Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is a tick-borne virus belonging to the genus Orthonairovirus within the family Nairoviridae.
It is the causative agent of Crimean-Congo Hemorrhagic Fever (CCHF), a severe viral disease characterized by sudden onset of fever, myalgia, dizziness, neck pain, and in severe cases, internal and external hemorrhages.
The virus is primarily transmitted to humans through bites of infected Hyalomma ticks or by direct contact with blood or tissues of infected animals or humans.
CCHFV is widely distributed across Africa, Asia, the Middle East, and parts of Eastern Europe, especially in regions with warm climates that support the Hyalomma tick population.
Human-to-human transmission can occur in healthcare settings due to poor infection control practices, leading to nosocomial outbreaks.
The virus has a single-stranded, negative-sense RNA genome divided into three segments: small (S), medium (M), and large (L).
CCHF is considered a high-priority emerging disease by the World Health Organization (WHO) due to its high fatality rate, potential for outbreaks, and lack of specific antiviral treatment or licensed vaccine.
Outbreaks of CCHF often occur in rural agricultural regions where people are more likely to come into contact with livestock and ticks.
Early diagnosis and prompt supportive care significantly improve the survival rate, while prevention relies heavily on vector control, protective clothing, and awareness in endemic areas.
Structure of Crimean-Congo Hemorrhagic Fever Virus
Crimean-Congo Hemorrhagic Fever Virus (CCHFV) belongs to the family Bunyaviridae and the genus Nairovirus, a group known for causing severe zoonotic diseases in humans.
The virus particles are spherical in shape, measuring approximately 90 to 120 nanometers in diameter, and they exhibit surface projections (spikes) that are about 5 to 10 nanometers long, which may assist in host cell attachment.
CCHFV is an enveloped virus, meaning its nucleocapsid is enclosed within a lipid bilayer envelope derived from the host cell membrane during viral budding.
The viral envelope is embedded with two surface glycoproteins, G1 and G2, which play crucial roles in virus entry, immune evasion, and host cell recognition.
Its genome is tripartite, meaning it consists of three distinct segments of negative-sense single-stranded RNA, known as:
Large (L) segment, which encodes the RNA-dependent RNA polymerase (also called L protein),
Medium (M) segment, which codes for the envelope glycoproteins G1 and G2,
Small (S) segment, which encodes the nucleocapsid protein (N protein).
These RNA genome segments are associated with nucleoproteins, forming nucleocapsid structures that protect the viral RNA and are involved in viral replication and transcription.
Each nucleocapsid is surrounded by the lipid envelope, providing the virus with protection and structural stability while aiding in entry into host cells.
The L protein, or RNA-dependent RNA polymerase, is packaged within the nucleocapsid and is essential for transcription and replication of the viral genome once inside the host cell.
Genome of Crimean-Congo Hemorrhagic Fever Virus
The genome of Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is linear, tripartite, and composed of segmented negative-sense single-stranded RNA.
It consists of three genomic segments:
Large (L) segment
Medium (M) segment
Small (S) segment
The L segment is approximately 12,164 nucleotides long, the M segment is 4,888 nucleotides, and the S segment is 1,712 nucleotides in length.
The viral genome encodes for approximately four to six proteins, depending on the functional reading frames of each segment.
All three segments—L, M, and S—contain conserved, terminal, complementary nucleotide sequences, which are essential for the replication and transcription processes of the virus.
The S segment of nairoviruses, including CCHFV, encodes only a large nucleocapsid (N) protein and has no known nonstructural protein-coding sequences.
The M segment of the virus appears to encode only the envelope glycoproteins G2 and G1, which are crucial for viral attachment and entry.
Sequencing of the L RNA segment of CCHFV has revealed it is 12,164 nucleotides long and encodes a polymerase protein consisting of 3,944 amino acids.
The viral RNA-dependent RNA polymerase (L protein) recognizes and binds to a promoter region on each encapsidated segment to initiate mRNA transcription.
During transcription, the viral L protein adds 5’ caps to the mRNAs using a mechanism known as cap-snatching, where it hijacks capped primers from host cell mRNAs.
Epidemiology of Crimean-Congo Hemorrhagic Fever Virus
Crimean-Congo hemorrhagic fever (CCHF) is endemic in Africa, the Balkans, the Middle East, and Asia, affecting countries south of the 50th parallel north as of 2025.
The virus is primarily transmitted by Hyalomma ticks, with principal vector species varying by region: Hyalomma marginatum in Europe and the Balkans; H. anatolicum in Iran, Pakistan, Turkmenistan, Tajikistan; H. asiaticum in Central Asia and China; H. rufipes in Africa.
Humans acquire CCHF through tick bites, contact with blood or tissues of infected animals (cattle, sheep, goats, ostriches), and human-to-human transmission via bodily fluids, notably in healthcare settings.
The case fatality rate (CFR) ranges from 10% to 40%, with recent studies estimating a global average mortality of about 11.7% (2021 data) and an estimated CFR of 35% in European cases reported up to 2025.
Seroprevalence studies (up to 2020) report approximately 22.5% antibody prevalence in humans, 4.5% in ticks, and 2.1% in animals worldwide, highlighting varying exposure risks among different populations.
The disease mostly affects rural and farming communities, especially those working with livestock, slaughterhouse personnel, and healthcare workers due to occupational exposure.
The epidemiology has evolved, with new cases and tick distribution expanding in Europe; by early 2025, at least 16 countries in the WHO European region reported human cases, many with detected viral genotypes in local tick populations.
Travel-associated cases have been identified globally; from 1980 to late 2024, 17 imported CCHF cases were documented, with 8 imported into European countries.
Control and prevention efforts focus on tick control, personal protective measures for high-risk groups, and strict infection prevention in healthcare, as no human vaccine is currently available.
Transmission of Crimean-Congo Hemorrhagic Fever Virus
Ixodid (hard) ticks, particularly those belonging to the genus Hyalomma, serve as both vectors and natural reservoirs of the Crimean-Congo Hemorrhagic Fever Virus (CCHFV).
Human infection typically occurs through direct contact with infected ticks, especially during activities such as farming, animal handling, or visiting tick-infested areas.
Transmission can also happen through exposure to the blood or tissues of infected animals, particularly during slaughtering or veterinary procedures.
Human-to-human transmission is possible and occurs via direct contact with blood, secretions, organs, or other bodily fluids of infected individuals, particularly in caregiving or clinical settings.
Nosocomial (hospital-acquired) outbreaks may arise from improper sterilization of medical instruments, reuse of contaminated needles, or handling of infected medical supplies, posing serious risks to healthcare workers and patients.
Replication of Crimean-Congo Hemorrhagic Fever Virus
The replication cycle begins when the virus attaches to host cell receptors via its surface glycoproteins, initiating endocytosis into vesicles within the host cell.
Inside the host, fusion of the viral envelope with the vesicle membrane enables the release of the ribonucleocapsid into the cytoplasm.
The RNA-dependent RNA polymerase (RdRp) complex then binds to the leader sequence at the 3′ end of the genomic negative-sense RNA, initiating transcription.
During transcription, the viral mRNAs are synthesized and capped in the cytoplasm using a cap-snatching mechanism, which borrows caps from host mRNAs.
For replication, the RdRp complex also binds to the leader sequence on the encapsidated (-)RNA genome, and begins synthesizing full-length antigenomes.
The newly synthesized antigenomes are encapsidated concurrently during replication and serve as templates for producing new negative-sense genome segments.
Assembled nucleocapsids trigger membrane curvature formation in the Golgi apparatus, where they are wrapped in a budding membrane derived from the host.
The mature, enveloped virions are released from the host cell by exocytosis, completing the viral replication cycle.
Pathogenesis of Crimean-Congo Hemorrhagic Fever
The infection process begins in the gut of the tick vector, where the virus initially replicates; after several days to weeks, the virus appears in the saliva of the tick.
During a blood meal, the infected tick transmits the virus through its saliva, which enters the capillaries or lymphatics of the human or other vertebrate host.
After exposure, the virus undergoes an incubation period of a few days, following which the host develops viremia, where the virus spreads through the bloodstream.
The infected individual becomes febrile, exhibiting the severe symptoms associated with the disease, such as hemorrhages, fever, and systemic inflammation.
In most cases, a humoral immune response develops, characterized by early production of Immunoglobulin M (IgM) followed by Immunoglobulin G (IgG), leading to the clearance of viremia and eventual clinical recovery.
In cases where the virus targets specific organs, particularly the liver and vascular endothelium, the infection becomes more severe and systemic.
Damage to the vascular endothelium results in hemostatic failure, initiated by platelet aggregation and degranulation, followed by activation of the intrinsic coagulation cascade, leading to bleeding complications.
Proinflammatory cytokines play a central role in disease severity and mortality; they act as key mediators in the immune response and vascular damage.
Elevated levels of Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α) have been consistently observed in fatal cases of CCHF, indicating their involvement in the severe inflammatory response.
Clinical manifestations of Crimean-Congo Hemorrhagic Fever
After an incubation period ranging from 3 to 21 days, the disease typically presents as a non-specific febrile illness with abrupt onset.
Early symptoms include headache, high fever, back pain, joint pain, abdominal pain, nausea, and non-bloody diarrhea.
Patients may also exhibit red eyes (conjunctival injection), flushed face, red throat, and petechiae (small red spots) on the soft palate.
As the illness progresses, systemic signs appear, including hypotension (low blood pressure), relative bradycardia (slow heart rate), tachypnea (rapid breathing), conjunctivitis, pharyngitis, and cutaneous flushing or rash.
In some cases, additional symptoms such as jaundice, and neurological changes including altered mood and sensory perception, may be observed.
The hemorrhagic phase is typically short-lived but progresses rapidly, featuring signs of widespread bleeding and hemorrhagic diathesis.
Hemorrhagic signs include petechiae, conjunctival hemorrhage, nosebleeds (epistaxis), vomiting of blood (hematemesis), coughing up blood (hemoptysis), and black tarry stools (melena).
Internal bleeding can also occur, notably in the retroperitoneal space and intracranial regions, contributing to the severity of the disease.
Hepatosplenomegaly (enlargement of the liver and spleen) may be present on physical examination.
In severe and untreated cases, death may result from multi-organ failure, disseminated intravascular coagulation (DIC), and circulatory shock.
Diagnosis of Crimean-Congo Hemorrhagic Fever Virus
Virus isolation is considered one of the most sensitive diagnostic methods, often performed through intracranial inoculation of suckling mice, which provides a highly sensitive biological system for virus detection.
In addition to animal models, several sensitive cell culture systems are also used for virus isolation, including Vero cells, LLC-MK2 cells, and BHK-21 cell lines, which support replication of CCHFV.
Immunohistochemical staining is employed to detect viral antigens in formalin-fixed tissues, particularly useful for postmortem diagnosis or in biopsy specimens.
Serological detection of antibodies against CCHFV is conducted using Enzyme-Linked Immunosorbent Assay (ELISA) to identify Immunoglobulin M (IgM) and Immunoglobulin G (IgG) antibodies, indicating recent or past infection.
Antigen-capture ELISA is used to directly detect viral antigens in blood or tissue samples, allowing for rapid diagnosis during the acute phase of infection.
Reverse Transcription Polymerase Chain Reaction (RT-PCR) is employed to detect CCHFV RNA sequences, offering high sensitivity and specificity, especially in early infection or fatal cases.
Diagnosis may involve a combination of virus isolation, serology, antigen detection, and molecular techniques depending on the stage of disease, availability of laboratory infrastructure, and biosafety considerations.
Treatment of Crimean-Congo Hemorrhagic Fever
Supportive treatment is the primary approach for managing CCHF and focuses on stabilizing the patient's vital functions throughout the illness.
Supportive care includes maintaining fluid balance, correcting electrolyte abnormalities, ensuring adequate oxygenation, and providing hemodynamic support to manage blood pressure and circulation.
The antiviral drug ribavirin has shown in vitro sensitivity against CCHFV and is commonly used in clinical settings for treating infected individuals.
Ribavirin is often administered in both intravenous (IV) and oral forms, and while definitive clinical trial data is limited, it has shown apparent benefit in reducing mortality and severity when administered early in the course of infection.
Prevention and control of Crimean-Congo Hemorrhagic Fever Virus
Currently, there is no safe and effective vaccine available for human use against Crimean-Congo Hemorrhagic Fever Virus.
In cases of known direct exposure to blood or body secretions of a probable or confirmed CCHF case—such as needlestick injuries or mucous membrane contact (eyes or mouth)—the recommended post-exposure protocol includes conducting baseline blood tests and initiating oral ribavirin as post-exposure prophylaxis.
Application of insect repellents on exposed skin and clothing helps reduce the risk of tick bites, especially in endemic or high-risk regions.
Wearing gloves and protective clothing is advised for individuals at risk, such as healthcare workers, veterinarians, slaughterhouse staff, and farmers, to minimize skin exposure.
Individuals should avoid direct contact with the blood and body fluids of livestock or humans displaying symptoms of CCHF, as transmission can occur through contact with infected fluids.
Strict adherence to proper infection control measures, such as using personal protective equipment (PPE) and standard disinfection protocols, is essential to prevent occupational exposure and nosocomial (hospital-acquired) transmission.
References
World Health Organization. Crimean-Congo haemorrhagic fever. WHO Health Topics. Updated 2019.
World Health Organization. Crimean-Congo haemorrhagic fever: Fact sheet. Updated February 2025.
Rodriguez LL, Maupin GO, Ksiazek TG. Crimean-Congo hemorrhagic fever: pathogenesis, transmission, and therapeutic advances. F1000Research. 2025; Abstract and review.
Walter R, Velay A. Changes in the epidemiology of Crimean-Congo hemorrhagic fever with emphasis on European regions and travel-associated cases. ScienceDirect. 2025.
Wikipedia contributors. Crimean–Congo hemorrhagic fever. Wikipedia, The Free Encyclopedia. Last updated July 2025.
Africa Centres for Disease Control and Prevention. Crimean-Congo Haemorrhagic Fever – Africa CDC. Updated 2025.
World Health Organization Regional Office for Africa. Overview (Crimean Congo haemorrhagic fever). 2019.
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