Crimean-Congo haemorrhagic fever virus

Abstract

Crimean-Congo haemorrhagic fever (CCHF) is a severe tick-borne illness with a wide geographical distribution and case fatality rates of 30% or higher. Caused by infection with the CCHF virus (CCHFV), cases are reported throughout Africa, the Middle East, Asia and southern and eastern Europe. The expanding range of the Hyalomma tick vector is placing new populations at risk for CCHF, and no licensed vaccines or specific antivirals exist to treat CCHF. Furthermore, despite cases of CCHF being reported annually, the host and viral determinants of CCHFV pathogenesis are poorly understood. CCHFV can productively infect a multitude of animal species, yet only humans develop a severe illness. Within human populations, subclinical infections are underappreciated and may represent a substantial proportion of clinical outcomes. Compared with other members of the Bunyavirales order, CCHFV has a more complex genomic organization, with many viral proteins having unclear functions in viral pathogenesis. In recent years, improved animal models have led to increased insights into CCHFV pathogenesis, and several antivirals and vaccines for CCHFV have shown robust efficacy in preclinical models. Translation of these insights and candidate therapeutics to the clinic will hopefully reduce the morbidity and mortality caused by CCHFV.

Fig. 1. Molecular biology of Crimean–Congo haemorrhagic fever virus.

a, Crimean–Congo haemorrhagic fever virus (CCHFV) is an enveloped, tri-segmented, negative-sense RNA virus. The virion is studded with the glycoproteins Gn and Gc, which mediate receptor binding and entry. Some evidence suggests that the GP38 accessory protein is also found on the virion but if so, with unclear localization or function. b, The three genomic segments of CCHFV are the small (S), medium (M) and large (L) segments. The S segment encodes the viral nucleoprotein (NP) in one reading frame and the small non-structural protein (NSs) in an opposite-sense open reading frame. The M segment is complex, encoding a glycoprotein precursor (GPC) that is processed by host proteases to produce a GP160/85 domain that is further processed to a mucin-like domain (MLD) and GP38, the Gn and Gc glycoproteins and the medium non-structural protein (NSm). The L segment of CCHFV is unusually large for bunyaviruses, and the encoded protein contains the viral RNA-dependent RNA polymerase (RdRP) and an ovarian tumour-like protease (OTU) at the N terminus. c, On attachment (stage 1), CCHFV undergoes clathrin-dependent and pH-dependent entry into the host cytoplasm (stages 2 and 3). After entry into the cytoplasm, viral genomes are converted to positive-sense mRNA by the RdRP and initiate translation of viral proteins. These proteins also coordinate to produce new negative-sense viral genomes that are coated with NP and a bound L protein to initiate replication on infection of the next cell (stage 4). The GPC is translated into the endoplasmic reticulum (ER) and during trafficking through the ER and Golgi apparatus is proteolytically processed to produce mature glycoproteins along with the accessory proteins MLD, NSm and GP38. Newly produced genomes are packaged into enveloped particles and the virus buds into the Golgi apparatus for release via the secretory pathway (stage 5). New virions are then released to infect additional cells, whereas GP160/85, MLD and GP38 are also released extracellularly but with unclear consequence (stage 6). In addition to facilitating viral replication, CCHFV proteins also block host apoptosis and innate immune pathways. The CCHFV NP can block the intrinsic pathway of apoptosis at a yet-to-be-defined step, whereas the CCHFV NSs promotes apoptosis through disruption of the mitochondrial membrane or extrinsic apoptotic pathways. CCHFV may also promote apoptosis through production of tumour necrosis factor (TNF) and the TNF death receptor pathway. The CCHFV NP is also cleaved by host caspase 3 but oligomeric conformations may block this cleavage. The OTU domain of the CCHFV L protein blocks RIG-I-dependent initiation of the type I interferon response via its deubiquitylating function. MAVS, mitochondrial antiviral signalling protein; vRNA, viral RNA.

Fig. 2. Clinical progression of Crimean–Congo haemorrhagic fever.

The clinical progression of Crimean–Congo haemorrhagic fever (CCHF) presents with four distinct stages. Initial CCHF virus (CCHFV) infection is often unrecognized following exposure via tick bites or animal husbandry (part a), but transmission may also occur via nosocomial or intrafamily transmission during the care of sick patients. After infection, the incubation period (part a) may be as short as 1–3 days depending on the route of exposure. After the incubation period, infected humans may progress to a pre-haemorrhagic stage characterized by nonspecific symptoms such as fever, malaise, myalgia and nausea (part b). This pre-haemorrhagic phase of disease can then rapidly progress to haemorrhagic disease in the first week after infection (part c). This phase of disease is characterized by uncontrolled bleeding, liver damage, inflammatory immune responses and, in severe cases, disseminated intravascular coagulation, shock and death. In patients who survive, recovery begins 10–14 days after infection and is associated with return to normal of blood chemistry and haematology and development of anti-CCHFV immunity (part d). Long-term sequelae following CCHFV infection are poorly studied.

Fig. 3. Prevention of Crimean–Congo haemorrhagic fever.

Prevention of Crimean–Congo haemorrhagic fever (CCHF) requires a multifactorial approach addressing public and veterinary health. a, Farm workers should wear long sleeves and pants to limit tick bites. Transmission of CCHF in the health-care and abattoir settings can be limited by wearing of proper personal protective equipment (PPE). Standard barrier PPE such as a laboratory gown, gloves, a face shield and a mask can limit exposure of health-care personnel to contaminated bodily fluids. Abattoir workers can be similarly protected by wearing PPE such as gowns and gloves and receiving proper training on how to butcher animals. b, Control of the tick vector is also important and may include deployment of acaracides to control tick populations on the farm and on livestock. c, Vaccines are also critically needed to prevent disease on CCHF virus (CCHFV) infection and could also be deployed in livestock populations to interrupt the CCHFV life cycle. d, Public health-directed educational efforts can help to inform at-risk populations to reduce activities that expose them to CCHFV-infected ticks or livestock, to recognize the risk of tick bites in transmission of CCHFV and to promptly recognize the early symptoms of CCHFV. e, Inspection and quarantine of animals moving from CCHFV-endemic areas can reduce exposure of humans to CCHFV-infected ticks and prevent introduction of CCHFV to new areas.

Fig. 4. Vaccines for Crimean–Congo haemorrhagic fever virus.

Multiple vaccine platforms for Crimean–Congo haemorrhagic fever virus (CCHFV) have reached various stages of preclinical testing and include nucleic acid-based vaccines such as plasmid DNA and mRNA, inactivated virus preparations, live-attenuated vaccines (LAVs) such as recombinant vesicular stomatitis virus, virally vectored vaccines such as adenovirus-vectored vaccines, virus-like particles (VLPs) and subunit vaccines with purified viral proteins (part a). The viral antigen expressed by these vaccines is likely to be important (part b), with protective efficacy demonstrated by vaccines expressing nucleoprotein (NP) and/or the glycoprotein precursor (GPC). Importantly, the correlates of protection for vaccines against CCHFV are unknown (part c) and neutralizing antibody is dispensable. Thus, vaccine-mediated protection may require effector functions such as viral opsonization, complement activation or antibody-dependent cellular cytotoxicity by natural killer (NK) cells. In studies demonstrating the protective efficacy of antibodies to the CCHFV NP alone, it remains unclear how antibodies to NP can protect. The role of cellular immunity such as cytotoxic T cell-mediated cytotoxicity is similarly unknown. CTL, cytotoxic T lymphocyte.