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PubMed2004

Rodent models for the study of therapy against flavivirus infections.

Flaviviruses cause a variety of diseases including (meningo)encephalitis and hemorrhagic fevers. There is no specific antiviral therapy available for the treatment of infections with flaviviruses and such therapy should be urgently developed. Small animal models that are reminiscent of the disease in man will be instrumental to identify therapeutic strategies against flavivirus infections. Here we review models in mice and hamsters that may be used to assess the efficacy of novel antiviral strategies against flavivirus infections.

Animals↗
PubMedDate not supplied

[Effectiveness of the interferon inducers ridostin and camedon in prevention and treatment of experimental alpha- and flavivirus infections].

Antiviral activity of rybamidil (virasol) and interferon inducers ridostine and camedone developed in Russia and introduced in practical medicine has been studied in mice with experimentally induced arboviral infections, flavivirus (tick-borne encephalitis-TBE, and yellow fever-YF) and alphavirus ones (Western and Eastern equine encephalomyelitis-WEE and EEE). Rybamidil injected subcutaneously proved to be ineffective both for prevention and treatment of these infections. Early interferon inducers ridostine and camedone (larifan) with a peak of interferon production 4 hours after injection, when used in doses of 5 and 150 mg/ kg, respectively, had a clear-cut prophylactic antiviral effect if injected 24 or 4 hours before infection. Ridostine had a distinct antiviral effect, providing up to 40% protection from TBE, YF, and WEE.

Acridines↗
PubMed2002

Reactivity of serum samples from patients with a flavivirus infection measured by immunofluorescence assay and ELISA.

Flavivirus infections are a significant public health problem, since several members of the Flaviviridae family are highly pathogenic to humans. Accurate diagnosis and differentiation of the infecting virus is important, especially in areas where many flaviviruses are circulating. In this study we evaluated a newly developed commercially available immunofluorescence assay (IFA) (INDX, Baltimore, MD, USA) for the detection of IgM and IgG antibodies against dengue virus, yellow fever virus, Japanese encephalitis virus and West Nile virus. IFA was compared with standard diagnostic enzyme immunoassays (EIAs) specific for the detection of IgM and IgG antibodies against these viruses. Forty-seven serum samples from patients with a defined flavivirus infection were tested. As controls, serum samples from individuals with antibodies against tick-borne encephalitis virus and hepatitis C virus as well as healthy individuals were included. The results obtained from this study indicate that IFA showed a significantly better discrimination for flavivirus specific IgM antibodies than did the standard IgM specific EIAs (the overall cross-reactivity varied between 4 and 10% by IFA and 30-44% by EIA for the respective viruses). In contrast, the detection of flavivirus specific IgG antibodies showed high cross-reactions in both IFA and EIAs (overall cross-reactivity 16-71 and 62-84%, respectively). This study clearly stated the complexity of flavivirus diagnosis, showing that one cannot rely on one assay or search for one virus only. The flavivirus IFA is a useful tool for the identification of flavivirus infections during the acute stage of disease. In particular, IFA can be an important diagnostic tool for testing samples from travellers who have been accidentally exposed to these viruses.

Antibodies, Viral↗
PubMed1998

Genetic control of host resistance to flavivirus infection in animals.

Flaviviruses are small, enveloped RNA viruses which are generally transmitted by arthropods to animals and man. Although flaviviruses cause important diseases in domestic animals and man, flaviviral infection of animals which constitute the normal vertebrate reservoir may be mild or sub-clinical, which suggests that some adaptation between virus and host may have occurred. While this possibility is difficult to study in wild animals, extensive studies using laboratory mice have demonstrated the existence of innate, flavivirus-specific resistance. Resistance is heritable and is attributable to the gene Flvr, which is located on chromosome 5 in this species. The mechanism of resistance is at present unknown, but acts early and limits the replication of flaviviruses in cells. While some evidence supports a role for Flvr in enhancing the production of defective interfering virus, thereby restricting the production of infectious virus, other reports suggest that Flvr interferes with either virus RNA replication or RNA packaging. Recent research suggests that cytoplasmic proteins bind to the viral replication complex and that allelic forms of these proteins in resistant mice may restrict the production of infectious progeny. Apparent resistance to flaviviruses has been described in other vertebrates, although it remains to be seen if this is attributable to a homologue of Flvr. Nonetheless, knowledge gained of the characteristics and function of Flvr in mice should be applicable to other host species, and improvement of resistance to flaviviral infection in domestic animals by selective breeding or gene technology may ultimately be possible.

Animals↗
PubMed2001

Modulation of transporter associated with antigen processing (TAP)-mediated peptide import into the endoplasmic reticulum by flavivirus infection.

In contrast to many other viruses that escape the cellular immune response by downregulating major histocompatibility complex (MHC) class I molecules, flavivirus infection can upregulate their cell surface expression. Previously we have presented evidence that during flavivirus infection, peptide supply to the endoplasmic reticulum is increased (A. Müllbacher and M. Lobigs, Immunity 3:207-214, 1995). Here we show that during the early phase of infection with different flaviviruses, the transport activity of the peptide transporter associated with antigen processing (TAP) is augmented by up to 50%. TAP expression is unaltered during infection, and viral but not host macromolecular synthesis is required for enhanced peptide transport. This study is the first demonstration of transient enhancement of TAP-dependent peptide import into the lumen of the endoplasmic reticulum as a consequence of a viral infection. We suggest that the increased supply of peptides for assembly with MHC class I molecules in flavivirus-infected cells accounts for the upregulation of MHC class I cell surface expression with the biological consequence of viral evasion of natural killer cell recognition.

ATP-Binding Cassette Transporters↗
PubMed2005

Development of immunoglobulin M capture enzyme-linked immunosorbent assay to differentiate human flavivirus infections occurring in Australia.

We report the development of a flavivirus immunoglobulin M (IgM) capture enzyme-linked immunosorbent assay (MAC-ELISA) which improves the determination of an infecting flavivirus serotype over that by current serological methods. A panel of 165 IgM-positive sera from flavivirus patients with specific diagnostic results was tested by the flavivirus MAC-ELISA using a panel of 10 antigens. For 134 of these sera (81.2%), the highest reactivity was demonstrated against the infecting virus, which was consistent with the original diagnostic result. Specific antibody reactions inconsistent with the original diagnosis were found for six sera (3.6%). In our experience, the flavivirus-serotyping ELISA provides a rapid and accurate alternative to other serological tests, such as hemagglutination inhibition, for the specific diagnosis of flavivirus infections.

Antibodies, Viral↗
PubMed2001

Innate resistance to flavivirus infection in mice controlled by Flv is nitric oxide-independent.

Innate resistance to flaviviruses in mice is active in the brain where it restricts virus replication. This resistance is controlled by a single genetic locus, FLV, located on mouse chromosome 5 near the locus encoding the neuronal form of nitric oxide synthase (Nos1). Since nitric oxide (NO) has been implicated in antiviral activity, its involvement in natural resistance to flaviviruses has been hypothesized. Here we present data on NO production before and during flavivirus infection in both brain tissue and peritoneal macrophages from two flavivirus-resistant (FLV(r)) and one congenic susceptible (FLV(s)) mouse strains. This study provides evidence that NO is not involved in the expression of flavivirus resistance controlled by FLV since: (a) there is no difference in brain tissue NO levels between susceptible and resistant mice, and (b) lipopolysaccharide-induced NO does not abrogate the difference in flavivirus replication in peritoneal macrophages from susceptible and resistant mice.

Animals↗
PubMed2005

[Flavivirus infections: yellow fever, dengue fever and Japanese encephalitis].

Flavivirus infections, such as dengue fever, yellow fever and Japanese encephalitis, are untreatable. As a result of the high prevalence of dengue fever in endemic areas, it poses a substantial risk for travellers to those areas. When it comes to Japanese encephalitis and yellow fever, the risk for travellers is limited but the diseases are extremely serious, creating a dilemma for the physician when it comes to deciding whether to vaccinate against them. The vaccines against both potentially have side effects. The indications and contraindications for vaccination are described in detail.

Adult↗
PubMed1986

Changes of natural killer cell activity in different mouse lines by acute and asymptomatic flavivirus infections.

Effect of certain flaviviruses on the activity of mouse natural killer (NK) cells was investigated using the classical mouse splenocyte system and YAC-1 cells for demonstration of NK cell cytotoxicity. Infection of mice with Langat and West Nile (WN) viruses was accompanied by temporary activation of NK cells. In mice infected with tick-borne encephalitis (TBE) virus the stimulation phase of NK cell cytotoxicity on days 2-4 post-infection (p.i.) was followed by suppression of their activity. As to the surface markers (sensitivity to antitheta and antiimmunoglobulin serum, respectively), the flavivirus-activated NK cells did not differ from the endogenous NK cells of intact mice. The stimulatory effect of flaviviruses on cytotoxicity of NK cells varied in different mouse lines. An increased NK cell activity at early stages of TBE virus infection was observed in mouse lines characterized by low (C57B1/6) and medium (BALB/c)--but not by high (CBA)-activity of their non-stimulated NK cells. Suppression of NK cell activity at later stages of TBE virus infection was not associated with virus multiplication in mouse splenocytes.

Acute Disease↗
PubMed1975

The damaging action of cellular immunity in flavivirus infections of mice.

The development of acute infections caused by different flaviviruses was studied in immunosuppressed inbred and non-inbred mice. Cyclophosphamide treatment of challenged animals resulted in an increase of the mean survival time by 24--144 hours in some but not all virus-mouse strain combinations. The transient protective action of cyclophosphamide was not due to suppression of the reproduction of tick-borne encephalitis (TBE) or dengue 2 (D2) virus in the brains of mice. In TBE or D2 infections of immunosuppressed mice the clinical signs of central nervous system lesions seemed to be associated with the development of cellular immunity measured by the splenobyte migration inhibition test. The transfer of sensitized splenocytes in immunosuppressed animals, challenged with TBE or D2 virus, shortened the incubation period. These results suggest that cellular immunity may have a damaging effect in acute flavivirus infections in mice, and also that the immunopathological response varies considerably in different strains of inbred mice.

Acute Disease↗
PubMed1998

Development of viremia and humoral and cellular parameters of immune activation after vaccination with yellow fever virus strain 17D: a model of human flavivirus infection.

To monitor early and late events of immune system activation after primary and secondary flavivirus infection, 17 healthy persons were vaccinated with the standard 17D vaccine virus strain of yellow fever (YF). Twelve of these persons had not received YF vaccine previously and 5 had been vaccinated once at least 10 years before. Viremia and various parameters of humoral and cellular immune activation were followed daily for 7 days and weekly thereafter. Viremia was detected by reverse transcriptase-polymerase chain reaction in all 12 first-time vaccinees beginning from the second to the sixth day after vaccination; most tested positive between the fourth and sixth day. Infectious 17D virus was detected using a plaque forming assay in the serum of 7 of the 12 first-time vaccinees. As first parameters of immune activation, neopterin and beta2-microglobulin markedly increased between day 2 and day 6 postvaccination. In parallel to the viremia, circulating CD8+ T-cells significantly increased, with peak levels at day 5 after primary vaccination, indicating an activation of the cellular immune system. Neither viremia nor significant changes of these activation markers were observed in the five revaccinated persons. Neutralizing antibodies directed against the 17D vaccine strain developed in all persons within 2 weeks after vaccination. No correlation was found between the extent of viremia and the titer of neutralizing antibodies. Revaccination was followed by a minor and transient increase of neutralizing antibodies. High titers of neutralizing antibodies persisted for at least 10 years after primary vaccination.

Adolescent↗
PubMed1986

Single-radial-haemolysis test for diagnosing flavivirus infections, particularly Japanese encephalitis.

Use of the single-radial-haemolysis (SRH) technique for the diagnosis of flavivirus infections is described. A large number of paired and single convalescent serum samples collected from cases of encephalitis during two major outbreaks in Kolar district of Karnataka State in India during 1977 and 1979 were tested by this technique. The results were compared with those obtained in the haemagglutination inhibition (HI) test in all cases, and the complement fixation (CF) and neutralization tests in some cases. Japanese encephalitis virus was shown by the SRH test to be the major etiologic agent responsible for both epidemics. This was corroborated by the HI, CF and neutralization test results. The single-radial-haemolysis test was found to be simpler and more specific and sensitive than the haemagglutination inhibition test.

Encephalitis, Japanese↗
PubMedDate not supplied

Trends in flavivirus infections in Japan.

Although Japanese encephalitis has declined as an important cause of illness and death in Japan, infection with other flaviviruses has become a public health concern. Recently, reports of imported dengue cases, as well as isolations of tick-borne encephalitis virus, have increased.

Dengue↗
PubMed2003

Acute encephalitis, a poliomyelitis-like syndrome and neurological sequelae in a hamster model for flavivirus infections.

Infection of hamsters with the murine flavivirus Modoc results in (meningo)encephalitis, which is, during the acute phase, frequently associated with flaccid paralysis, as also observed in patients with West Nile virus encephalitis. Twenty percent of the hamsters that recover from the acute encephalitis develop life-long neurological sequelae, reminiscent of those observed, for example, in survivors of Japanese encephalitis. Magnetic resonance imaging and histology revealed severe lesions predominantly located in the olfactory-limbic system, both in hamsters with acute encephalitis as in survivors. Prominent pathology was also detected in the spinal cord of hamsters with paralysis. Modoc virus infections in hamsters provide a unique model for the study of encephalitis, a poliomyelitis-like syndrome and neurological sequelae following flavivirus infection.

Animals↗
PubMed1999

Markers for trans-Golgi membranes and the intermediate compartment localize to induced membranes with distinct replication functions in flavivirus-infected cells.

Replication of the flavivirus Kunjin virus is associated with virus-induced membrane structures within the cytoplasm of infected cells; these membranes appear as packets of vesicles associated with the sites of viral RNA synthesis and as convoluted membranes (CM) and paracrystalline arrays (PC) containing the components of the virus-specified protease (E. G. Westaway, J. M. Mackenzie, M. T. Kenney, M. K. Jones, and A. A. Khromykh, J. Virol. 71:6650-6661, 1997). To determine the cellular origins of these membrane structures, we compared the immunolabelling patterns of several cell markers in relation to these sites by immunofluorescence and immunoelectron microscopy. A marker for the trans-Golgi membranes and the trans-Golgi network, 1,4-galactosyltransferase (GalT), was redistributed to large foci in the cytoplasm of Kunjin virus-infected cells, partially coincident with immunofluorescent foci associated with the putative sites of viral RNA synthesis. As determined by immunoelectron microscopy, the induced vesicle packets contained GalT, whereas the CM and PC contained a specific protein marker for the intermediate compartment (ERGIC53). A further indicator of the role of cellular organelles in their biogenesis was the observation that the Golgi apparatus-disrupting agent brefeldin A prevented further development of immunofluorescent foci of induced membranes if added before the end of the latent period but that once formed, these membrane foci were resistant to brefeldin A dispersion. Reticulum membranes emanating from the induced CM and PC were also labelled with the rough endoplasmic reticulum marker anti-protein disulfide isomerase and were obviously redistributed during infection. This is the first report identifying trans-Golgi membranes and the intermediate compartment as the apparent sources of the flavivirus-induced membranes involved in events of replication.

Animals↗
PubMed2001

A novel model for the study of the therapy of flavivirus infections using the Modoc virus.

The murine Flavivirus Modoc replicates well in Vero cells and appears to be as equally sensitive as both yellow fever and dengue fever virus to a selection of antiviral agents. Infection of SCID mice, by either the intracerebral, intraperitoneal, or intranasal route, results in 100% mortality. Immunocompetent mice and hamsters proved to be susceptible to the virus only when inoculated via the intranasal or intracerebral route. Animals ultimately die of (histologically proven) encephalitis with features similar to Flavivirus encephalitis in man. Viral RNA was detected in the brain, spleen, and salivary glands of infected SCID mice and the brain, lung, kidney, and salivary glands of infected hamsters. In SCID mice, the interferon inducer poly IC protected against Modoc virus-induced morbidity and mortality and this protection was associated with a reduction in infectious virus content and viral RNA load. Infected hamsters shed the virus in the urine. This allows daily monitoring of (inhibition of) viral replication, by means of a noninvasive method and in the same animal. The Modoc virus model appears attractive for the study of chemoprophylactic or chemotherapeutic strategies against Flavivirus infections.

Animals↗
PubMed1994

Studies on serological cross-reaction in sequential flavivirus infections.

Acute- and convalescent-phase sera from patients with dengue (DEN) hemorrhagic fever (DHF) and Japanese encephalitis (JE) that contained pre-existing flavivirus antibodies were tested for cross-reacting antibodies to DEN, JE and yellow fever (YF) viruses by a neutralization (N) test. A fourfold or greater rise in N antibody titer in the convalescent-phase was considered significant. Of 39 DHF cases, obtained at Chiang Mai University Hospital, Thailand, 15 (38.5%) showed a rise in DEN antibody titer, while another 15 (38.5%) showed a significant rise in both DEN and JE N antibody titers. On the other hand, eight (61.5%) of 13 JE cases obtained at the same Hospital, showed a significant rise in JE antibody titer, while two (15.4%) showed a significant rise in both DEN and JE antibody titers. Sucrose gradient centrifugation and fractionation of these two cross-reactive JE sera revealed that IgM class antibody was specific for JE, while IgG class antibody was cross-reactive. Of three JE cases with pre-existing YF antibody obtained in Okinawa, Japan, two showed a significant rise in YF and JE antibodies. Both IgM and IgG class antibodies to YF virus were elevated. These results indicate that the cross-reactivity among flaviviruses in different subgroups (complexes), was observed quite often, even by the N test, in sequential flavivirus infection.

Acute Disease↗