Last data update: Jun 17, 2024. (Total: 47034 publications since 2009)
Records 1-17 (of 17 Records) |
Query Trace: Dodd KA [original query] |
---|
Marburgvirus resurgence in Kitaka Mine bat population after extermination attempts, Uganda.
Amman BR , Nyakarahuka L , McElroy AK , Dodd KA , Sealy TK , Schuh AJ , Shoemaker TR , Balinandi S , Atimnedi P , Kaboyo W , Nichol ST , Towner JS . Emerg Infect Dis 2014 20 (10) 1761-4 Marburg virus (MARV) and Ravn virus (RAVV), collectively called marburgviruses, cause Marburg hemorrhagic fever (MHF) in humans. In July 2007, 4 cases of MHF (1 fatal) occurred in miners at Kitaka Mine in southern Uganda. Later, MHF occurred in 2 tourists who visited Python Cave, ≈50 km from Kitaka Mine. One of the tourists was from the United States (December 2007) and 1 was from the Netherlands (July 2008); 1 case was fatal (1,2,3). The cave and the mine each contained 40,000–100,000 Rousettus aegyptiacus bats (Egyptian fruit bats). | | Longitudinal investigations of the outbreaks at both locations were initiated by the Viral Special Pathogens Branch of the Centers for Disease Control and Prevention (CDC, Atlanta, GA, USA, and Entebbe, Uganda) in collaboration with the Uganda Wildlife Authority (UWA) and the Uganda Virus Research Institute (UVRI). During these studies, genetically diverse MARVs and RAVVs were isolated directly from bat tissues, and infection levels of the 2 viruses were found to increase in juvenile bats on a predictable bi-annual basis (4,5). However, investigations at Kitaka Mine were stopped when the miners exterminated the bat colony by restricting egress from the cave with papyrus reed barriers and then entangling the bats in fishing nets draped over the exits. The trapping continued for weeks, and the entrances were then sealed with sticks and plastic. These depopulation efforts were documented by researchers from UVRI, the CDC, the National Institute of Communicable Diseases (Sandringham, South Africa), and UWA during site visits to Kitaka Mine (Technical Appendix Figure). In August 2008, thousands of dead bats were found piled in the forest, and by November 2008, there was no evidence of bats living in the mine; whether 100% extermination was achieved is unknown. CDC, UVRI, and UWA recommended against extermination, believing that any results would be temporary and that such efforts could exacerbate the problem if bat exclusion methods were not complete and permanent (6,7). |
Ebola Virus Disease Diagnostics, Sierra Leone: Analysis of Real-time Reverse Transcription-Polymerase Chain Reaction Values for Clinical Blood and Oral Swab Specimens.
Erickson BR , Sealy TK , Flietstra T , Morgan L , Kargbo B , Matt-Lebby VE , Gibbons A , Chakrabarti AK , Graziano J , Presser L , Flint M , Bird BH , Brown S , Klena JD , Blau DM , Brault AC , Belser JA , Salzer JS , Schuh AJ , Lo M , Zivcec M , Priestley RA , Pyle M , Goodman C , Bearden S , Amman BR , Basile A , Bergeron E , Bowen MD , Dodd KA , Freeman MM , McMullan LK , Paddock CD , Russell BJ , Sanchez AJ , Towner JS , Wang D , Zemtsova GE , Stoddard RA , Turnsek M , Guerrero LW , Emery SL , Stovall J , Kainulainen MH , Perniciaro JL , Mijatovic-Rustempasic S , Shakirova G , Winter J , Sexton C , Liu F , Slater K , Anderson R , Andersen L , Chiang CF , Tzeng WP , Crowe SJ , Maenner MJ , Spiropoulou CF , Nichol ST , Stroher U . J Infect Dis 2016 214 S258-S262 During the Ebola virus outbreak of 2013-2016, the Viral Special Pathogens Branch field laboratory in Sierra Leone tested approximately 26 000 specimens between August 2014 and October 2015. Analysis of the B2M endogenous control Ct values showed its utility in monitoring specimen quality, comparing results with different specimen types, and interpretation of results. For live patients, blood is the most sensitive specimen type and oral swabs have little diagnostic utility. However, swabs are highly sensitive for diagnostic testing of corpses. |
Effect of Vandetanib on Andes virus survival in the hamster model of Hantavirus pulmonary syndrome
Bird BH , Shrivastava-Ranjan P , Dodd KA , Erickson BR , Spiropoulou CF . Antiviral Res 2016 132 66-69 Hantavirus pulmonary syndrome (HPS) is a severe disease caused by hantavirus infection of pulmonary microvascular endothelial cells leading to microvascular leakage, pulmonary edema, pleural effusion and high case fatality. Previously, we demonstrated that Andes virus (ANDV) infection caused up-regulation of vascular endothelial growth factor (VEGF) and concomitant downregulation of the cellular adhesion molecule VE-cadherin leading to increased permeability. Analyses of human HPS-patient sera have further demonstrated increased circulating levels of VEGF. Here we investigate the impact of a small molecule antagonist of the VEGF receptor 2 (VEGFR-2) activation in vitro, and overall impact on survival in the Syrian hamster model of HPS. |
Humanized mouse model of Ebola virus disease mimics immune responses in human disease
Bird BH , Spengler JR , Chakrabarti AK , Khristova ML , Sealy TK , Coleman-McCray JD , Martin BE , Dodd KA , Goldsmith CS , Sanders J , Zaki SR , Nichol ST , Spiropoulou CF . J Infect Dis 2015 213 (5) 703-11 Animal models recapitulating human Ebola virus disease (EVD) are critical for insights into virus pathogenesis. Ebola virus (EBOV) isolates derived directly from human specimens do not cause disease in immunocompetent adult rodents without adaptation. Here we describe EVD in humanized BLT mice (hu-BLT) engrafted with human immune cells. Hu-BLT mice developed EVD following wild-type EBOV infection. Infection with high-dose EBOV resulted in rapid lethal EVD with high viral loads, alterations in key human antiviral immune cytokines and chemokines, and severe histopathology similar to that shown in the limited human post-mortem data available. A dose- and donor- dependent clinical course was observed in hu-BLT infected with lower doses of either Mayinga (1976) or Makona (2014) isolates derived from human EBOV cases. Engraftment of the human cellular immune system appeared to be essential for the observed virulence, as non-engrafted mice did not support productive EBOV replication or develop lethal disease. Hu-BLT mice offer a unique model for investigating the human immune response in EVD; and offer an alternative animal model for EVD pathogenesis studies and therapeutic screening. |
Ebola virus diagnostics: the US Centers for Disease Control and Prevention laboratory in Sierra Leone, August 2014 to March 2015
Flint M , Goodman CH , Bearden S , Blau DM , Amman BR , Basile AJ , Belser JA , Bergeron E , Bowen MD , Brault AC , Campbell S , Chakrabarti AK , Dodd KA , Erickson BR , Freeman MM , Gibbons A , Guerrero LW , Klena JD , Lash RR , Lo MK , McMullan LK , Momoh G , Massally JL , Goba A , Paddock CD , Priestley RA , Pyle M , Rayfield M , Russell BJ , Salzer JS , Sanchez AJ , Schuh AJ , Sealy TK , Steinau M , Stoddard RA , Taboy C , Turnsek M , Wang D , Zemtsova GE , Zivcec M , Spiropoulou CF , Stroher U , Towner JS , Nichol ST , Bird BH . J Infect Dis 2015 212 Suppl 2 S350-8 In August 2014, the Viral Special Pathogens Branch of the US Centers for Disease Control and Prevention established a field laboratory in Sierra Leone in response to the ongoing Ebola virus outbreak. Through March 2015, this laboratory tested >12 000 specimens from throughout Sierra Leone. We describe the organization and procedures of the laboratory located in Bo, Sierra Leone. |
Kyasanur Forest disease virus infection in mice is associated with higher morbidity and mortality than infection with the closely related Alkhurma hemorrhagic fever virus
Dodd KA , Bird BH , Jones ME , Nichol ST , Spiropoulou CF . PLoS One 2014 9 (6) e100301 BACKGROUND: Kyasanur Forest disease virus (KFDV) and Alkhurma hemorrhagic fever virus (AHFV) are closely related members of the Flavivirus genus and are important causes of human disease in India and the Arabian Peninsula, respectively. Despite high genetic similarity, the viruses have distinctly different host ranges and ecologies. Human cases of KFDV or AHFV develop a spectrum of disease syndromes ranging from liver pathology to neurologic disease. Case reports suggest KFDV is more commonly associated with hepatic and gastrointestinal manifestations whereas AHFV is more commonly associated with neurologic disease. METHODOLOGY/PRINCIPAL FINDINGS: Inoculation of three immunocompetent laboratory mouse strains revealed that KFDV was consistently more lethal than AHFV. In subsequent studies utilizing C57BL/6J mice, we demonstrated that KFDV infection was associated with higher viral loads and significantly higher mortality. KFDV-infected mice rapidly developed more severe disease than AHFV-infected mice, as evidenced by significant abnormalities on clinical chemistry panels and more severe pathology in the brain and gastrointestinal tract. CONCLUSIONS/SIGNIFICANCE: Infections of C57BL/6J mice with KFDV or AHFV resulted in clinical disease syndromes that closely approximate the diseases seen in human cases. Despite high genetic similarity, there were clear differences in survival, viral kinetics, clinical chemistry data and histology. These results suggest that distinct mouse models for AHFV and KFDV are necessary in order to gain a better understanding of the unique pathogenesis of each virus, as well as to provide platforms for testing promising vaccines and therapeutics. |
Rift Valley fever virus encephalitis is associated with an ineffective systemic immune response and activated T cell infiltration into the CNS in an immunocompetent mouse model
Dodd KA , McElroy AK , Jones TL , Zaki SR , Nichol ST , Spiropoulou CF . PLoS Negl Trop Dis 2014 8 (6) e2874 BACKGROUND: Rift Valley fever virus (RVFV) causes outbreaks of severe disease in livestock and humans throughout Africa and the Arabian Peninsula. In people, RVFV generally causes a self-limiting febrile illness but in a subset of individuals, it progresses to more serious disease. One manifestation is a delayed-onset encephalitis that can be fatal or leave the afflicted with long-term neurologic sequelae. In order to design targeted interventions, the basic pathogenesis of RVFV encephalitis must be better understood. METHODOLOGY/PRINCIPAL FINDINGS: To characterize the host immune responses and viral kinetics associated with fatal and nonfatal infections, mice were infected with an attenuated RVFV lacking NSs (DeltaNSs) that causes lethal disease only when administered intranasally (IN). Following IN infection, C57BL/6 mice developed severe neurologic disease and succumbed 7-9 days post-infection. In contrast, inoculation of DeltaNSs virus subcutaneously in the footpad (FP) resulted in a subclinical infection characterized by a robust immune response with rapid antibody production and strong T cell responses. IN-inoculated mice had delayed antibody responses and failed to clear virus from the periphery. Severe neurological signs and obtundation characterized end stage-disease in IN-inoculated mice, and within the CNS, the development of peak virus RNA loads coincided with strong proinflammatory responses and infiltration of activated T cells. Interestingly, depletion of T cells did not significantly alter survival, suggesting that neurologic disease is not a by-product of an aberrant immune response. CONCLUSIONS/SIGNIFICANCE: Comparison of fatal (IN-inoculated) and nonfatal (FP-inoculated) DeltaNSs RVFV infections in the mouse model highlighted the role of the host immune response in controlling viral replication and therefore determining clinical outcome. There was no evidence to suggest that neurologic disease is immune-mediated in RVFV infection. These results provide important insights for the future design of vaccines and therapeutic options. |
Inhibitors of the tick-borne, hemorrhagic fever-associated flaviviruses.
Flint M , McMullan LK , Dodd KA , Bird BH , Khristova M , Nichol ST , Spiropoulou CF . Antimicrob Agents Chemother 2014 58 (6) 3206-16 No antiviral therapies are available for the tick-borne flaviviruses associated with hemorrhagic fevers: Kyasanur Forest disease virus (KFDV), both classical and the Alkhurma hemorrhagic fever virus (AHFV) subtype, and Omsk hemorrhagic fever virus (OHFV). We tested compounds reported to have antiviral activity against members of the Flaviviridae family for their ability to inhibit AHFV replication. 6-azauridine (6-azaU), 2' -C-methylcytidine (2' -CMC), and interferon-alpha2a (IFNalpha) inhibited the replication of AHFV and also KFDV, OHFV and Powassan virus. The combination of IFNalpha and 2' -CMC exerted an additive antiviral effect on AHFV and the combination of IFNalpha and 6-azaU was moderately synergistic. The combination of 2' -CMC and 6-azaU was complex, being strongly synergistic but with a moderate level of antagonism. The antiviral activity of 6-azaU was reduced by the addition of cytidine, but not guanosine, suggesting that it acted by inhibiting pyrimidine biosynthesis. To investigate the mechanism of action of 2' -CMC, AHFV variants with reduced susceptibility to 2' -CMC were selected. We used a replicon system to assess the substitutions present in the selected AHFV population. A double NS5 mutant S603T/C666S and a triple mutant S603T/C666S/M644V were more resistant to 2' -CMC than the wild-type replicon. The S603T/C666S mutant had a reduced level of replication which was increased when M644V was also present, though the replication of this triple mutant was still below that of wild-type. The S603 and C666 residues were predicted to lie in the active site of the AHFV NS5 polymerase, implicating the catalytic center of the enzyme as the binding site for 2' -CMC. |
Rift Valley fever virus clearance and protection from neurologic disease are dependent on CD4+ T cell and virus-specific antibody responses
Dodd KA , McElroy AK , Jones ME , Nichol ST , Spiropoulou CF . J Virol 2013 87 (11) 6161-71 Rift Valley fever virus (RVFV) causes outbreaks of severe disease in people and livestock throughout Africa and the Arabian Peninsula. Human RVFV infections generally manifest as a self-limiting febrile illness, but in some individuals, the disease can progress to a fatal encephalitis or hemorrhagic syndrome. Little is known about the host characteristics that predispose development of more severe disease. Early in infection, interferon-mediated antiviral responses are critical for controlling RVFV replication, but the roles of downstream adaptive immune responses in determining clinical outcome have not been examined. Here, using a C57BL/6 mouse disease model, we evaluated the roles of B cells and T cells in RVFV pathogenesis. Given the profound inhibition of the innate response by the viral NSs protein and rapid course of wild-type infection, we utilized an attenuated RVFV lacking NSs to examine host responses following primary infection. Experiments utilizing B cell deficient mice or targeted T cell depletions of wild-type mice demonstrated that B cells and CD4+ T cells, but not CD8+ T cells, were critical for mediating viral clearance, even in the presence of a functional innate response. One-third of CD4-depleted mice developed severe neurologic disease following infection, in contrast to virus-infected mock-depleted mice that showed no clinical signs. CD4+ T cells were required for robust IgG and neutralizing antibody responses that correlated with RVFV clearance from peripheral tissues. Further, CD4-depleted mice demonstrated significantly stronger pro-inflammatory responses relative to controls, suggesting CD4+ T cells regulate immune responses to RVFV infection. Together, these results indicate CD4+ T cells are critical determinants of RVFV pathogenesis and play an important role in preventing onset of neurologic disease. |
Severe hemorrhagic fever in strain 13/n guinea pigs infected with Lujo virus
Bird BH , Dodd KA , Erickson BR , Albarino CG , Chakrabarti AK , McMullan LK , Bergeron E , Stroeher U , Cannon D , Martin B , Coleman-McCray JD , Nichol ST , Spiropoulou CF . PLoS Negl Trop Dis 2012 6 (8) e1801 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. |
Reverse genetics recovery of Lujo virus and role of virus RNA secondary structures in efficient virus growth.
Bergeron E , Chakrabarti AK , Bird BH , Dodd KA , McMullan LK , Spiropoulou CF , Nichol ST , Albarino CG . J Virol 2012 86 (19) 10759-65 Arenaviruses are rodent-borne viruses with a bisegmented RNA genome. A genetically unique arenavirus, Lujo virus, was recently discovered as the causal agent of a nosocomial outbreak of acute febrile illness with hemorrhagic manifestations in Zambia and South Africa. The outbreak had a case fatality of 80%. A reverse genetics system to rescue infectious Lujo virus from cDNA was established to investigate the biological properties of this virus. Sequencing the genomic termini showed unique nucleotides at the 3' terminus of the S segment promoter element. While developing this system, we discovered that reconstructing infectious Lujo virus using the previously reported L segment intergenic region (IGR), comprising the arenaviral transcription termination signal, yielded an attenuated Lujo virus. Resequencing revealed that the correct L segment IGR was 36 nucleotide longer, and incorporating it into the reconstructed Lujo virus restored growth rate to that of the authentic clinical virus isolate. These additional nucleotides were predicted to more than double the free energy of the IGR main stem-loop structure. In addition, incorporating the newly determined L-IGR into a replicon reporter system enhanced the expression of a luciferase reporter L segment. Overall, these results imply that an extremely stable secondary structure within the L-IGR is critical for Lujo virus propagation and viral protein production. The technology for producing recombinant Lujo virus now provides a method to precisely investigate the molecular determinants of virulence of this newly identified pathogen. |
Single-dose immunization with virus replicon particles confers rapid robust protection against Rift Valley fever virus challenge
Dodd KA , Bird BH , Metcalfe MG , Nichol ST , Albarino CG . J Virol 2012 86 (8) 4204-12 Rift Valley fever virus (RVFV) causes outbreaks of severe disease in people and livestock throughout Africa and the Arabian Peninsula. The potential for RVFV introduction outside the area of endemicity highlights the need for fast-acting, safe, and efficacious vaccines. Here, we demonstrate a robust system for the reverse genetics generation of a RVF virus replicon particle (VRP(RVF)) vaccine candidate. Using a mouse model, we show that VRP(RVF) immunization provides the optimal balance of safety and single-dose robust efficacy. VRP(RVF) can actively synthesize viral RNA and proteins but lacks structural glycoprotein genes, preventing spread within immunized individuals and reducing the risk of vaccine-induced pathogenicity. VRP(RVF) proved to be completely safe following intracranial inoculation of suckling mice, a stringent test of vaccine safety. Single-dose subcutaneous immunization with VRP(RVF), although it is highly attenuated, completely protected mice against a virulent RVFV challenge dose which was 100,000-fold greater than the 50% lethal dose (LD(50)). Robust protection from lethal challenge was observed by 24 h postvaccination, with 100% protection induced in as little as 96 h. We show that a single subcutaneous VRP(RVF) immunization initiated a systemic antiviral state followed by an enhanced adaptive response. These data contrast sharply with the much-reduced survivability and immune responses observed among animals immunized with nonreplicating viral particles, indicating that replication, even if confined to the initially infected cells, contributes substantially to protective efficacy at early and late time points postimmunization. These data demonstrate that replicon vaccines successfully bridge the gap between safety and efficacy and provide insights into the kinetics of antiviral protection from RVFV infection. |
Rift Valley fever virus vaccine lacking the NSs and NSm genes is safe, nonteratogenic, and confers protection from viremia, pyrexia, and abortion following challenge in adult and pregnant sheep.
Bird BH , Maartens LH , Campbell S , Erasmus BJ , Erickson BR , Dodd KA , Spiropoulou CF , Cannon D , Drew CP , Knust B , McElroy AK , Khristova ML , Albarino CG , Nichol ST . J Virol 2011 85 (24) 12901-9 Rift Valley fever virus (RVFV) is a mosquito-borne human and veterinary pathogen causing large outbreaks of severe disease throughout Africa and the Arabian Peninsula. Safe and effective vaccines are critically needed, especially those that can be used in a targeted one-health approach to prevent both livestock and human disease. We report here on the safety, immunogenicity, and efficacy of the DeltaNSs-DeltaNSm recombinant RVFV (rRVFV) vaccine (which lacks the NSs and NSm virulence factors) in a total of 41 sheep, including 29 timed-pregnant ewes. This vaccine was proven safe and immunogenic for adult animals at doses ranging from 1.0 x 10(3) to 1.0 x 10(5) PFU administered subcutaneously (s.c.). Pregnant animals were vaccinated with 1.0 x 10(4) PFU s.c. at day 42 of gestation, when fetal sensitivity to RVFV vaccine-induced teratogenesis is highest. No febrile reactions, clinical illness, or pregnancy loss was observed following vaccination. Vaccination resulted in a rapid increase in anti-RVFV IgM (day 4) and IgG (day 7) titers. No seroconversion occurred in cohoused control animals. A subset of 20 ewes progressed to full-term delivery after vaccination. All lambs were born without musculoskeletal, neurological, or histological birth defects. Vaccine efficacy was assessed in 9 pregnant animals challenged at day 122 of gestation with virulent RVFV (1.0 x 10(6) PFU intravenously). Following challenge, 100% (9/9) of the animals were protected, progressed to full term, and delivered healthy lambs. As expected, all 3 sham-vaccinated controls experienced viremia, fetal death, and abortion postchallenge. These results demonstrate that the DeltaNSs-DeltaNSm rRVFV vaccine is safe and nonteratogenic and confers high-level protection in sheep. |
Ancient ancestry of KFDV and AHFV revealed by complete genome analyses of viruses isolated from ticks and mammalian hosts.
Dodd KA , Bird BH , Khristova ML , Albarino CG , Carroll SA , Comer JA , Erickson BR , Rollin PE , Nichol ST . PLoS Negl Trop Dis 2011 5 (10) e1352 BACKGROUND: Alkhurma hemorrhagic fever virus (AHFV) and Kyasanur forest disease virus (KFDV) cause significant human disease and mortality in Saudi Arabia and India, respectively. Despite their distinct geographic ranges, AHFV and KFDV share a remarkably high sequence identity. Given its emergence decades after KFDV, AHFV has since been considered a variant of KFDV and thought to have arisen from an introduction of KFDV to Saudi Arabia from India. To gain a better understanding of the evolutionary history of AHFV and KFDV, we analyzed the full length genomes of 16 AHFV and 3 KFDV isolates. METHODOLOGY/PRINCIPAL FINDINGS: Viral genomes were sequenced and compared to two AHFV sequences available in GenBank. Sequence analyses revealed higher genetic diversity within AHFVs isolated from ticks than human AHFV isolates. A Bayesian coalescent phylogenetic analysis demonstrated an ancient divergence of AHFV and KFDV of approximately 700 years ago. CONCLUSIONS/SIGNIFICANCE: The high sequence diversity within tick populations and the presence of competent tick vectors in the surrounding regions, coupled with the recent identification of AHFV in Egypt, indicate possible viral range expansion or a larger geographic range than previously thought. The divergence of AHFV from KFDV nearly 700 years ago suggests other AHFV/KFDV-like viruses might exist in the regions between Saudi Arabia and India. Given the human morbidity and mortality associated with these viruses, these results emphasize the importance of more focused study of these significant public health threats. |
The major determinant of attenuation in mice of the Candid1 vaccine for Argentine hemorrhagic fever is located in the G2 glycoprotein transmembrane domain
Albarino CG , Bird BH , Chakrabarti AK , Dodd KA , Flint M , Bergeron E , White DM , Nichol ST . J Virol 2011 85 (19) 10404-8 Candid1, a live-attenuated Junin virus vaccine strain, was developed during the early 1980s to control Argentine hemorrhagic fever, a severe and frequently fatal human disease. Six amino acid substitutions were found to be unique to this vaccine strain, and their role in virulence attenuation in mice was analyzed using a series of recombinant viruses. Our results indicate that Candid1 is attenuated in mice through a single amino acid substitution in the transmembrane domain of the G2 glycoprotein. This work provides insight into the molecular mechanisms of attenuation of the only arenavirus vaccine currently available. |
Efficient rescue of recombinant Lassa virus reveals the influence of S segment noncoding regions on virus replication and virulence.
Albarino CG , Bird BH , Chakrabarti AK , Dodd KA , Erickson BR , Nichol ST . J Virol 2011 85 (8) 4020-4 Lassa virus (LASV), is a significant cause of severe often fatal hemorrhagic fever in humans throughout western Africa with an estimated 100,000 infections each year. No vaccines are commercially available. We report the development of an efficient reverse genetics system to rescue recombinant LASV and to investigate the contributions of the long 5' and 3' non-coding regions (NCR) of the S genomic segment on in vitro growth and in vivo virulence. This work demonstrates that deletions of large portions of these NCRs confer an attenuated phenotype, and are a first step towards further insights on the high virulence of LASV. |
Reverse genetics generation of chimeric infectious Junin/Lassa virus is dependent on interaction of homologous glycoprotein stable signal peptide and G2 cytoplasmic domains.
Albarino CG , Bird BH , Chakrabarti AK , Dodd KA , White DM , Bergeron E , Shrivastava-Ranjan P , Nichol ST . J Virol 2010 85 (1) 112-22 The Arenaviridae are a diverse and globally distributed collection of viruses that are primarily maintained by rodent reservoirs. Junin virus (JUNV) and Lassa virus (LASV) can both cause significant outbreaks of severe and often fatal human disease throughout their respective endemic areas. In an effort to improve upon the existing live attenuated JUNV Candid 1 vaccine, we generated a genetically homogenous stock of this virus from cDNA copies of the virus S and L segments using a reverse genetics system. Further, these cDNAs were used in combination with LASV cDNAs to successfully generate two recombinant Candid1 JUNV/LASV chimeric viruses (via GPC envelope exchange). It was found that while the GPC extra-virion domains were readily exchangeable, homologous stable signal peptide (SSP) and G2 transmembrane and cytoplasmic tail domains were essential for correct GPC maturation and production of infectious chimeric viruses. The switching of the JUNV and LASV G1/G2 ectodomains within the Candid1 vaccine background did not alter the attenuated phenotype of the vaccine strain in a lethal mouse model. These recombinant chimeric viruses shed light on the fundamental requirements of arenavirus GPC maturation and may serve as a strategy for the development of bivalent JUNV and LASV vaccine candidates. |
- Page last reviewed:Feb 1, 2024
- Page last updated:Jun 17, 2024
- Content source:
- Powered by CDC PHGKB Infrastructure