Crimean-Congo Hemorrhagic Fever Virus- An Overview

Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is a tick-borne virus that belongs to the family Bunyaviridae and the genus Nairovirus. It is the causative agent of a severe and often fatal disease in humans, known as Crimean-Congo Hemorrhagic Fever (CCHF).

CCHFV has a spherical shape and measures approximately 90 to 120 nm in diameter with 5-10 nm projections visible on the surface. These projections are formed by two glycoproteins, Gn and Gc, which are responsible for receptor binding and entry into host cells. CCHFV is an enveloped virus, meaning it has a lipid bilayer membrane that surrounds its nucleocapsid.

The nucleocapsid of CCHFV contains a tripartite, segmented, negative-sense RNA genome. The genome consists of three segments: large (L), medium (M) and small (S), which are associated with proteins to form ribonucleoproteins (RNPs). The L segment encodes the RNA-dependent RNA polymerase (RdRp), which is involved in transcription and replication of the viral RNA. The M segment encodes the glycoproteins Gn and Gc, as well as a non-structural protein GP38, which is secreted by infected cells and has an unknown function. The S segment encodes the nucleoprotein (N), which binds to the viral RNA and forms the core of the nucleocapsid.

The genome segments of CCHFV have terminal, complementary nucleotide sequences that are conserved among nairoviruses. These sequences serve as promoters for the RdRp and also facilitate the packaging and reassortment of the segments during viral assembly.

The structure of CCHFV is shown in Figure 1.

Figure 1: Structure of CCHFV. Source: Nature Reviews Microbiology

Crimean-Congo Hemorrhagic Fever Virus (CCHFV) belongs to the genus Nairovirus and the family Bunyaviridae. Like all bunyaviruses, CCHFV has a tripartite, linear, single-stranded RNA genome of negative polarity. The genome consists of three segments: large (L), medium (M), and small (S), which are encapsidated by the nucleoprotein (N) and associated with the RNA-dependent RNA polymerase (L protein).

The L segment is about 12 kb in length and encodes the L protein, which is responsible for the transcription and replication of the viral RNA. The L protein also has cap-snatching activity, which allows it to acquire a 5` cap from host mRNA for the initiation of viral mRNA synthesis.

The M segment is about 6.8 kb in length and encodes two glycoproteins (G1 and G2), which are embedded in the viral envelope and mediate the attachment and entry of the virus into host cells. The M segment also encodes a non-structural protein (NSm), which may play a role in virus assembly and budding.

The S segment is about 3 kb in length and encodes only the N protein, which forms the nucleocapsid with the viral RNA segments. The N protein also interacts with the L protein and regulates its activity.

The three segments of CCHFV have conserved terminal sequences that are complementary to each other and serve as promoters for transcription and replication. The segments also have different copy numbers in the virion, with the S segment being the most abundant, followed by the M segment and then the L segment.

CCHFV exhibits a high degree of genetic diversity due to its error-prone RNA polymerase, frequent reassortment of its segmented genome, and adaptation to different hosts and vectors. CCHFV strains can be classified into seven distinct genotypes based on their S segment sequences: Africa 1, Africa 2, Africa 3, Asia 1, Asia 2, Europe 1, and Europe 2. These genotypes have different geographic distributions, host ranges, and pathogenicities.

Crimean-Congo hemorrhagic fever (CCHF) is a zoonotic disease that affects humans and animals. The virus is endemic in Africa, Asia, Europe and the Middle East, where it circulates among ticks and various wild and domestic vertebrates. The geographic distribution of CCHF corresponds to the presence of suitable tick vectors, mainly of the genus Hyalomma.

The disease was first described in the Crimea in 1944, where it caused an outbreak among agricultural workers. It was later identified as the same virus that caused a sporadic case in the Congo in 1956. Since then, CCHF has been reported in more than 30 countries, with outbreaks occurring periodically in some regions.

The incidence and prevalence of CCHF vary depending on the ecological and climatic factors that influence the abundance and activity of ticks, as well as the human exposure to tick bites or infected animals. The disease is more common in rural areas where people have frequent contact with livestock or wildlife. The risk of infection is highest during the spring and summer months, when ticks are most active.

The case fatality rate of CCHF ranges from 10% to 40%, depending on the virus strain, the host factors and the quality of medical care. The disease can cause severe hemorrhagic manifestations and multi-organ failure in some patients. There is no specific treatment or vaccine available for CCHF, and prevention relies on avoiding tick bites and contact with infected animals or humans.

Crimean-Congo hemorrhagic fever virus (CCHFV) is mainly transmitted to humans by the bites of infected ticks, especially those of the genus Hyalomma. These ticks are widely distributed in Africa, Asia, and Europe, and can feed on a variety of wild and domestic animals, such as cattle, sheep, goats, and hares. These animals can serve as amplifying hosts for the virus, but they do not show any apparent signs of disease.

Another mode of transmission is through direct contact with the blood or tissues of infected animals during or after slaughter. This can pose a risk for people who work in the livestock industry, such as farmers, herders, veterinarians, and slaughterhouse workers. People who handle raw meat or animal products from endemic areas may also be exposed to the virus.

Human-to-human transmission can also occur when there is close contact with the blood, secretions, organs, or other bodily fluids of infected persons. This can happen in health care settings, where improper sterilization of medical equipment, reuse of injection needles, and contamination of medical supplies can result in nosocomial outbreaks. It can also happen in household or community settings, where family members or caregivers may come into contact with infected patients.

The risk of transmission is higher when the patient is in the later stages of the disease, when bleeding and hemorrhage may occur. The virus can also be transmitted through sexual contact or breastfeeding. However, there is no evidence of airborne transmission or transmission by mosquitoes or other insects.

Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is an enveloped virus with a tripartite, negative-sense RNA genome. The genome consists of three segments: large (L), medium (M) and small (S), which encode for the RNA-dependent RNA polymerase (L protein), the glycoproteins (G1 and G2) and the nucleoprotein (N protein), respectively.

The replication process of CCHFV can be summarized as follows:

• CCHFV binds to an unknown cellular receptor and enters the host cell by clathrin-mediated endocytosis.
• The virus particles are transported to early endosomes and then to multivesicular bodies (MVBs), where the viral envelope fuses with the endosomal membrane and releases the ribonucleoprotein complexes (RNPs) into the cytoplasm.
• The L protein binds to the leader sequence at the 3` end of each genomic segment and initiates transcription of viral mRNAs, which are capped by a cap-snatching mechanism that involves cleavage of host mRNAs by the L protein.
• The viral mRNAs are translated into the N, L, and G proteins in the cytoplasm. The N protein forms a complex with the genomic RNA segments and protects them from degradation. The G protein precursor (GPC) is translocated into the endoplasmic reticulum (ER) and cleaved by host proteases into G1 and G2.
• The L protein also binds to the leader sequence at the 5` end of each antigenomic segment and initiates replication of the viral genome. The antigenome is concomitantly encapsidated by the N protein and serves as a template for synthesis of more genomic segments.
• The newly synthesized RNPs associate with the G proteins at the ER-Golgi intermediate compartment (ERGIC) and bud into vesicles that acquire a lipid envelope. The vesicles are transported to the plasma membrane and released by exocytosis.

The replication cycle of CCHFV is illustrated in Figure 1.

Figure 1: Replication cycle of Crimean-Congo Hemorrhagic Fever Virus. Adapted from .

Crimean-Congo hemorrhagic fever (CCHF) is caused by infection with a tick-borne virus (Nairovirus) in the family Bunyaviridae. The disease is characterized by high fever, bleeding disorders, and multiorgan failure. The pathogenesis of CCHF is not fully understood, but it is likely a result of the direct injury of virus-infected tissues and the indirect effects of host immune responses.

The virus enters the human body through the bite of an infected tick or contact with infected animal blood or body fluids. The virus then infects various cell types, such as endothelial cells (ECs), macrophages, dendritic cells, hepatocytes, and lymphocytes. The virus replicates in the cytoplasm of these cells and produces viral proteins and genomic segments that are assembled into new virions and released by budding or cell lysis.

The infection of ECs is thought to play a key role in the pathogenesis of CCHF, as it leads to endothelial activation, dysfunction, and damage. This results in increased vascular permeability, edema, hemorrhage, and hypotension. The virus also induces the expression of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), on ECs. These molecules attract and activate immune cells, such as neutrophils, monocytes, and natural killer cells, which further contribute to endothelial injury and inflammation.

The infection of immune cells also affects the pathogenesis of CCHF, as it modulates the innate and adaptive immune responses. The virus can impair the antiviral activity of interferons (IFNs) by inhibiting their production or signaling pathways. The virus can also delay the induction of specific antibodies and cytotoxic T cells by partially activating dendritic cells and macrophages. Moreover, the virus can induce apoptosis of lymphocytes and hemophagocytosis of blood cells by macrophages. These mechanisms lead to immunosuppression, uncontrolled viral replication, systemic spread of the virus, and increased susceptibility to secondary infections.

The pathogenesis of CCHF is also influenced by viral factors, such as genetic diversity and reassortment. The virus has three genomic segments (L, M, and S) that can vary in their nucleotide sequences among different isolates. This diversity may affect the virulence, antigenicity, and host range of the virus. Reassortment occurs when two different viruses infect the same cell and exchange their genomic segments during replication. This may generate novel viruses with different phenotypes and fitness.

In summary, the pathogenesis of CCHF is a complex process that involves multiple interactions between the virus and the host. The virus infects various cell types and causes direct tissue damage and indirect immune-mediated effects. The virus also modulates the host immune responses and exhibits genetic diversity and reassortment. These factors determine the severity and outcome of CCHF.

Crimean-Congo Hemorrhagic Fever (CCHF) is a severe viral disease that can affect humans and animals. The clinical manifestations of CCHF vary from mild to fatal, depending on the host factors, viral load, and immune response.

The incubation period of CCHF is usually 3 to 21 days after exposure to the virus, either by tick bite or contact with infected blood or tissues. The onset of symptoms is sudden and abrupt, with fever, headache, malaise, myalgia, sore throat, dizziness, abdominal pain, nausea, vomiting, conjunctivitis, and photophobia. These symptoms are non-specific and can mimic other febrile illnesses.

As the disease progresses, some patients may develop hemorrhagic manifestations, such as petechiae, ecchymoses, epistaxis, gingival bleeding, hematemesis, hemoptysis, melena, hematuria, and vaginal bleeding. These signs indicate damage to the vascular endothelium and coagulation system. Hemorrhage can also occur internally, leading to retroperitoneal or intracranial bleeding.

Other signs and symptoms that may occur in CCHF include jaundice, hepatosplenomegaly, lymphadenopathy, rash, flushing, red eyes, red throat, confusion, mood changes, sensory disturbances, and coma. The severity of symptoms may vary depending on the organ involvement and the degree of shock.

The case fatality rate of CCHF ranges from 10% to 40%, depending on the outbreak and the quality of care. Death usually occurs within the second week of illness due to multiorgan failure, disseminated intravascular coagulation (DIC), or circulatory collapse. Survivors may recover slowly and experience weakness, fatigue, depression, memory loss, or hearing impairment.

CCHF is a serious and potentially fatal disease that requires early diagnosis and supportive treatment. There is no specific antiviral therapy or vaccine available for CCHF. Prevention and control measures include avoiding tick bites, wearing protective clothing and gloves when handling animals or their products, and applying standard precautions when caring for patients with suspected or confirmed CCHF.

Crimean-Congo hemorrhagic fever (CCHF) virus infection can be diagnosed by several different laboratory tests that can detect the presence of the virus or its antibodies in blood or tissue samples. The most commonly used tests are:

• Antigen-capture enzyme-linked immunosorbent assay (ELISA): This test can detect viral antigens (proteins) in the blood or tissue samples of patients during the acute phase of the disease. It is a rapid and sensitive test that can confirm the diagnosis of CCHF within hours.
• Reverse transcriptase polymerase chain reaction (RT-PCR): This test can detect viral RNA (genetic material) in the blood or tissue samples of patients during the acute phase of the disease. It is a highly specific and sensitive test that can identify the virus strain and monitor viral load.
• Virus isolation by cell culture: This test can grow the virus in cell cultures from blood or tissue samples of patients during the acute phase of the disease. It is a definitive test that can provide live virus for further characterization and research, but it is time-consuming and requires biosafety level 4 facilities.
• Detection of antibody by ELISA (IgG and IgM): This test can detect antibodies (immune response) against the virus in the blood or tissue samples of patients during the convalescent phase of the disease. It is a simple and reliable test that can confirm previous exposure to CCHF virus, but it cannot distinguish between acute and past infections.

Other tests that can be used to diagnose CCHF virus infection include serum neutralization, immunohistochemical staining, and immunofluorescence assay. However, these tests are less widely available and require specialized equipment and expertise.

The diagnosis of CCHF virus infection should be based on a combination of clinical, epidemiological, and laboratory criteria. The laboratory tests should be performed by trained personnel in reference laboratories with appropriate biosafety measures. The samples should be collected and transported with proper precautions to avoid exposure and contamination. The results should be interpreted with caution and confirmed by additional tests if necessary. The diagnosis should be reported to the relevant health authorities for surveillance and outbreak response purposes.

There is no specific antiviral drug or vaccine available for CCHF. The mainstay of treatment is supportive care, which includes:

• Careful attention to fluid balance and correction of electrolyte abnormalities
• Oxygenation and hemodynamic support
• Appropriate treatment of secondary infections
• Replacement therapy with blood products, according to the results of the complete blood count

The virus is sensitive in vitro to the antiviral drug ribavirin, a synthetic purine nucleoside analogue that inhibits viral replication. Ribavirin has been used in the treatment of CCHF patients reportedly with some benefit, but its efficacy and safety have not been established by randomized controlled trials. The optimal dose and duration of ribavirin therapy are also unclear. Some experts recommend a loading dose of 30 mg/kg followed by 15 mg/kg every six hours for four days, then 7.5 mg/kg every eight hours for six days.

The prevention and control of CCHF depend on interrupting the transmission cycle of the virus among ticks, animals, and humans. This can be achieved by:

• Avoiding or minimizing exposure to tick bites by wearing protective clothing, using repellents, and removing attached ticks promptly
• Implementing infection control measures in health care settings to prevent nosocomial transmission, such as using gloves, gowns, masks, and eye protection; sterilizing equipment; and disposing of contaminated materials safely
• Educating people at risk, such as livestock workers, slaughterhouse workers, and veterinarians, about the signs and symptoms of CCHF and the need to seek medical attention promptly if they develop fever or bleeding
• Enhancing surveillance and laboratory capacity to detect and confirm CCHF cases and outbreaks
• Developing and evaluating new drugs and vaccines for CCHF

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