponding recombinant TCRVs. We successfully rescued viruses with both direct and cleavable reporter fusions at the C-terminus of Z, as well as cleavable N-terminal fusions with NP. These viruses all displayed detectable reporter activity, but were also moderately attenuated. Finally, reporter proteins were inserted into a flexible hinge region within L. These viruses were also viable and showed moderate attenuation; however, reporter expression was only detectable for the luminescent virus. These strategies provide an exciting range of new tools for research into the molecular biology of TCRV that can likely also be adapted to other arenaviruses.


Assuntos
Arenaviridae , Arenavirus , Arenavirus do Novo Mundo , Arenaviridae/genética , Arenaviridae/metabolismo , Arenavirus/genética , Arenavirus do Novo Mundo/genética , Nucleoproteínas/genética , Nucleoproteínas/metabolismo , Replicação Viral
11.
Viruses ; 14(6)2022 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-35746604

RESUMO

Junín virus (JUNV) belongs to the Arenaviridae family and is the causative agent of Argentine hemorrhagic fever (AHF), a severe human disease endemic to agricultural areas in Argentina. At this moment, there are no effective antiviral therapeutics to battle pathogenic arenaviruses. Cumulative reports from recent years have widely provided information on cellular factors playing key roles during JUNV infection. In this review, we summarize research on host molecular determinants that intervene in the different stages of the viral life cycle: viral entry, replication, assembly and budding. Alongside, we describe JUNV tight interplay with the innate immune system. We also review the development of different reverse genetics systems and their use as tools to study JUNV biology and its close teamwork with the host. Elucidating relevant interactions of the virus with the host cell machinery is highly necessary to better understand the mechanistic basis beyond virus multiplication, disease pathogenesis and viral subversion of the immune response. Altogether, this knowledge becomes essential for identifying potential targets for the rational design of novel antiviral treatments to combat JUNV as well as other pathogenic arenaviruses.


Assuntos
Arenaviridae , Arenavirus , Febre Hemorrágica Americana , Vírus Junin , Antivirais , Arenaviridae/genética , Humanos , Vírus Junin/fisiologia , Replicação Viral
12.
Medicina (B Aires) ; 82(3): 344-350, 2022.
Artigo em Espanhol | MEDLINE | ID: mdl-35639054

RESUMO

Since the identification of Junin virus in the 1950s, many studies were carried out in wild rodents within the endemic area of the Argentine Hemorrhagic Fever (AHF) that recorded also the activity of the lymphocytic choriomeningitis virus (LCMV) and the Latino virus (LATV). The absence of confirmed cases of AHF since the 1990s in the department of Rio Cuarto, Córdoba province, promoted ecoepidemiological surveillance of infection of Calomys musculinus (Junin virus reservoir) and the search of reservoirs of the other mammarenaviruses. During two years of seasonal sampling, with a capture, mark and release system, 857 rodents were captured, corresponding 57.3% to the rodent reservoirs: C. musculinus, C. venustus and Mus musculus, being the first the most abundant species. Antibodies were detected and the three viral agents were molecularly characterized, showing a prevalence of infection of 3.5% (9/254) for Junin virus, 100% (3/3) for LCMV and 24.1% (21/87) for LATV. In conclusion, we demonstrated Junin virus circulation in its rodent reservoir in a region considered historic for AHF with potential risk for the population and the spatio-temporal co-circulation of the three mammarenaviruses in the central region of Argentina.


Desde la identificación del virus Junin en la década del 50, se realizaron numerosos estudios en roedores silvestres dentro del área endémica de la Fiebre Hemorrágica Argentina (FHA) que permitieron registrar, además, actividad del virus de la coriomeningitis linfocitaria (LCMV) y del virus Latino (LATV). La ausencia de casos confirmados de FHA desde la década del 90 en el departamento Río Cuarto, provincia de Córdoba, promovió la vigilancia ecoepidemiológica y de infección del Calomys musculinus (reservorio del virus Junin) y la búsqueda de reservorios e infección de los otros mammarenavirus. Durante dos años de muestreo estacional, con un sistema de captura, marcación y liberación capturamos 857 roedores, que correspondieron 57.3% a los reservorios: C. musculinus (especie más abundante), C. venustus y Mus musculus. Detectamos anticuerpos y caracterizamos molecularmente los tres agentes virales. Observamos una prevalencia de infección de 3.5% (9/254) para virus Junin, 100% (3/3) para LCMV y 24.1% (21/87) para LATV. En conclusión, demostramos circulación de virus Junin en su roedor reservorio, en una región considerada histórica para FHA con riesgo potencial para la población y cocirculación espacio-temporal de los tres mammarenavirus en la región central de Argentina.


Assuntos
Arenaviridae , Arenavirus do Novo Mundo , Febre Hemorrágica Americana , Vírus Junin , Animais , Reservatórios de Doenças , Febre Hemorrágica Americana/epidemiologia , Humanos , Camundongos , Roedores
13.
Arch Virol ; 167(9): 1727-1738, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35579715

RESUMO

Guanarito virus (GTOV) is a member of the family Arenaviridae and has been designated a category A bioterrorism agent by the US Centers for Disease Control and Prevention. It is endemic to Venezuela's western region, and it is the etiological agent of "Venezuelan hemorrhagic fever" (VHF). Similar to other arenaviral hemorrhagic fevers, VHF is characterized by fever, mild hemorrhagic signs, nonspecific symptoms, thrombocytopenia, and leukopenia. Patients with severe disease usually develop signs of internal bleeding. Due to the absence of reference laboratories that can handle GTOV in endemic areas, diagnosis is primarily clinical and epidemiological. No antiviral therapies are available; thus, treatment includes only supportive analgesia and fluids. GTOV is transmitted by contact with the excreta of its rodent reservoir, Zygodontomys brevicauda. The main reasons for the emergence of the disease may be the increase in the human population, migration, and changes in land use patterns in rural areas. Social and environmental changes could make VHF an important cause of underdiagnosed acute febrile illnesses in regions near the endemic areas. Although there is evidence that GTOV circulates among rodents in different Venezuelan states, VHF cases have only been reported in the states of Portuguesa and Barinas. However, due to the increased frequency of invasions by humans into wildlife habitats, it is probable that VHF could become a public health problem in the nearby regions of Colombia and Brazil. The current Venezuelan political crisis is causing an increase in the migration of people and livestock, representing a risk for the redistribution and re-emergence of infectious diseases.


Assuntos
Infecções por Arenaviridae , Arenaviridae , Arenavirus do Novo Mundo , Febres Hemorrágicas Virais , Animais , Febres Hemorrágicas Virais/diagnóstico , Febres Hemorrágicas Virais/epidemiologia , Humanos , Roedores , Sigmodontinae
14.
Viruses ; 14(3)2022 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-35337059

RESUMO

Lassa virus (LASV), an Old World arenavirus, is responsible for hemorrhagic fevers in western Africa. The privileged tropism of LASV for endothelial cells combined with a dysregulated inflammatory response are the main cause of the increase in vascular permeability observed during the disease. Mopeia virus (MOPV) is another arenavirus closely related to LASV but nonpathogenic for non-human primates (NHPs) and has never been described in humans. MOPV is more immunogenic than LASV in NHPs and in vitro in human immune cell models, with more intense type I IFN and adaptive cellular responses. Here, we compared the transcriptomic and proteomic responses of human umbilical vein endothelial cells (HUVECs) to infection with the two viruses to further decipher the mechanisms involved in their differences in immunogenicity and pathogenicity. Both viruses replicated durably and efficiently in HUVECs, but the responses they induced were strikingly different. Modest activation was observed at an early stage of LASV infection and then rapidly shut down. By contrast, MOPV induced a late but more intense response, characterized by the expression of genes and proteins mainly associated with the type I IFN response and antigen processing/presentation. Such a response is consistent with the higher immunogenicity of MOPV relative to LASV, whereas the lack of an innate response induced in HUVECs by LASV is consistent with its uncontrolled systemic dissemination through the vascular endothelium.


Assuntos
Arenaviridae , Arenavirus , Febre Lassa , Animais , Arenaviridae/genética , Células Endoteliais , Humanos , Vírus Lassa , Proteômica
15.
Ecohealth ; 19(1): 22-39, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35247117

RESUMO

In the Americas, infectious viral diseases caused by viruses of the genus Mammarenavirus have been reported since the 1960s. Such diseases have commonly been associated with land use changes, which favor abundance of generalist rodent species. In the Americas-where the rates of land use change are among the highest worldwide-at least 1326 of all 2277 known rodent species have been reported. We conducted a literature review of studies between 1960 and 2020, to establish the current and historical knowledge about genotypes of mammarenaviruses and their rodent reservoirs in the Americas. Our overall goal was to show the importance of focusing research efforts on the American continent, since the conditions exist for future viral hemorrhagic fever (VHF) outbreaks caused by rodent-borne viruses, in turn, carried by widely distributed rodents. We found 47 species identified down to the species level, and one species identified only down to the genus level (Oryzomys sp.), reported in the Americas as reservoirs of mammarenaviruses, most these are ecological generalists. These species associate with 29 genotypes of Mammarenavirus, seven of which have been linked to VHFs in humans. We also highlight the need to monitor these species, in order to prevent viral disease outbreaks in the region.


Assuntos
Arenaviridae , Roedores , América , Animais , Arenaviridae/classificação , Arenaviridae/genética , Reservatórios de Doenças/virologia , Febres Hemorrágicas Virais/virologia , Roedores/virologia
16.
Nat Commun ; 13(1): 558, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35091550

RESUMO

Five New World mammarenaviruses (NWMs) cause life-threatening hemorrhagic fever (HF). Cellular entry by these viruses is mediated by human transferrin receptor 1 (hTfR1). Here, we demonstrate that an antibody (ch128.1/IgG1) which binds the apical domain of hTfR1, potently inhibits infection of attenuated and pathogenic NWMs in vitro. Computational docking of the antibody Fab crystal structure onto the known structure of hTfR1 shows an overlapping receptor-binding region shared by the Fab and the viral envelope glycoprotein GP1 subunit that binds hTfR1, and we demonstrate competitive inhibition of NWM GP1 binding by ch128.1/IgG1 as the principal mechanism of action. Importantly, ch128.1/IgG1 protects hTfR1-expressing transgenic mice against lethal NWM challenge. Additionally, the antibody is well-tolerated and only partially reduces ferritin uptake. Our findings provide the basis for the development of a novel, host receptor-targeted antibody therapeutic broadly applicable to the treatment of HF of NWM etiology.


Assuntos
Antígenos CD/metabolismo , Arenaviridae/metabolismo , Febre Hemorrágica Americana/metabolismo , Receptores da Transferrina/metabolismo , Proteínas do Envelope Viral/metabolismo , Células A549 , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/farmacologia , Antígenos CD/imunologia , Arenaviridae/efeitos dos fármacos , Arenaviridae/fisiologia , Chlorocebus aethiops , Febre Hemorrágica Americana/prevenção & controle , Febre Hemorrágica Americana/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Vírus Junin/efeitos dos fármacos , Vírus Junin/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Simulação de Acoplamento Molecular , Ligação Proteica/efeitos dos fármacos , Receptores da Transferrina/antagonistas & inibidores , Receptores da Transferrina/imunologia , Células Vero
17.
Infect Genet Evol ; 98: 105204, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34999003

RESUMO

Mammarenaviruses have been a growing concern for public health in Africa since the 1970s when Lassa virus cases in humans were first described in west Africa. In southern Africa, a single outbreak of Lujo virus was reported to date in South Africa in 2008 with a case fatality rate of 80%. The natural reservoir of Lassa virus is Mastomys natalensis while for the Lujo virus the natural host has yet to be identified. Mopeia virus was described for the first time in M. natalensis in the central Mozambique in 1977 but few studies have been conducted in the region. In this study, rodents were trapped between March and November 2019in villages, croplands fields and mopane woodland forest. The aim was to assess the potential circulation and to evaluate the genetic diversity of mammarenaviruses in M. natalensis trapped in the Limpopo National Park and its buffer zone in Massingir district, Mozambique. A total of 534 M. natalensis were screened by RT-PCR and the overall proportion of positive individuals was 16.9%. No significant differences were detected between the sampled habitats (χ2 = 0.018; DF = 1; p = 0.893). The Mopeia virus (bootstrap value 91%) was the Mammarenavirus circulating in the study area sites, forming a specific sub-clade with eight different sub-clusters. We concluded that Mopeia virus circulates in all habitats investigated and it forms a different sub-clade to the one reported in central Mozambique in 1977.


Assuntos
Infecções por Arenaviridae/veterinária , Arenaviridae/isolamento & purificação , Murinae , Doenças dos Roedores/epidemiologia , Animais , Infecções por Arenaviridae/epidemiologia , Ecossistema , Moçambique/epidemiologia , Parques Recreativos
18.
J Biomol Struct Dyn ; 40(16): 7283-7302, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-33719908

RESUMO

Lassa mammarenavirus (LASMV) is responsible for a specific type of acute viral hemorrhagic fever known as Lassa fever. Lack of effective treatments and counter-measures against the virus has resulted in a high mortality rate in its endemic regions. Therefore, in this study, a novel epitope-based vaccine has been designed using the methods of immunoinformatics targeting the glycoprotein and nucleoprotein of the virus. After numerous robust analyses, two CTL epitopes, eight HTL epitopes and seven B-cell epitopes were finally selected for constructing the vaccine. All these most promising epitopes were found to be antigenic, non-allergenic, nontoxic and non-human homolog, which made them suitable for designing the subunit vaccine. Furthermore, the selected T-cell epitopes which were found to be fully conserved across different isolates of the virus, were also considered for final vaccine construction. After that, numerous validation experiments, i.e. molecular docking, molecular dynamics simulation and immune simulation were conducted, which predicted that our designed vaccine should be stable within the biological environment and effective in combating the LASMV infection. In the end, codon adaptation and in silico cloning studies were performed to design a recombinant plasmid for producing the vaccine industrially. However, further in vitro and in vivo assessments should be done on the constructed vaccine to finally confirm its safety and efficacy.Communicated by Ramaswamy H. Sarma.


Assuntos
Arenaviridae , Nucleoproteínas , Arenaviridae/genética , Epitopos de Linfócito B , Epitopos de Linfócito T , Glicoproteínas , Simulação de Acoplamento Molecular , Nigéria , Nucleoproteínas/genética , Vacinas de Subunidades
19.
Viruses ; 15(1)2022 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-36680139

RESUMO

Mammarenaviruses are hosted by several rodent species, a small number of which have been known to be zoonotic. Host surveillance among small mammals has identified a large diversity of previously undescribed mammarenaviruses. Intensified biosurveillance is warranted to better understand the diversity of these agents. Longitudinal host surveillance involving non-volant small mammals at a site in the Limpopo province, South Africa, was conducted. The study reports on the screening results of 563 samples for the presence of mammarenavirus RNA. PCR-positive samples were subjected to sequencing using Miseq amplicon sequencing. Sequences with close similarity to Mariental and Lunk viruses were identified from two rodent species, Micaelamys namaquensis and Mus minutoides. This represents the first description of these viruses from South Africa. The genomic sequences reported here partially satisfied the requirements put forward by the International Committee on the Taxonomy of Viruses' criteria for species delineation, suggesting that these may be new strains of existing species. The known distribution of these mammarenaviruses is thus expanded further south in Africa.


Assuntos
Arenaviridae , Animais , Arenaviridae/genética , Filogenia , África Austral , Mamíferos , Murinae
20.
Emerg Infect Dis ; 27(12): 3092-3102, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34808083

RESUMO

We conducted a survey for group-specific indirect immunofluorescence antibody to mammarenaviruses by using Lassa fever and Mopeia virus antigens on serum specimens of 5,363 rodents of 33 species collected in South Africa and Zimbabwe during 1964-1994. Rodents were collected for unrelated purposes or for this study and stored at -70°C. We found antibody to be widely distributed in the 2 countries; antibody was detected in serum specimens of 1.2%-31.8% of 14 species of myomorph rodents, whereas 19 mammarenavirus isolates were obtained from serum specimens and viscera of 4 seropositive species. Phylogenetic analysis on the basis of partial nucleoprotein sequences indicates that 14 isolates from Mastomys natalensis, the Natal multimammate mouse, were Mopeia virus, whereas Merino Walk virus was characterized as a novel virus in a separate study. The remaining 4 isolates from 3 rodent species potentially constitute novel viruses pending full characterization.


Assuntos
Arenaviridae , Doenças dos Roedores , Animais , Reservatórios de Doenças , Vírus Lassa , Murinae , Filogenia , África do Sul/epidemiologia , Zimbábue/epidemiologia
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