Crimean congo hemorrhagic fever virus

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Classification

Domain- virus, Phylum- not assigned, Class- not assigned, Order- not assigned, Family- Bunyaviridae, Genus- Nairovirus, Species- Crimean-Congo hemorrhagic fever virus (8)

Description and significance

In the 12th century, a physician in Tadzhikistan described a disease that appeared much like the present day CCHF. The virus came back into attention in 1944-1945 when 200 Soviets were infected while serving in Crimea. At this time it was named Crimean hemorrhagic fever. After research done in 1967 in Moscow it was found out that this virus was the same as the hemorrhagic diseases seen in the Congo and Uganda, and the virus was renamed CHF-Congo virus, but has been adapted to be called Crimean-Congo hemorrhagic fever virus (CCHFV) as a simpler name (10). Crimean-Congo Hemorrhagic Fever (CCHF) is caused by this virus (CCHFV). 1 out of 5 people exposed to the virus get the disease. Depending on the route of transmission, the incubation time varies. The fastest incubation time occurs with tick bites (1-9 days), then by blood (5-6 days), and finally by an infected animal (5-13 days) (8). In general the disease presents itself as influenza in the first 3 days of the onset of infection. The disease progresses into extreme hemorrhaging (2). This results in death in 15-30% of infected patients within the first 5-14 days of the disease. Because the disease progresses so quickly and is easily transmittable if one is not careful, early diagnosis is very important. To diagnosis if a patient has CCHF, a list of symptoms and their history is needed. It is crucial to know if the patient travelled to areas known for tick bites or has had the possibility of being exposed to the blood or tissues of infected livestock or humans. To differentiate between CCHF and other hemorrhagic disease, further evaluation is required. The most resent and preferred method is by reverse transcription PCR that can give a good indication if the individual has the disease within 8 hours (8). Because of this high risk of infection, CCHFV is classified by the CDC as a biosafety level-4 pathogen. This means prevention techniques are of paramount importance. Only labs equipped with the safety regulations for a level-4 pathogen should work with this virus. For the general public, the best way to avoid infection is to avoid exposure. For those working with animals, such as vets and slaughterhouse worker, bare skin should be covered so to limit the possibility of contaminated blood from infecting them. Those in the medical field must also limit contact with CCHF patients. Treatment of livestock with acaricide can kill off ticks and the use of insect repellants can protect against tick bites. Body inspection for tick bites and quick removal of the tick can help protect oneself. Although these protective measures can be taken, in areas where ticks are prevalent it is impossible to completely prevent tick bites and subsequent infection (10).

Genome structure

Crimean-Congo hemorrhagic fever virus has three negative strands of RNA that encode the genetic information. It includes the S (small), M (medium), and L (large) segments. Each segment encodes for different information. The S segment codes for a nucleoprotein, the M segment codes for a glycoprotein precursor, and the L segment codes for RNA polymerase (8). The small segment is a linear piece of single stranded RNA 1,672 nucleotides in length. It has 45% GC content and 86% of the gene is coding. It codes for 1 gene and 1 protein (7). The medium segment is also a linear piece of single stranded RNA but 5,366 nucleotides in length. It has 43% GC content and 94% of the gene is coding. It also codes for 1 gene and 1 protein (6). The long segment, as suggested from the name, is the longest nucleotide sequence of the three. It is a linear single stranded RNA 12,108 nucleotides long. It has 41% GC content and 97% of it is coding. It also encodes for 1 gene and 1 protein (5).

Cell structure, metabolism & life cycle

The virus particle, or virion, is spherical and about 100 nm in diameter. Their outer envelope that acts as a protective layer is derived from their host. It is about 5-7 nm thick and is a lipid bilayer. Through this bilayer, glycoproteins protrude out which are 8-10 nm long. For the CCHFV to continue on, it must replicate its genetic material. It does this by first attaching to the host cell by use of its protruding glycoproteins recognizing receptors on the host cell’s surface (9). It then enters the cell by clathrin-dependent endocytosis resulting in membrane fusion (2). This dumps the RNA polymerase into the cytoplasm of the host. Transcription and translation produce viral proteins and the RNA is replicated as well. Then the new CCHFV buds off through the plasma membrane of the host, ready to enter another cell (10).

The CCHF virus is transmitted to humans via an enzootic tick-vertebrate-tick life cycle in areas where the virus is present. Hard ticks, such as those in the genus Hyalomma, are very susceptible to the CCHF virus. During the entire 2 year life cycle of these ticks, they can have the virus. They are able to transmit the virus both by mother to egg and larvae to adult transmissions. Ticks then infect vertebrates by biting them. Animals such as sheep and cattle amplify the virus and can give it to humans if safe handling of these animals is not done. Other vertebrates such as birds do not show the infection but can be carriers and help in the transmission of the virus (2).

To detect if someone has the virus, a blood sample is required. After viral RNA is isolated, reverse transcription PCR is conducted to see if the RNA is CCHFV RNA. That RNA used to amplify one segment, such as the small segment to fully sequence it to ensure it is CCHFV and to find out what strain it is (1).

Ecology (including pathogenesis)

The habitat in which CCHFV lives in is an animal host. It is transmitted by ticks. It has been identified in over 30 countries in Africa, Asia, southeast Europe, and the Middle East (10). This huge range of regions makes it the most widespread tick-borne virus that affects humans (8).

Once the virus has entered the body by tick bite, infection from an animal, or from infected blood, the virus begins to infect the host. Only humans and newborn mice show the symptoms of infection. Other animals including ticks can carry the disease, but they do not exhibit the symptoms which makes it harder to tell what organisms are infected and thus harder to prevent further infection. The disease is caused by the virus spreading from its original site of infection to the nearby lymph nodes and then the liver and spleen. Here the virus infects macrophages and dendritic cells. The infected macrophages release soluble factors. These cells also release chemokines that stimulate more macrophages to come to the infected cells, allowing the virus to easily infect those macrophages. The combination of these events leads to the apoptosis of lymphocytes. The infection of the hepatocytes, the tissue of the liver, leads to an impairment of the synthesis of clotting factors. Also, because hepatocytes are not functioning as well, there is also a reduced synthesis in albumin which causes weakened plasma osmotic pressure and edema, or swelling of the body due to a build-up of fluids (10). Patients who are exhibiting the symptoms of Crimean-Congo Hemorrhagic Fever will progress through the 4 phases of the illness: incubation, prehemorrhagic, hemorrhagic, and convalescence. Depending on the mode of transmission, the incubation period could be anywhere from 1 to 13 days. The prehemorrhagic phase brings a very high fever of 39-41°C for 5-12 days, chills, severe headache, dizziness, and back and abdominal pains. There is also nausea, vomiting, diarrhea, and a loss of appetite. Some people experience sharp changes in mood and feeling confused and aggressive. If the infection is severe, 3-6 days after the initial symptoms were seen, the patient enters the hemorrhagic phase. This brings petechiae, small red or purple spots of broken blood vessels beneath the skin, ecchymosis, or bruising. The bleeding can be in the form of melena, black fecal bleeding associated with gastrointestinal hemorrhaging, hematemesis, vomiting up of blood from the gastrointestinal tract, and epistaxis, or bleeding from the noise (10). 15-30% of people will die in this phase, but the ones that survive will endter the convalescence phase (8). This is the recovery phase that starts 15-20 after the onset of the illness. It is characterized by weakness, dizziness, poor vision, and a loss of hearing and memory which can last for a year or longer in some cases (10).

Interesting feature

CCHF has a few treatment options, but only recently have studies been conducted to show their efficacy. One option used 3 decades ago was giving the serum of a CCHF infected patient to an infected patient by intramuscular injection. This was proved to help in recovery, but it had to be administered early on in the progression of the disease. The treatment currently used is ribavirin. It has been seen that intravenous administration of ribavirin is a good treatment in viral hemorrhagic fevers. It is absorbed through the gastrointestinal tract. It has now been shown that both intravenous and oral ribavirin is a good treatment of CCHF, having an 80% success rate (4). Unfortunately, ribavirin’s mechanism of action is unknown except for the fact that it seems to have antiviral properties (3).

References

(1) Aradaib, Imadeldin E. "Nosocomial Outbreak of Crimean-Congo Hemorrhagic Fever, Sudan." Emerging Infectious Diseases 16.5 (2010). May 2010. Web. 1 Nov. 2011. <http://wwwnc.cdc.gov/eid/article/16/5/pdfs/09-1815.pdf>. (2) Connolly-Andersen, Anne-Marie. "Pathogenesis of an Emerging Pathogen- Crimean-Congo Hemorrhagic Fever Virus." (2010). Karolinska Institutet, 2010. Web. 31 Oct. 2011. <http://publications.ki.se/jspui/bitstream/10616/40313/1/Anne-Marie%20Connolly-Andersen%20Bok%20bib.pdf>. (3) Flora, Kenneth D. "How Does Ribavirin Work?" Journal Watch Specialties. Massachusetts Medical Society, 12 May 2004. Web. 1 Nov. 2011. <http://gastroenterology.jwatch.org/cgi/content/full/2004/512/4>. (4) Mardani, M., M. Keshtkar Jahromi, K. Holakouie Naieni, and M. Zeinali. "The Efficacy of Oral Ribavirin in the Treatment of Crimean‐Congo Hemorrhagic Fever in Iran." Clinical Infectious Diseases 36.12 (2003): 1613-618. 15 June 2003. Web. 1 Nov. 2011. <http://cid.oxfordjournals.org/content/36/12/1613.full.pdf>. (5) NCBI. "Crimean-Congo Hemorrhagic Fever Virus Segment L, Complete Sequence." NCBI. Department of Health and Human Services. Web. 31 Oct. 2011. <http://www.ncbi.nlm.nih.gov/genome?Db=genome&Cmd=ShowDetailView&TermToSearch=17506>. (6) NCBI. "Crimean-Congo Hemorrhagic Fever Virus Segment M, Complete Sequence." NCBI. Department of Health and Human Services. Web. 31 Oct. 2011. <http://www.ncbi.nlm.nih.gov/genome?Db=genome&Cmd=ShowDetailView&TermToSearch=17505>. (7) NCBI. "Crimean-Congo Hemorrhagic Fever Virus Segment S, Complete Sequence." NCBI. Department of Health and Human Services. Web. 31 Oct. 2011. <http://www.ncbi.nlm.nih.gov/genome?Db=genome&Cmd=ShowDetailView&TermToSearch=17507>. (8) "Virus Taxonomy: 2009 Release." International Committee on Taxonomy of Viruses. 2010. Web. 31 Oct. 2011. <http://www.ictvonline.org/virusTaxonomy.asp?src=NCBI&ictv_id=20073306>. (9) Wattam, Rebecca. "Crimean-Congo Hemorrhagic Fever (CCHF) Virus." CyberInfrastructure Group. Virginia Bioinformatics Institute Phase I, 06 Sept. 2006. Web. 01 Nov. 2011. <http://ci.vbi.vt.edu/pathinfo/pathogens/CCHF.html>. (10) Whitehouse, Chris A. "Crimean Congo Hemorrhagic Fever." Antiviral Research 64.3 (2004): 145-60. ScienceDirect. Web. 31 Oct. 2011. <http://www.sciencedirect.com/science/article/pii/S0166354204001639>.