Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus

Zivcec, Marko; Scholte, Florine E. M.; Spiropoulou, Christina F.; Spengler, Jessica R.; Bergeron, Éric

Following a brief incubation period (usually <7 days), CCHFV infection initially causes non-specific symptoms, including a rapid onset high-grade fever, fatigue, and myalgia, frequently accompanied by vomiting and diarrhea. Progression to severe disease is characterized by thrombocytopenia, elevated circulating liver enzymes, and hemorrhagic manifestation (petechiae, ecchymosis, and epistaxis, as well as gingival, gastrointestinal, and cerebral hemorrhages) [1] [2] [3] [4] . Severity of CCHF correlates with increased viral load and dissemination, low anti-CCHFV antibody titers, severity of thrombocytopenia, increased clotting times, hemorrhage, high levels of pro-inflammatory cytokines (e.g., tumor necrosis factor α (TNFα), interleukin 6 (IL-6)), and elevated aspartate aminotransferase and alanine aminotransferase [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] . Fatal outcome is typically the result of disseminated intravascular coagulopathy, shock, and/or multi-organ failure [1] [2] [3] [4] 19] . During the course of disease, CCHFV is widely distributed throughout the body, and has been detected in spleen, lung, heart, and intestinal tissues in fatal human cases [19] . The main cellular targets of infection are mononuclear phagocytes, endothelial cells, and hepatocytes [19] . Infection of monocyte-derived macrophages, endothelial cells, and dendritic cells are confirmed in vitro [20] [21] [22] . Together, vRNA, NP, and RdRp form the genomic ribonucleoprotein complexes (RNP) inside a cellular membrane-derived envelope coated with the mature glycoproteins Gn and Gc. CCHFV attaches to an unidentified cellular receptor and enters the cells in a clathrin-dependent manner. After fusion with the cellular membrane, the viral genomic segments are uncoated and transcribed by L protein into viral mRNA that gain host cell-derived 5 1 caps by cap snatching. The viral mRNAs are translated into the NP and L proteins by cytoplasmic ribosomes, while the glycoprotein precursor (GPC) appears to be translated by endoplasmic reticulum (ER)-associated ribosomes. A portion of the newly synthesized NP and L protein are used to replicate the genomic RNA by forming an RNP containing antigenomic RNA (cRNA). The GPC undergoes processing and maturation in the ER and the Golgi, and yields the Gn and Gc. Upon the accumulation of nascent mature glycoproteins and genomic RNPs, new CCHFV particles assembly is believed to occur in the Golgi followed by virion release in Golgi-derived vesicles. with the cellular membrane, the viral genomic segments are uncoated and transcribed by L protein into viral mRNA that gain host cell-derived 5′ caps by cap snatching. The viral mRNAs are translated into the NP and L proteins by cytoplasmic ribosomes, while the glycoprotein precursor (GPC) appears to be translated by endoplasmic reticulum (ER)-associated ribosomes. A portion of the newly synthesized NP and L protein are used to replicate the genomic RNA by forming an RNP containing antigenomic RNA (cRNA). The GPC undergoes processing and maturation in the ER and the Golgi, and yields the Gn and Gc. Upon the accumulation of nascent mature glycoproteins and genomic RNPs, new CCHFV particles assembly is believed to occur in the Golgi followed by virion release in Golgi-derived vesicles.