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1.
The results of the isolation and identification of the causative agent of a haemorrhagic fever outbreak in the Stavropol Territory are presented. The virus isolated from blood of haemorrhagic fever patients by virological methods was identified in serological and molecular tests as Crimean haemorrhagic fever virus. This epidemiological analysis testify to increased activity of the natural focus of Crimean-Congo haemorrhagic fever in this area due to a number of natural and other factors leading to intensification of its epidemic realization.  相似文献   

2.
After the prolonged (about 30 years) absence of Crimean-Congo hemorrhagic fever (CCHF) morbidity in the Stavropol territory cases of this infection were registered, and received laboratory confirmation, in summer of 1999-2000. At the end of the 1999 season antibodies to CCHF virus were detected among cattle-breeders in all 7 inspected regions of the territory. According to the data of the determination of virus contamination of Ixodes ticks (the season of 2000), the circulation of CCHF on the territory of 14 regions out of 24 expected was established. An essential factor of the exacerbation of the epidemic situation was a rise in the number of Hyalomma marginatum ticks, the main vector of the causative agent of CCHF in the south of Russia.  相似文献   

3.

Background

Crimean-Congo hemorrhagic fever (CCHF) is a severe tick-borne disease well recognized through Europe and Asia where diagnostic tests and medical surveillance are available. However, it is largely neglected in Africa, especially in the tropical rainforest of Central Africa where only sporadic human cases have been reported and date back to more than 30 years. We describe here an isolated human case that occurred in the Democratic Republic of the Congo in 2008 and performed phylogenetic analysis to investigate whether it resulted from a regional re-emergence or from the introduction of a novel virus in the area.

Methods and Findings

Near complete segment S and partial segment M sequences were characterized. Bayesian phylogenetic analysis and datation were performed to investigate the relationship between this new strain and viral strains from Africa, Europe and Asia. The new strain is phylogenetically close to the previously described regional genotype (II) that appears to be specific to Central Africa. Phylogenetic discrepancy between segment S and M suggested genetic exchange among local sublineages, which was dated back to 130–590 years before present.

Conclusions

The phylogenetic analyses presented here suggest ongoing CCHF virus circulation in Central Africa for a long time despite the absence of reported human cases. Many infections have most probably been overlooked, due to the weakness of healthcare structures and the absence of available diagnostic procedure. However, despite the lack of accurate ecological data, the sporadic reporting of human cases could also be partly associated with a specific sylvatic cycle in Central Africa where deforestation may raise the risks of re-emergence. For these reasons, together with the high risk of nosocomial transmission, public health authorities'' attention should be drawn to this etiological agent.  相似文献   

4.
Crimean-Congo hemorrhagic fever (CCHF) is an increasing health concern in Turkey since 2002. There were also some recent human cases from the South Marmara region of Turkey; thus, a tick survey was performed, and possible vector tick species for the CCHF virus were determined in the region. A total of 740 adult ticks were collected from infested livestock from five locations: Çanakkale-Biga, Bursa-Orhaneli, Bursa-Keles, Bal?kesir and Bilecik. Total of 11 tick species from the genera Hyalomma, Rhipicephalus, Dermacentor, Ixodes and Haemaphysalis were identified. Rhipicephalus ticks were dominant in the region; the most frequently observed tick species was R. turanicus, (53.1 %), and only 15.4 % of the identified ticks were H. marginatum. The occurrence of H. rufipes infestation in the region fort he first time. A total of 73 pools of adult ticks were tested with both an antigen-detecting ELISA and RT real-time PCR (RT rt PCR). The presence of the CCHF virus was demonstrated in 9 (12.3 %) of the tested tick pools. Although seven of the tick pools were positive for the CCHF virus with both of the methods, one pool was positive only with RT rt PCR and the other pool was only positive with the ELISA. Positive results were obtained from ticks collected from cattle, sheep and goats from two locations, Bursa-Orhaneli and Bilecik. The CCHF virus was detected in R. turanicus (n = 3), R. bursa (n = 2), H. marginatum (n = 2) and D. marginatus (n = 2) ticks. The results of this study confirm the presence of the CCHF virus and present preliminary data on the vector tick species in the southern Marmara region of Turkey.  相似文献   

5.
Crimean-Congo hemorrhagic fever virus (CCHFV) belongs to the genus Nairovirus within the family Bunyaviridae and is the causative agent of severe hemorrhagic fever. Despite increasing knowledge about hemorrhagic fever viruses, the factors determining their pathogenicity are still poorly understood. The interferon-induced MxA protein has been shown to have an inhibitory effect on several members of the Bunyaviridae family, but the effect of MxA against CCHFV has not previously been studied. Here, we report that human MxA has antiviral activity against CCHFV. The yield of progeny virus in cells constitutively expressing MxA was reduced up to 1,000-fold compared with control cells, and accumulation of viral genomes was blocked. Confocal microscopy revealed that MxA colocalizes with the nucleocapsid protein (NP) of CCHFV in the perinuclear regions of infected cells. Furthermore, we found that MxA interacted with NP by using a coimmunoprecipitation assay. We also found that an amino acid substitution (E645R) within the C-terminal domain of MxA resulted in a loss of MxA antiviral activity and, concomitantly, in the capacity to interact with CCHFV NP. These results suggest that MxA, by interacting with a component of the nucleocapsid, prevents replication of CCHFV viral RNA and thereby inhibits the production of new infectious virus particles.  相似文献   

6.
The RNA virus that causes the Crimean Congo Hemorrhagic Fever (CCHF) is a tick-borne pathogen of the Nairovirus genus, family Bunyaviridae. Unlike many zoonotic viruses that are only passed between animals and humans, the CCHF virus can also be transmitted from human to human with an overall mortality rate approaching 30%. Currently, there are no atomic structures for any CCHF virus proteins or for any Nairovirus proteins. A critical component of the virus is the envelope Gn glycoprotein, which contains a C-terminal cytoplasmic tail. In other Bunyaviridae viruses, the Gn tail has been implicated in host-pathogen interaction and viral assembly. Here we report the NMR structure of the CCHF virus Gn cytoplasmic tail, residues 729-805. The structure contains a pair of tightly arranged dual ββα zinc fingers similar to those found in the Hantavirus genus, with which it shares about 12% sequence identity. Unlike Hantavirus zinc fingers, however, the CCHF virus zinc fingers bind viral RNA and contain contiguous clusters of conserved surface electrostatics. Our results provide insight into a likely role of the CCHF virus Gn zinc fingers in Nairovirus assembly.  相似文献   

7.
8.
Crimean-Congo hemorrhagic fever virus (CCHFV) is an etiological agent of a disease with mortality rates in patients averaging 30%. The disease is characterized by fever, myalgia, and hemorrhage. Mechanisms underlying the hemorrhage have to our knowledge not been elucidated for CCHFV. Possibly, a direct or indirect viral effect on tight junctions (TJ) could cause the hemorrhage observed in patients, as TJ play a crucial role in vascular homeostasis and can cause leakage upon deregulation. Moreover, there is no knowledge regarding the site of entry and release of CCHFV in polarized epithelial cells. Such cells represent a barrier to virus dissemination within the host, and as a site of viral entry and release, they could play a key role in further spread. For the first time, we have shown preferential basolateral entry of CCHFV in Madin-Darby canine kidney 1 (MDCK-1) epithelial cells. Furthermore, we demonstrated basolateral release of CCHFV in polarized epithelial cells. Interestingly, by measuring transepithelial electrical resistance, we found no effect of CCHFV replication on the function of TJ in this study. Neither did we observe any difference in the localization of the TJ proteins ZO-1 and occludin in CCHFV-infected cells compared to mock-infected cells.  相似文献   

9.
Regulation of apoptosis during infection has been observed for several viral pathogens. Programmed cell death and regulation of apoptosis in response to a viral infection are important factors for host or virus survival. It is not known whether Crimean-Congo hemorrhagic fever virus (CCHFV) infection regulates the apoptosis process in vitro. This study for the first time suggests that CCHFV induces apoptosis, which may be dependent on caspase-3 activation. This study also shows that the coding sequence of the S segment of CCHFV contains a proteolytic cleavage site, DEVD, which is conserved in all CCHFV strains. By using different recombinant expression systems and site-directed mutagenesis, we demonstrated that this motif is subject to caspase cleavage. We also demonstrate that CCHFV nucleocapsid protein (NP) is cleaved into a 30-kDa fragment at the same time as caspase activity is induced during infection. Using caspase inhibitors and cells lacking caspase-3, we clearly demonstrate that the cleavage of NP is caspase-3-dependent. We also show that the inhibition of apoptosis induced progeny viral titers of ~80-90%. Thus, caspase-3-dependent cleavage of NP may represent a host defense mechanism against lytic CCHFV infection. Taken together, these data suggest that the most abundant protein of CCHFV, which has several essential functions such as protection of viral RNA and participation in various processes in the replication cycle, can be subjected to cleavage by host cell caspases.  相似文献   

10.
Crimean-Congo hemorrhagic fever (CCHF) virus is a tick-borne, negative-sense, single-stranded RNA [ssRNA(−)] nairovirus that produces fever, prostration, and severe hemorrhages in humans. With fatality rates for CCHF ranging up to 70% based on several factors, CCHF is considered a dangerous emerging disease. Originally identified in the former Soviet Union and the Congo, CCHF has rapidly spread across large sections of Europe, Asia, and Africa. Recent reports have identified a viral homologue of the ovarian tumor protease superfamily (vOTU) within its L protein. This protease has subsequently been implicated in downregulation of the type I interferon immune response through cleavage of posttranslational modifying proteins ubiquitin (Ub) and the Ub-like interferon-simulated gene 15 (ISG15). Additionally, homologues of vOTU have been suggested to perform similar roles in the positive-sense, single-stranded RNA [ssRNA(+)] arteriviruses. By utilizing X-ray crystallographic techniques, the structure of vOTU covalently bound to ubiquitin propylamine, a suicide substrate of the enzyme, was elucidated to 1.7 Å, revealing unique structural elements that define this new subclass of the OTU superfamily. In addition, kinetic studies were carried out with aminomethylcoumarin (AMC) conjugates of monomeric Ub, ISG15, and NEDD8 (neural precursor cell expressed, developmentally downregulated 8) substrates in order to provide quantitative insights into vOTU''s preference for Ub and Ub-like substrates.Crimean-Congo hemorrhagic fever (CCHF) is characterized in humans by the sudden onset of fever, myalgia, headache, dizziness, sore eyes, photophobia, and hyperanemia as well as severe hemorrhages (28, 43, 46). The causative agent of CCHF is the CCHF virus, which is a tick-borne, negative-sense, single-stranded RNA [ssRNA(−)] virus of the genus Nairovirus, belonging to the viral family Bunyaviridae. Originally named after outbreaks in the former Soviet Union and in the Congo during the mid-20th century, the affected area of this disease has rapidly spread to large areas of sub-Saharan Africa, the Balkans, Northern Greece, European Russia, Pakistan, the Arabian Peninsula, Iran, Afghanistan, Iraq, Turkey, and recently, the Xinjiang province of China (43, 46). The CCHF viral genome, as well as those of the closely related Dugbe and Nairobi viruses, consists of three negative-sense RNA segments, small (S), medium (M), and large (L). Incubation of CCHF is 5 to 6 days, with fatalities occurring less than 7 days after signs of infection. Fatality rates for patients infected with the CCHF virus ranged from 5% to 70%, depending on phylogenetic variation of the virus, transmission route, treatment facility, and the reporting and confirmation of the case statistics (19, 32, 43, 47).The innate immune system serves as the human''s first line of defense from invading pathogens, including CCHF virus. The type I interferon (IFN) response comprises a key component of this system by upregulating more than 300 IFN-stimulated genes (ISGs) whose products detect viral molecules, promote amplification of the type I IFN response, modulate other signaling pathways, and directly provide antiviral activity (34). Regulation of the type I IFN response has been shown to rely on posttranslational modification by ubiquitin (Ub) and the Ub-like interferon-simulated gene 15 (ISG15) (14, 23). Both Ub and ISG15 are expressed in a proform and cleaved to leave a double-glycine C terminus that forms an isopeptide bond with predominantly the ɛ-NH2 of lysine residues of a target protein through a three-step enzymatic process. In addition to forming isopeptide bonds with target proteins, Ub, which contains seven lysine residues, has been observed to form poly-Ub chains. The most studied of these moieties are K29-linked, K48-linked, and K63-linked poly-Ub. While K29-linked and K48-linked polyubiquitination of proteins leads to their degradation in the lysosome and proteasome, respectively, conjugation of K63-linked poly-Ub to proteins has an activating effect, resulting in an enhanced type I IFN response (2, 7, 18, 33, 40). Currently, more than 150 proteins have been identified as forming conjugates with ISG15, with the number of proteins forming Ub conjugates far exceeding that number (12, 48). A subset of type I IFN signaling and effector proteins that Ub and ISG15 have been shown to stabilize includes JAK1, STAT1/2, double-stranded RNA-dependent protein kinase (PKR), myxovirus-resistant protein A (MxA), and RIG-I (17). MxA has particularly shown to be important in type I IFN response to CCHF infection. RIG-I and several other proteins have also been shown to be targets for K63-linked poly-Ub (4).Recently, investigators have identified a cysteine viral ovarian tumor domain (vOTU) protease colocated with the RNA-dependent RNA polymerase in the L protein of the CCHF virus (14). Interestingly, as CCHF is an ssRNA(−) virus, no protease is required to cleave a viral polypeptide to facilitate viral replication as in positive-sense ssRNA [ssRNA(+)] viruses. Furthermore, recent reports have observed that vOTU is not required for RNA-dependent RNA polymerase activity and for vOTU protease activity linked to impairment of the type I IFN response through its deubiquitinating and deISGylating activity (6, 14). Additional studies have also tentatively identified the presence of vOTU homologues in the Arterivirus genus of the Arteriviridae family, suggesting that they too may facilitate impairment of the type I IFN response (14). Since the discovery of the first ovarian tumor domain (OTU) protease in Drosophila oogenesis and prior to the identification of vOTU, OTU superfamily members could be divided into three subclasses according to their sequence homology, otubains, A20-like OTUs, and ubiquitin thioesterase ZRANB1 (22). With the addition of the viral OTU subclass, OTU superfamily members in more than 100 eukaryotic, bacterial, and viral proteins have now been identified (6, 27). Predominantly, OTU proteases have been linked to ubiquitin (Ub) removal and/or remodeling of Ub-conjugated proteins, placing them among five protease superfamilies that facilitate signal transduction cascades and play key roles in protein stability (22). However, vOTU is unique in that it is the only OTU to have shown both deubiquitinating and deISGylating activity (14). Instead, Otubain1/2 (OTUB1/2) plays a key role in T cell response and prefers K48-linked poly-Ub or NEDD8 (neural precursor cell expressed, developmentally downregulated 8) as a substrate (12). A20 and A20-like Cezanne OTU proteases are negative regulators of the NF-κB-mediated inflammation response, selectively cleaving K63-linked poly-Ub targets. DUBA also shows preference for K63-linked poly-Ub (20). In attempts to better understand the OTU superfamily, structures of OTUB and A20-like OTU domains have been elucidated (12, 21, 30). An X-ray structure of the yeast ovarian tumor 1 (yOTU1) domain, which interacts with Cdc48 and has a preference for K48-linked poly-Ub, was achieved in complex with mono-Ub (27). However, since yOTU1 has a preference for K48-linked Ub and possesses low sequence identity to vOTU and other OTU domain proteases, only limited information on vOTU could be obtained. In addition to vOTU, several other viral proteases, such as papain-like protease (PLpro) from the severe acute respiratory syndrome (SARS) coronavirus, have also shown deubiquitinating and deISGylating activity to evade the innate immune system (6, 8, 43, 49). However, no viral proteases that are known to possess deISGylating activity have been visualized as being bound to Ub or Ub-like substrates. To address this issue and elucidate the atomic-level structure of a member from the viral OTU superfamily subclass, we have obtained the X-ray crystal structure of vOTU bound with Ub (vOTU-Ub). We also have characterized the vOTU substrate specificity for mono-Ub, ISG15, and NEDD8 and compared the results with those from human OTUB2 (hOTUB2). Additionally, we assessed vOTU''s deubiquitinating activity toward K48- and K63-linked poly-Ub.  相似文献   

11.
12.
The structural glycoproteins of Crimean-Congo hemorrhagic fever virus (CCHFV; genus Nairovirus, family Bunyaviridae) are derived through endoproteolytic cleavage of a 1,684-amino-acid M RNA segment-encoded polyprotein. This polyprotein is cotranslationally cleaved into the PreGN and PreGC precursors, which are then cleaved by SKI-1 and a SKI-1-like protease to generate the N termini of GN and GC, respectively. However, the resulting polypeptide defined by the N termini of GN and GC is predicted to be larger (58 kDa) than mature GN (37 kDa). By analogy to the topologically similar M segment-encoded polyproteins of viruses in the Orthobunyavirus genus, the C-terminal region of PreGN that contains four predicted transmembrane domains may also contain a nonstructural protein, NSM. To characterize potential PreGN C-terminal cleavage events, a panel of epitope-tagged PreGN truncation and internal deletion mutants was developed. These constructs allowed for the identification of a C-terminal endoproteolytic cleavage within, or very proximal to, the second predicted transmembrane domain following the GN ectodomain and the subsequent generation of a C-terminal fragment. Pulse-chase experiments showed that PreGN C-terminal cleavage occurred shortly after synthesis of the precursor and prior to generation of the GN glycoprotein. The resulting fragment trafficked to the Golgi compartment, the site of virus assembly. Development of an antiserum specific to the second cytoplasmic loop of PreGN allowed detection of cell-associated NSM proteins derived from transient expression of the complete CCHFV M segment and also in the context of virus infection.  相似文献   

13.
14.
15.
16.
The results of the epidemiological analysis of the outbreak of hemorrhagic fever which was caused by Crimean-Congo hemorrhagic fever virus and occurred during the period of July 3-19, 1999, in the Oblivskaya district of Rostov Province are presented. The specific epidemiological features of the outbreak have been determined. The possible versions of the appearance of the focus of infection and the role of Ixodes ticks in the circulation of the infective agent are discussed.  相似文献   

17.
In this article, we published the role of three species of ticks Amblyomma variegatum (Fabricius, 1974), Hyalomma marginatum rufipes (Koch, 1844) and Hyalomma truncatum (Koch, 1844) in the maintenance and transmission of the CCHF virus. The imagos of these species were infected by intracoelomic route. Vertical transmission (transtasial and transovarial) and horizontal transmission for different stases were studied by isolation on newborn mice, polymerase chain reaction, indirect immunofluorescence and ELISA. Our results proved that 15 days after inoculation, infection rates of 100% were noted with Hyalomma marginatum rufipes and Hyalomma truncatum. This rate is about 60% for Amblyomma variegatum. The imagos of the three species infected have transmitted the virus to their host during blood feeding (100%). A high transovarial transmission for Hyalomma marginatum rufipes and Hyalomma truncatum were observed (respectively 53 and 50%). This rate is about 12% for Amblyomma variegatum. The tick infection does not persist up to the first generation for the three species studied. Ticks are temporary reservoirs vectors but not permanent reservoirs of CCHF virus.  相似文献   

18.
Parasitological data, the results of virological and serological investigations of materials, collected in nature and during the study of the immune structure of the population and indicative of the circulation of CCHF, virus in the Crimea and the possibility of human infection, are presented. The data on the spontaneous CCHF virus infection of 4 tick species belonging to the genus Ixodes have been confirmed, and evidence on the participation of Dermacentor marginatus in this process obtained for the first time in this region. The study has revealed for the first time that, besides European brown hares, scilly shrews, common voles and field mice may contribute to the maintenance of the natural foci of this infection. The low activity of the Crimean focus of CCHF may be the result of the intensive use of land, the widely spread stall-feeding of cattle, as well as a sharp decrease in the number of hares on the territories of hunting preserves.  相似文献   

19.
20.
A new formula for the calculation of the endemicity index of the territory affected by hemorrhagic fever with renal syndrome (HFRS) based on empiric data collected in the Volga region near Saratov in 1982-2000 is proposed. As found in this research 21% of the administrative districts of the region have a high endemicity level (with the average index for several years reaching 35 points), 8% of the districts have a medium enemicity level (20 points) and 71% of the districts--a low endemicity level (9 points). It is pointed out that under conditions of financial constraints territories with high and medium endemicity levels should be first examined for HFRS; these territories should also be given priority in prophylactic deratization in the field and human settlements.  相似文献   

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