Tick-borne flaviviruses.

There has been a remarkable increase in tick-borne flaviviral disease incidence throughout the past 2 decades. Transmission of tick-borne viruses, like other vector-borne agents, is impacted by a very broad set of factors, both natural (eg, climate and ecology) and man-made (eg, human mobility and agricultural patterns). As our encroachment into areas of virus endemicity intensifies, and as changes in global economic and environmental conditions continue to promote the expansion of tick populations, we will undoubtedly continue to observe attendant increases in rates of disease attributable to these vector-borne pathogens. This article focuses on a some of the major tick-borne flaviviral diseases, caused in particular by tick-borne encephalitis virus, louping ill virus, Powassan virus, Kyasanur Forest disease virus, and Omsk hemorrhagic fever virus, as well as their subtypes.

Usutu virus infection in a patient who underwent orthotropic liver transplantation, Italy, August-September 2009.

We report a case of Usutu virus (USUV)-related illness in a patient that underwent an orthotropic liver transplant (OLT). Post transplant, the patient developed clinical signs of a possible neuroinvasive disease with a significant loss of cerebral functions. USUV was isolated in Vero E6 cells from a plasma sample obtained immediately before the surgery, and USUV RNA was demonstrated by RT-PCR and sequencing. This report enlarges the panel of emerging mosquito-borne flavivirus-related disease in humans.

Innate resistance to flavivirus infections and the functions of 2'-5' oligoadenylate synthetases.

Mouse susceptibility to experimental infections with flaviviruses is significantly influenced by a cluster of genes on chromosome 5 encoding a family of proteins with enzymatic properties, the 2'-5' oligoadenylate synthetases (OAS). Positional cloning of the locus in question has revealed that susceptibility of laboratory inbred strains to this class of virus is associated with a nonsense mutation in the gene encoding the OAS1B isoform. Analysis of the molecular structure of the cluster in different mammalian species including human indicates that the cluster is extremely polymorphic with a highly variable number of genes and pseudogenes whose functions are not yet completely established. Although still preliminary, a few recent observations also substantiate a possible role for OAS1 in human susceptibility to viral infections (West Nile virus, SARS, etc.) and its possible involvement in some other diseases such as type 1 diabetes and multiple sclerosis. Finally, convergent observations indicate that the molecules encoded by the 2 '-5' OAS cluster might be involved in other fundamental cellular functions such as cell growth and differentiation, gene regulation, and apoptosis.

Secuencias de infección viral asociadas a la fiebre del dengue durante la epidemia de dengue 3 en la ciudad de La Habana, 2001-2002 / Viral infection sequences related to dengue fever in dengue 3 epidemics occurred in the City of Havana, 2001-2002

Objetivo: estudiar el papel de la infección secundaria y de la influencia de determinadas secuencias de infección virales en los casos de fiebre del dengue durante la epidemia de dengue 3, en la ciudad de La Habana, 2001-2002. Métodos: se estudiaron 141 muestras clínicas de casos confirmados de dengue en la epidemia cubana dengue 3. Todos los casos incluidos fueron clasificados de acuerdo con el criterio de la OMS como casos de fiebre del dengue, 101 de estas muestras fueron colectadas en la fase aguda de la enfermedad y 40 colectadas en la fase convaleciente tardía (16-18 meses después de la enfermedad). Resultados: los sueros colectados en la fase convaleciente tardía permitieron conocer las secuencias virales de infección, las cuales en orden descendiente fueron DEN-1/DEN-3, DEN-2/DEN-3 y DEN-1/DEN-2/DEN-3. Conclusiones: los resultados confirman que la secuencia de infección DEN-2/DEN-3 estuvo asociada a los casos de fiebre del dengue y no a los de fiebre hemorrágica del dengue; un porcentaje elevado de los casos estudiados se correspondió con una infección secundaria.

Objective: To study the role of secondary infection and of certain viral infection sequences in dengue fever cases during the dengue 3 epidemics occurred in the City of Havana. Methods: One hundred and forty one laboratory-confirmed clinical samples from dengue 3 cases were studied. According to WHO criteria, all included cases were classified as dengue fever cases; 101 of these samples were collected at the acute phase of the disease whereas 40 were collected in the late convalescence (16 to 18 months after the onset of disease). Results: The late convalescence serum samples allowed identifying the viral dengue infection sequences, which in downward order were DENV-1/DENV-3, DENV-2/DENV-3 and DENV-1/DENV-2/DENV-3. Conclusions: The results confirmed that the sequence infection DENV-2 / DENV-3 was associated with Dengue Fever Cases but not with the Dengue Hemorrhagic Fever Cases and that a high percentage of studied cases proved to be secondary infection.

Secuencias de infección viral asociadas a la fiebre del dengue durante la epidemia de dengue 3 en la ciudad de La Habana, 2001-2002 / Viral infection sequences related to dengue fever in dengue 3 epidemics occurred in the City of Havana, 2001-2002

Objetivo: estudiar el papel de la infección secundaria y de la influencia de determinadas secuencias de infección virales en los casos de fiebre del dengue durante la epidemia de dengue 3, en la ciudad de La Habana, 2001-2002. Métodos: se estudiaron 141 muestras clínicas de casos confirmados de dengue en la epidemia cubana dengue 3. Todos los casos incluidos fueron clasificados de acuerdo con el criterio de la OMS como casos de fiebre del dengue, 101 de estas muestras fueron colectadas en la fase aguda de la enfermedad y 40 colectadas en la fase convaleciente tardía (16-18 meses después de la enfermedad). Resultados: los sueros colectados en la fase convaleciente tardía permitieron conocer las secuencias virales de infección, las cuales en orden descendiente fueron DEN-1/DEN-3, DEN-2/DEN-3 y DEN-1/DEN-2/DEN-3. Conclusiones: los resultados confirman que la secuencia de infección DEN-2/DEN-3 estuvo asociada a los casos de fiebre del dengue y no a los de fiebre hemorrágica del dengue; un porcentaje elevado de los casos estudiados se correspondió con una infección secundaria(AU)

Objective: To study the role of secondary infection and of certain viral infection sequences in dengue fever cases during the dengue 3 epidemics occurred in the City of Havana. Methods: One hundred and forty one laboratory-confirmed clinical samples from dengue 3 cases were studied. According to WHO criteria, all included cases were classified as dengue fever cases; 101 of these samples were collected at the acute phase of the disease whereas 40 were collected in the late convalescence (16 to 18 months after the onset of disease). Results: The late convalescence serum samples allowed identifying the viral dengue infection sequences, which in downward order were DENV-1/DENV-3, DENV-2/DENV-3 and DENV-1/DENV-2/DENV-3. Conclusions: The results confirmed that the sequence infection DENV-2 / DENV-3 was associated with Dengue Fever Cases but not with the Dengue Hemorrhagic Fever Cases and that a high percentage of studied cases proved to be secondary infection(AU)

Complement and its role in protection and pathogenesis of flavivirus infections.

The complement system is a family of serum and cell surface proteins that recognize pathogen-associated molecular patterns, altered-self ligands, and immune complexes. Activation of the complement cascade triggers several antiviral functions including pathogen opsonization and/or lysis, and priming of adaptive immune responses. In this review, we will examine the role of complement activation in protection and/or pathogenesis against infection by Flaviviruses, with an emphasis on experiments with West Nile and Dengue viruses.

[Global warming: trailblazer for tropical infections in Germany?]. / Globale Erwärmung: Wegbereiter für tropische Infektionskrankheiten in Deutschland?

Since 1850, the CO (2) content of the atmosphere has increased from 280 to 360 ppm, and the average surface temperature has risen from 14.6 to 15.3 C . A further increase between 1.8 and 4.0 C is expected for the 21st century. Temperate and cold climate zones are affected predominantly, but tropical regions are not spared. At the same time, the world wide climate effects of the "El Niño Southern Oscillation" are amplified. Global warming enhances the growth of tropical pathogens (malarial plasmodia, leishmania, yellow fever virus, dengue virus, West Nile virus, Vibrio cholerae) and vectors (anopheles, aedes, culex, and phlebotomus mosquitos; hard ticks). Global warming may lead to the emergence of diseases which at present are not endemic in Germany, like West Nile fever, Dengue fever, or Leishmaniases, and to enhanced transmission of borreliosis and tick-borne encephalitis. Malaria and cholera, in contrast, are influenced more strongly by socioeconomic factors. Improved surveillance and intensified research on the relationship between climate change and infectious diseases is needed.

Secretion of flaviviral non-structural protein NS1: from diagnosis to pathogenesis.

Flaviviruses are major arthropod-borne human pathogens responsible for life-threatening encephalitis, hepatitis and haemorrhagic fevers. These enveloped, single-stranded, positive-sense RNA viruses encode a polyprotein precursor of about 3400 amino acids, processed into three structural and seven non-structural proteins. The non-structural glycoprotein NS1 is essential for flavivirus viability. During host-cell infection in vitro, NS1 is found associated with intracellular organelles as a requisite for its role in viral replication, or is transported to the cell surface where it may trigger specific signalling pathways. In addition, a secreted form of the protein is released from flavivirus-infected mammalian cells. We have previously shown that the NS1 protein circulates during the acute phase of the disease in the plasma of patients infected with dengue virus type 1 and have extended our retrospective studies to dengue type 2 and type 3 cohorts, confirming the value of the NS1 antigen as an alternative diagnostic marker. Interestingly, detection of the NS1 protein in yellow fever virus and West Nile virus infections suggests that NS1 secretion is a hallmark of human flavivirus infections. The objectives of our current studies are to define the biological properties of the secreted form of the NS1 protein, to evaluate its possible contribution to viral pathogenesis, and to validate this protein as a candidate target for passive immunoprophylaxis against flaviviruses.

Immune modulation by flaviviruses.

Flaviviruses cause pleomorphic disease with significant morbidity and mortality worldwide. Interestingly, in contrast to most viruses, which subvert or avoid host immune systems, members of the neurotropic Japanese encephalitis serocomplex cause functional changes associated with increased efficacy of the immune response. These viruses induce increased cell surface expression of immune recognition molecules, including class I and II major histocompatibility complex (MHC) and various adhesion molecules. Increases are functional: infected cells are significantly more susceptible to both virus- and MHC-specific cytotoxic T cell lysis. Induced changes are modulated positively or negatively by Th1 and Th2 cytokines, as well as by cell cycle position and adherence status at infection. Infection also increases costimulatory molecule expression on Langerhans cells in the skin. Local interleukin-1 beta production causes accelerated migration of phenotypically altered Langerhans cells to local draining lymph nodes, where initiation of antiviral immune responses occur. The exact mechanism(s) of upregulation is unclear, but changes are associated with NF-kappa B activation and increased MHC and ICAM-1 gene transcription, independently of interferon (IFN) or other proinflammatory cytokines. Increased MHC and adhesion molecule expression may contribute to the pathogenesis of flavivirus encephalitis. Results from a murine model of flavivirus encephalitis developed in this laboratory suggest that fatal disease is immunopathological in nature, with IFN-gamma playing a crucial role. We hypothesize that these viruses may decoy the adaptive immune system into generating low-affinity T cells, which clear virus poorly, as part of their survival strategy. This may enable viral growth and immune escape in cycling cells, which do not significantly upregulate cell surface molecules.

Tick-borne flaviviruses.

Tick-borne encephalitis (TBE), one of the most dangerous neuroinfections in Europe and Asia, is caused by tick-borne encephalitis virus (TBEV) and currently involves approximately 11,000 human cases annually, mostly in Russia. This chapter describes the main problems associated with the epidemiology, ecology, pathogenesis, and control of this disease. We have attempted to review the factors that influence the incidence and distribution of TBE, and to discuss possible reasons for the different clinical manifestations including most commonly observed asymptomatic infections, fever forms, acute encephalitis, and the less frequently registered biphasic milk fever and chronic encephalitis. Epidemiologic data concerning the other tick-borne flaviviruses, namely Louping ill virus, Langat virus, and Powassan virus that also produce encephalitis on a smaller scale, are also presented. Here we describe the history and current epidemiological role of Omsk hemorrhagic fever virus and Kyasanur forest disease virus, two viruses that are genetically closely related to TBEV, but produce hemorrhagic fever instead of encephalitis, and provide possible explanations for these differences. The other viruses in the tick-borne flavivirus group are also included despite the fact that they do not play an essential epidemiologic role in humans. This chapter contains a brief history of vaccination against TBE including the trials with live attenuated vaccine and reviews the modern trends in development of vaccine virus strains.

Detection of transfusion-associated hepatitis caused by non-A, non-B, non-C flavivirus.

Sera of patients suffering from acute hepatitis, and different forms of chronic hepatitis were found to be reactive to reagents prepared from the yellow fever virus (YF) vaccine strain. Serum samples of 1974 patients were tested, and 133 of them were positive. Hepatitis C virus specific antibodies were absent from the majority of them. The frequency of antibodies to other flaviviruses (tick-borne encephalitis, West Nile) and hepatitis B virus markers was similar to that measured among the population in Hungary positive for any of the surrogate markers of hepatitis infections. Results of both immunofluorescence tests, and Western blots suggest that there is a non-A, non-B, non-C hepatitis virus circulating among the Hungarian population, which possesses antigenic cross-reactivity with the yellow fever virus, but the identity to any of the known flaviviruses could not be verified yet. No history of yellow fever vaccination could be revealed in any of the patients included into this study. The anamnestic data on previous transfusions or surgical operations can be verified only in the case of the half of YFV-positive patients, nevertheless, the sexual transmission seems to be very infrequent. Attempts are continued in order to detect the viral RNA using polymerase chain reaction, and clone cDNA sequences for sequence analysis.