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Kyasanur Forest disease (KFD) is a tick-borne, acute, febrile viral illness endemic in southern India. No major studies have been done to understand the adaptive immune response during KFDV infection in humans. In this study, KFDV-positive patients were prospectively enrolled, and repeated peripheral blood collections were performed. Clinical and virologic characterization of these samples is reported along with phenotypic analysis of cellular immunity and quantitation of humoral immunity. We noted robust T and B cell responses, particularly of CD8 T cells, during KFDV infection in most of the patients. Virus clearance from the blood coincided with peak CD8 T cell activation and the appearance of KFDV-specific IgG. Increased frequency of plasmablasts and very few activated B cells were observed in the acute phase of KFD infection. Notably, only humoral immunity and activated B cell frequency in the acute phase correlated with prior KFDV vaccination, and only with 2 or more doses. This novel work has implications in KFD vaccine research as well as in understanding the pathogenesis.

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Kyasanur Forest disease virus (KFDV) is a highly pathogenic tick-borne flavivirus enzootic to India. In humans, KFDV causes a severe febrile disease. In some infected individuals, hemorrhagic manifestations, such as bleeding from the nose and gums and gastrointestinal bleeding with hematemesis and/or blood in the stool, have been reported. However, the mechanisms underlying these hemorrhagic complications remain unknown, and there is no information about the specific target cells for KFDV. We investigated the interaction of KFDV with vascular endothelial cells (ECs) and monocyte-derived dendritic cells (moDCs), which are key targets for several other hemorrhagic viruses. Here, we report that ECs are permissive to KFDV infection, which leads to their activation, as demonstrated by the upregulation of E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 at the mRNA and protein levels. Increased expression of these adhesive molecules correlated with increased leukocyte adhesion. Infected ECs upregulated the expression of interleukin (IL)-6 but not IL-8. Additionally, moDCs were permissive to KFDV infection, leading to increased release of IL-6 and tumor necrosis factor-α. Supernatants from KFDV-infected moDCs caused EC activation, as measured by leukocyte adhesion. The results indicate that ECs and moDCs can be targets for KFDV and that both direct and indirect mechanisms can contribute to EC activation.

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BACKGROUND: Kyasanur forest disease (KFD), a tick-borne viral disease with hemorrhagic manifestations, is localised in five districts of Karnataka state, India. Annual rounds of vaccination using formalin inactivated tissue-culture vaccine have been conducted in the region since 1990. Two doses of vaccine are administered to individuals aged 7-65 years at an interval of one month followed by periodic boosters after 6-9 months. In spite of high effectiveness of the vaccine reported in earlier studies, KFD cases among vaccinated individuals have been recently reported. We analysed KFD vaccination and case surveillance data from 2005 to 2010. METHODOLOGY/PRINCIPAL FINDINGS: We calculated KFD incidence among vaccinated and unvaccinated populations and computed the relative risk and vaccine effectiveness. During 2005-2010, a total of 343,256 individuals were eligible for KFD vaccination (details of vaccination for 2008 were not available). Of these, 52% did not receive any vaccine while 36% had received two doses and a booster. Of the 168 laboratory-confirmed KFD cases reported during this 5-year period, 134 (80%) were unvaccinated, nine each had received one and two doses respectively while 16 had received a booster during the pre-transmission season. The relative risks of disease following one, two and booster doses of vaccine were 1.06 (95% CI = 0.54-2.1), 0.38 (95% CI = 0.19-0.74) and 0.17 (95% CI = 0.10-0.29) respectively. The effectiveness of the vaccine was 62.4% (95% CI = 26.1-80.8) among those who received two doses and 82.9% (95% CI = 71.3-89.8) for those who received two doses followed by a booster dose as compared to the unvaccinated individuals. CONCLUSIONS: Coverage of KFD vaccine in the study area was low. Observed effectiveness of the KFD vaccine was lower as compared to the earlier reports, especially after a single dose administration. Systematic efforts are needed to increase the vaccine coverage and identify the reasons for lower effectiveness of the vaccine in the region.

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In the spring of 1957, an outbreak of severe disease was documented in people living near the Kyasanur forest in Karnataka state, India, which also affected wild nonhuman primates. Collection of samples from dead animals and the use of classical virological techniques led to the isolation of a previously unrecognized virus, named Kyasanur forest disease virus (KFDV), which was found to be related to the Russian spring-summer encephalitis (RSSE) complex of tick-borne viruses. Further evaluation found that KFD, which frequently took the form of a hemorrhagic syndrome, differed from most other RSSE virus infections, which were characterized by neurologic disease. Its association with illness in wild primates was also unique. Hemaphysalis spinigera was identified as the probable tick vector. Despite an estimated annual incidence in India of 400-500 cases, KFD is historically understudied. Most of what is known about the disease comes from studies in the late 1950s and early 1960s by the Virus Research Center in Pune, India and their collaborators at the Rockefeller Foundation. A report in ProMED in early 2012 indicated that the number of cases of KFD this year is possibly the largest since 2005, reminding us that there are significant gaps in our knowledge of the disease, including many aspects of its pathogenesis, the host response to infection and potential therapeutic options. A vaccine is currently in use in India, but efforts could be made to improve its long-term efficacy.

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A 2009 deployment of military units from several Saudi Arabian provinces to Jazan Province, Saudi Arabia, enabled us to evaluate exposure to Alkhurma, Crimean-Congo, dengue, and Rift Valley hemorrhagic fever viruses. Seroprevalence to all viruses was low; however, Alkhurma virus seroprevalence was higher (1.3%) and less geographically restricted than previously thought.

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Kyasanur forest disease (KFD) was first recognised as a febrile illness in the Shimoga district of Karnataka state of India. The causative agent, KFD virus (KFDV), is a highly pathogenic member in the family Flaviviridae, producing a haemorrhagic disease in infected human beings. KFD is a zoonotic disease and has so far been localised only in a southern part of India. The exact cause of its emergence in the mid 1950s is not known. A variant of KFDV, characterised serologically and genetically as Alkhurma haemorrhagic fever virus (AHFV), has been recently identified in Saudi Arabia. KFDV and AHFV share 89% sequence homology, suggesting common ancestral origin. Homology modelling of KFDV envelope (E) protein exhibited a structure similar to those of other flaviviruses, suggesting a common mechanism of virus-cell fusion. The possible mechanism of receptor-ligand interaction involved in infection by KFDV may resemble that of other flavivirses. Present understanding is that KFDV may be persisting silently in several regions of India and that antigenic and structural differences from other tick borne viruses may be related to the unique host specificity and pathogenicity of KFDV. From January 1999 through January 2005, an increasing number of KFD cases have been detected in Karnataka state of Indian subcontinent despite routine vaccination, suggesting insufficient efficacy of the current vaccine protocol. However, the exact cause of the increase of KFD cases needs further investigation. Considering the requirement of safer and more effective vaccines in general, there is clearly a need for developing an alternative vaccine as well as a rapid diagnostic system for KFD. The changing ecology of the prime focus of the KFD also warrants attention, as it may lead to establishment of the disease in newer localities, never reported before.

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With the development and licensure of a recombinant vaccine for the tick-borne infection Lyme disease, more attention has been paid to other vaccines that have been used or are being developed for the prevention of other tick-borne infections. This review highlights vaccine information for Lyme borreliosis, tick-borne encephalitis (TBE), Rocky Mountain spotted fever, tularaemia, Query (Q) fever, Kyasanur Forest disease (KFD) and tick paralysis. Additionally, discussion on the use of immunisation against the tick itself is included which not only can decrease veterinary tick burdens but may also decrease the transmission of arthropod-transmitted diseases.

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Endogenous interferon (IFN) levels were monitored in acute (51) and convalescent phase (19) sera collected from patients suffering from Kyasanur forest disease (KFD). Levels of circulating IFN in the acute samples (GM 216.3 +/- 8.7) collected between 4 to 7 post onset day (POD) were significantly higher (P less than 0.001) than the convalescent samples (GM 13.19 +/- 1.6) collected between 30th to 90th POD. Interferonemia was concomitant with the viraemic phase. Neutralization studies indicated that the endogenous (circulating) IFN was antigenically similar to acid stable form of IFN-alpha.

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In 1957, a fatal disease occurred among monkeys in a forested area of Shimoga District, Karnataka State, India. Concurrently, there was an outbreak of febrile, occasionally fatal illness among people living in the vicinity. The disease was caused by a new tick-borne flavivirus belonging to the Russian spring-summer encephalitis complex of viruses. The early clinical description of the disease included severe cases with hemorrhagic manifestations, including intermittent epistaxis, hematemesis, melena, and frank blood in the stools. Pathologic and hematologic investigations emphasized similarities with Omsk hemorrhagic fever. Two years later there was a shift in clinical emphasis from hemorrhagic to neurologic complications; this could have resulted from the special interests or bias of the principal investigator or the changing patterns of intercurrent infections. Clinical, clinicopathologic, hematologic, and hemostatic features of Kyasanur Forest disease (KFD) are described, particularly in relation to IgE as a cofactor in the immunopathology of KFD and possibly of other hemorrhagic fevers.

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