Tick-transmitted thogotovirus gains high virulence by a single MxA escape mutation in the viral nucleoprotein

Abstract

Infections with emerging and re-emerging arboviruses are of increasing concern for global health. Tick-transmitted RNA viruses of the genus Thogotovirus in the Orthomyxoviridae family have considerable zoonotic potential, as indicated by the recent emergence of Bourbon virus in the USA. To successfully infect humans, arboviruses have to escape the restrictive power of the interferon defense system. This is exemplified by the high sensitivity of thogotoviruses to the antiviral action of the interferon-induced myxovirus resistance protein A (MxA) that inhibits the polymerase activity of incoming viral ribonucleoprotein complexes. Acquiring resistance to human MxA would be expected to enhance the zoonotic potential of these pathogens. Therefore, we screened a panel of 10 different thogotovirus isolates obtained from various parts of the world for their sensitivity to MxA. A single isolate from Nigeria, Jos virus, showed resistance to the antiviral action of MxA in cell culture and in MxA-transgenic mice, whereas the prototypic Sicilian isolate SiAr126 was fully MxA-sensitive. Further analysis identified two amino acid substitutions (G327R and R328V) in the viral nucleoprotein as determinants for MxA resistance. Importantly, when introduced into SiAr126, the R328V mutation resulted in complete MxA escape of the recombinant virus, without causing any viral fitness loss. The escape mutation abolished viral nucleoprotein recognition by MxA and allowed unhindered viral growth in MxA-expressing cells and in MxA-transgenic mice. These findings demonstrate that thogotoviruses can overcome the species barrier by escaping MxA restriction and reveal that these tick-transmitted viruses may have a greater zoonotic potential than previously suspected.

Comprehensive Review of Emergence and Virology of Tickborne Bourbon Virus in the United States

“…After an endosome has formed, acidification of the endocytic compartment triggers a conformational change in the GP that causes fusion of the viral envelope with the endosomal membrane and release of the genome into the cytoplasm ( 5 , 13 ). All 6 genomic RNA segments are encapsidated by viral NPs, forming viral ribonucleoprotein complexes ( 14 ). Intracellular trafficking of viral ribonucleoprotein complexes into the nucleus, the site of replication for thogotoviruses, is driven by viral NPs, which contain a nuclear translocation signal and are known to accumulate in the nucleus during active infection ( 14 , 15 ).…”

“…All 6 genomic RNA segments are encapsidated by viral NPs, forming viral ribonucleoprotein complexes ( 14 ). Intracellular trafficking of viral ribonucleoprotein complexes into the nucleus, the site of replication for thogotoviruses, is driven by viral NPs, which contain a nuclear translocation signal and are known to accumulate in the nucleus during active infection ( 14 , 15 ). Virus replication is induced by heterotrimeric polymerase complexes formed from PB1, PB2, and PA protein subunits and is believed to be consistent with mechanisms described for other orthomyxoviruses ( 16 ).…”

“…To survive in its human host, BRBV must first overcome the interferon-induced myxovirus resistance protein A (MxA) to avoid the host’s innate antiviral defense system. Thogotoviruses are normally susceptible to inactivation by MxA, but a recent study of Jos virus showed that mutations in the viral NP can lead to resistance ( 14 ). Although this position is conserved among viruses in the Thogotovirus genus, only 1 amino acid change in the viral NP was required to fully escape MxA without replicative fitness loss.…”

Prevalence of Tick-Borne Viruses from Ticks Breeding on Camels Imported to Egypt During the Period from January 2019 to April 2021

“…In the Orthomyxoviridae family, TBVs are represented by two suggested genera, Quarjavirus and genus Thogotovirus 6 . Thogotoviruses are distinct from other representatives of this family in that they are transferred by ticks and are found in a wide range of mammalian species, including rodents, cattle, camels, and sheep 33 . The associates of the genus Thogotovirus are arboviruses transferred by ticks that infect humans and livestock in Europe, Africa, and Asia 34 .…”

“…The patients who attracted Thogotovirus infections developed a febrile illness that was frequently accompanied by neurological symptoms. Both individuals' illness development was marked by severe respiratory complications and liver damage 33 .…”