It must be borne in mind, however, that the rhesus model differs from humans with Lassa fever in their higher mortality rate and the prominence of meningo-encephalomyelitis, pulmonary vascular lesions e. Although Lassa virus is pantropic, the most consistent findings are mild hepatic focal necrosis without significant inflammatory response, some evidence of interstitial edema and focal adrenal cortical necrosis.
In addition even though the liver is the most affected organ, biochemical measures of liver function and the extent of tissue necrosis are inadequate to account for death due to hepatic failure Likewise, the absence of significant disturbances in coagulation makes disseminated intravascular coagulation DIC unlikely as a primary pathologic process. Trombocytopenia is rare, but platelet function is markedly depressed.
The existence of a plasma inhibitor of platelet aggregation has been suggested in patients with Lassa fever 38, 39, 56, There is also evidence for disturbance of endothelial function related to depression in production of prostacyclin in postmortem vascular samples from Lassa infected animals compared to uninfected controls Presumably these changes in vascular function could be enough to account for the failure of integrity in the intravascular compartment leading to edema, shock and effusions observed at the autopsies The viral glycoprotein G2 has been found associated with circulating neutrophils and although the significance of this finding is uncertain since the platelet inhibitor may also affect neutrophil function some consideration should be given to the role of neutrophils in the pathogenesis of severe Lassa fever The use of a BSL-3 virus, LCMV-WE, instead of Lassa, has allowed us to do monkey research at a lower biosafety level, and it is much easier to find facilities that will support this research.
In rhesus and cynomolgus monkeys the infection with the WE strain of LCMV is fatal within two weeks and the disease course resembles the severest form of Lassa fever. Initial leukopenia is followed by a leukocytosis, and primarily neutrophilia as it has been previously observed in Lassa fever infected primates and humans. All monkeys show intradermal hemorrhage petechia and ecchymoses and epistaxis. At the autopsy large effusions have been found and high titers of virus have been detected in all tissues. Junin and Machupo virus infections of non-human primates also simulate the disease in humans, with fever, anorexia, weight loss and gastrointestinal symptoms.
The animals die with cachexia and severe dehydration 11, 52, 84, Most infected monkeys seroconvert with antibodies being detectable by immune-fluorescence or complement fixation. Early antibody responses are neither associated with reduced viremia nor with recovery from disease.
Lassa Virus Genome
In contrast the neutralizing antibody response was undetectable before 45 days, suggesting that neutralizing antibody was not critical to viremia clearance In vitro lymphocyte proliferation tests during the acute phase of the disease show impaired responses to non-specific mitogens suggesting inhibition of lymphocyte function that could explain the lack of inflammatory infiltration observed in tissues from Lassa infected humans and monkeys , Past vaccine studies have suggested an important role the cell-mediated immunity in protection against a lethal challenge with Lassa fever virus LFV in monkeys 59, These suggestions stem from weak humoral responses and highlight the abysmal absence of cell-mediated immunity CMI data in the literature.
A recent study in our laboratory provides the first measure of cytotoxic T lymphocytes CTL responses in monkey surviving lethal exposure to an Old World arenavirus According to this, cytotoxic T lymphocytes would be playing a crucial role in recovery after infection and protection against the otherwise lethal iv challenge with the WE strain of LCMV. This study shows also the ability of the avirulent Arm strain given by iv or intragastric ig routes to cross-protect against lethal challenge with the WE strain.
By performing several immunological measurements of infected monkeys our lab addresses a large gap in the literature. Arenavirus vaccines and treatments The development of a safe and effective vaccine for arenavirus infections of humans has proved difficult. Several killed and live attenuated vaccines have been tested for Lassa, Junin and Machupo viruses, none of which has shown to be suitable for widespread human use.
Many of these vaccines are still in the stage of animal trials. A live attenuated Junin virus vaccine, Candid1, has been shown to be safe and immunogenic in non-human primates 16, 37, Laboratory animals infected with various avirulent viruses serologically related to Lassa virus, including LCMV, Mopeia and Mobala viruses, survived a subsequent challenge with virulent Lassa virus 77, Similar strategies for protection against Junin virus with heterologous live vaccines have repeatedly demonstrated protection against Junin virus in guinea pigs and hamsters Other vaccine trials with inactivated Lassa and Machupo viruses have given mixed results, although they are immunogenic.
Immunization with inactivated Lassa virus protects Papio hamadryas monkeys from a subsequent challenge with Lassa virus 86 , but fails to protect rhesus monkeys even though there is a secondary, high titer antibody response to the major structural proteins of Lassa virus in these vaccinated monkeys Killed antigen vaccine has proved ineffective for Lassa virus and an attenuated virus vaccine is not available; so a live recombinant vaccine provides a very attractive alternative.
Recombinant vaccinia virus vaccines, which express either the Lassa virus nucleoprotein or the glycoprotein gene, successfully protect guinea pigs from a lethal Lassa virus infection, but offer incomplete protection in primates 9, 10, A third of the monkeys were Cynomolgus macaques and the remainder monkeys were Rhesus and all of them were challenged with a lethal dose pfu of Lassa virus Josiah strain.
The data indicate that vaccines delivering all genes of the Lassa S RNA both N and G are more protective than vaccines with only the glycoprotein genes and these later are more protective than vaccines with only the N gene Vaccine trials so far have suggested but not proved that cell-mediated immune response must be activated to protect against challenge with arenaviruses. In this case, low-level immunization may accelerate development of immunopathology.
High dose immune-supression, often mentioned by the Zinkernagel lab, is caused by high viral antigen being inappropriately presented thereby inactivating the cell response This example illustrates the potential value of CTL vaccines and highlights at the same time the limitations of subunit vaccines. To protect an outbred population in an MHC-restricted fashion, it will be necessary to make a vaccine that consists of a cocktail of relevant peptides and to ensure that none of its components aggravates the disease in a subsequent virus challenge.
LCMV-induced persistent infection in mice is a classic example of viral persistence and serves as a model to study basic principles of immune clearance in persistent and disseminated infections in general. This model system makes it possible to test the potential of specific immune therapy to clear virus from a chronically infected host and to study the effector mechanisms responsible for clearing such infections. Volkert was the first to show that the adoptive transfer of spleen cells from LCMV-challenged immune adult mice results in reduction of infectious virus in carrier mice This has been confirmed by a number of workers 1, 3, 13, Nevertheless there is no evidence for persistent arenavirus infection of man and our monkey model is more applicable for the acute human disease.
Clearance of viral materials infectious virus, viral nucleic acid and proteins from several organs of persistently infected mice probably occurs by reconstitution of LCMV-specific CTL that had been deleted during viral infection. The effector mechanisms responsible for eliminating the persistent and disseminated LCMV infection of mice are dependent on the lytic ability of CTL, because perforin-negative transgenic mice are unable to clear infection Likewise, the important role played in protection by the CMI has also been observed through cross-protection experiments carried out using spleen cells from guinea pigs inoculated with Lassa, Mopeia or LCMV Armstrong and syngeneic guinea pig kidney target cells.
Spleen cells from guinea pigs infected with Lassa virus lyse infected kidney cell targets. Unfortunately, adoptive transfer of effector cells has been a failure in human trials 66 and is not really a viable approach for treatment of outbred populations e. Early success of Lassa virus immune plasma in the treatment of Lassa fever 92 and immunotherapy of Machupo virus infections in primates 53 showed promise for the treatment of arenavirus infections in humans. However, better understandings of the limitations of this approach and reduced success in subsequent cases have restricted its use.
Passive antibody therapy depends on collection of plasma from people known to have been infected with the virus, testing the plasma or screening the donor for antibodies to blood-borne agents such as hepatitis and proper storage of plasma until it is used. In summary, research is needed in primate models of acute arenavirus infection to further define vaccines, treatments and immune correlates of protection. The antiviral drug ribavirin has proved effective in the treatment of Lassa fever in laboratory animals 75, 76 and in humans , especially when administered during the first 6 days after the onset of illness.
Later the pathogenesis of the infection is less reversible. Ribavirin is perhaps more effective if given intravenously than orally , It is the drug of choice for treatment and for prophylaxis in cases of possible exposure to Lassa virus, in laboratory or hospitals. Studies with Junin virus infections indicate that ribavirin may also have beneficial effect in Argentine hemorrhagic fever A study for combined antibody and Ribavirin therapy has also been performed in the mouse model and shows that the two treatments are complementary.
References 1. Immune therapy of a persistent and disseminated viral infection. Virus-lymphocyte interaction: T cells of the helper subset are infected with lymphocytic choriomeningitis virus during persistent infection in vivo. J Virol ; Immune T cells can protect or induce fatal neurological disease in murine lymphocytic choriomeningitis.
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Cell Immunol ; Neurol Neurocir Psiquiatr ; J Acquir Immune Defic Syndr ; High genetic divergence and recombination in Arenaviruses from the Americas. Virology ; Armstrong C, Lillie RD. Experimental lymphocytic choriomeningitis of monkeys and mice produced by a virus encountered in studies of the St Louis encephalitis epidemic. Pub Health Rep Washington ; — First outbreak of callitrichid hepatitis in Germany: genetic characterization of the causative lymphocytic choriomeningitis virus strains. Auperin DD. Salvato ed. Construction and evaluation of recombinant virus vaccines for Lassa fever.
Plenum Press, New York, , p. Construction of a recombinant vaccinia virus expressing the Lassa virus glycoprotein gene and protection of guinea pigs from a lethal Lassa virus infection. Virus Res ; Protection of Junin virus-infected marmosets by passive administration of immune serum: association with late neurologic signs.
J Med Virol ; Induction of protective cytotoxic T cells with viral proteins. Eur J Immunol ; Induction or prevention of immunopathological disease by cloned cytotoxic T cell lines specific for lymphocytic choriomeningitis virus. Teratogenic effects of neonatal arenavirus infection on the developing rat cerebellum are abrogated by passive immunotherapy.
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Udem, and M. Infectious measles virus from cloned cDNA. Embo J ; Toward a vaccine against Argentine hemorrhagic fever. Bull Pan Am Health Organ ; Brief report: treatment of a laboratory-acquired Sabia virus infection. N Engl J Med ; Lymphocytic choriomeningitis virus: an unrecognized teratogenic pathogen.
Emerg Infect Dis ; Lymphocytic choriomeningitis in laboratory personnel exposed to hamsters inadvertently infected with LCM virus. J Am Vet Med Assoc ; Effects of promyelocytic leukemia protein on virus-host balance. Infection of lymphocytes by a virus that aborts cytotoxic T lymphocyte activity and establishes persistent infection. J Exp Med ; Oliveros virus: a novel arenavirus from Argentina. Phylogenetic analysis of the Arenaviridae: patterns of virus evolution and evidence for cospeciation between arenaviruses and their rodent hosts. Mol Phylogenet Evol ; The phylogeny of New World Tacaribe complex arenaviruses.
Bridgen A, Elliott RM. Bruns M, Lehmann-Grube F. Lymphocytic choriomeningitis virus. Structural alterations of the virion by treatment with proteolytic enzymes without loss of infectivity. J Gen Virol ; 65 Pt 8 Buchmeier MJ. Arenaviruses: protein structure and function. Curr Top Microbiol Immunol ; Monoclonal antibodies to lymphocytic choriomeningitis and pichinde viruses: generation, characterization, and cross-reactivity with other arenaviruses.
Protein structure and expression among arenaviruses. Identification of alpha-dystroglycan as a receptor for lymphocytic choriomeningitis virus and Lassa fever virus. Science ; Gastric acid secretion in cholera patients. The Whitewater Arroyo virus: natural evidence for genetic recombination among Tacaribe serocomplex viruses family Arenaviridae.
Human-rodent contact and infection with lymphocytic choriomeningitis and Seoul viruses in an inner-city population. Am J Trop Med Hyg ; New arenavirus isolated in Brazil. Lancet ; — Rapid vascular clearance of two strains of Junin virus in Calomys musculinus: selective macrophage clearance. Acta Virol ; A plasma inhibitor of platelet aggregation in patients with Lassa fever.
Br J Haematol ; A plasma inhibitor of platelet aggregation in patients with Argentine hemorrhagic fever. Morphological and cytochemical studies on lymphocytic choriomeningitis virus. In Czech. Experimentalni inhalacni nakaza opic druhu macacus cynomolgus a macacus rhesus virem lymphocitarni choriomeningitidy kmenem WE. Bratisl Lek Listy ; Replication of lymphocytic choriomeningitis virus is restricted in terminally differentiated neurons.
Kinetics and pH dependence of acid-induced structural changes in the lymphocytic choriomeningitis virus glycoprotein complex. Acidic pH triggers LCMV membrane fusion activity and conformational change in the glycoprotein spike. Sequence comparison of the large genomic RNA segments of two strains of lymphocytic choriomeningitis virus differing in pathogenic potential for guinea pigs. Virus Genes ; Mucosal immunization with Salmonella typhimurium expressing Lassa virus nucleocapsid protein cross-protects mice from lethal challenge with lymphocytic choriomeningitis virus.
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Antiviral treatment of Argentine hemorrhagic fever. Some arenaviruses are zoonotic pathogens and are generally associated with rodent —transmitted disease in humans.
Each virus usually is associated with a particular rodent host species in which it is maintained. Arenaviruses persist in nature by infecting rodents first and then transmitted into humans. Humans can be infected through mucosal exposure to aerosols, or by direct contact of abraded skin with the infectious material, derived from infected rodents. Most of the Arenaviruses caught by humans are within their own homes when these rodents seek shelter.
The virus can be caught in factories, from food that has been contaminated, or within agricultural work areas. Humans' risk of contracting the Arenavirus infection is related to age, race, or sex within the degree of contact with the dried rodent excreta. All of these diseases pose a great threat to public health in the regions where it is taking place.
For example, when the Old World Lassa virus turns into Lassa fever, this usually results in a significant amount of mortality. Similarly the New World Junin virus causes Argentine hemorrhagic fever. This fever is a several illness with hemorrhagic and neurological manifestations and a case fatality of fifteen to thirty percent. This traveling has led to the importation of Lassa fever into non-endemic metropolitan areas all over the world. A new species of arenavirus named the Lujo virus has been linked to five patients who exhibited symptoms of viral hemorrhagic fever in South Africa.
The results of genetic sequencing tests conducted by epidemiologists at Columbia University in New York City , USA, and at the Special Pathogens Branch of the Centers for Disease Control in Atlanta , USA, provided evidence that the causative agent of the disease is a virus from the family Arenaviridae, which ultimately resulted in the deaths of four out of the five infected in Zambia and South Africa during the outbreak which began in September Arenavirus has also recently pinpointed as the cause of death of three donor organ recipients in Australia who contracted the virus after receiving kidney and a liver donations from a single infected organ donor in late All three died in the first week of WHO and its Global Outbreak Alert and Response Network GOARN partners continue to support the Ministries of Health of the two countries in various facets of the outbreak investigation, including laboratory diagnosis, investigations, active case finding and follow-up of contacts.
This virus can be very devastating yet there are very few treatment methods available. The current lack of a licensed vaccine and limited therapeutic options for the Arenavirus make it arguably among the most neglected virus to be dealt with. The only licensed drug for the treatment of human Arenavirus infection is the nucleoside analogue ribavirin. Ribavirin displays mixed success in treating severe Arenaviral disease and is associated with significant toxicities.
For this reason high throughput screening HTS of small molecular libraries could be the answer to finding a better remedy. From Wikipedia, the free encyclopedia. May PLoS Pathog. Journal of Virology.
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Retrieved 23 May Stenglein et al. Buchmeier et al. April Genome Biology and Evolution. Retrieved 16 February He is currently using reverse genetics techniques Figure 7 to rescue recombinant viruses carrying mutations on NP that affect its ability to counteract the IFN response and determine its contribution in viral pathogenesis. Figure 7. Arenavirus plasmid-based reverse genetics techniques: Plasmids encoding the viral proteins required for replication and transcription and the two viral RNA segments are co-transfected into BHK21 cells.