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Structures of human-infecting Thogotovirus fusogens support a common ancestor with insect baculovirus

Significance Thogotoviruses belong to Orthomyxoviridae family and infect a variety of mammalian hosts, including humans. The emergence of these viruses poses great threats to public health and the economy. In this work, we performed structural and phylogenic analyses on the fusogenic glycoproteins of Thogoto and Dhori viruses, two representatives of the Thogotovirus genus that cause severe human infections. Previous studies have shown that thogotovirus glycoproteins share ∼28% sequence identity with baculovirus Gp64s. Our structural analysis confirmed their homology in evolution and identified them as class III viral fusogens, in contrast to class I members of influenza viruses. Our studies provide structural evidence to help us to understand the evolution of these viruses and indicate a potential target for antiviral drug design. Thogotoviruses are emerging tick-borne zoonotic orthomyxoviruses infecting both humans and domestic animals with severe clinical consequences. These viruses utilize a single-envelope glycoprotein (Gp) to facilitate their entry into host cells. Here, we present the Gp structures of Thogoto and Dhori viruses, both of which are members of the Thogotovirus genus in the family Orthomyxoviridae. These structures, determined in the postfusion conformation, identified them as class III viral fusion proteins. It is intriguing that the Gp structures are similar to the envelope protein of baculovirus, although sharing a low sequence identity of ∼28%. Detailed structural and phylogenic analyses demonstrated that these Gps originated from a common ancestor. Among the structures, domain I is the most conserved region, particularly the fusion loops. Domain II showed the highest variability among different viruses, which might be related to their distinct host tropism. These findings increase our understanding of the divergent evolution processes of various orthomyxoviruses and indicate potential targets for developing antiviral therapeutics by intercepting virus entry.