The first decade of research advances in influenza D virus

Abstract

From its initial isolation in the USA in 2011 to the present, influenza D virus (IDV) has been detected in cattle and swine populations worldwide. IDV has exceptional thermal and acid stability and a broad host range. The virus utilizes cattle as its natural reservoir and amplification host with periodic spillover to other mammalian species, including swine. IDV infection can cause mild to moderate respiratory illnesses in cattle and has been implicated as a contributor to bovine respiratory disease (BRD) complex, which is the most common and costly disease affecting the cattle industry. Bovine and swine IDV outbreaks continue to increase globally, and there is increasing evidence indicating that IDV may have the potential to infect humans. This review discusses recent advances in IDV biology and epidemiology, and summarizes our current understanding of IDV pathogenesis and zoonotic potential.

Keywords: zoonotic potential; epidemiology; genetic and antigenic evolution; influenza D virus; pathogenicity.

Fig. 1.

Overview of four types of influenza viruses. (a) Genomes and viral particles of influenza A, B, C and D viruses. Influenza A and B virus particles possess eight genomic segments (left), while influenza C and D virus particles contain seven genomic segments (right). The envelope and membrane proteins HEF (ICV/IDV), HA and NA (IAV/IBV), and M2 project from the virion surface with the M1 protein just underneath the inner leaflet of the membrane, which encases the virion core containing the virus genome. Each vRNA segment forms a vRNP together with the NP and RNA polymerase complex (PB2, PB1 and PA/P3). (b) Summary of general characteristics of four types of influenza viruses.

Fig. 2.

Phylogenetic tree of IDV HEF segment. Maximum-likelihood analysis in combination with 1000 bootstrap replicates was used to derive an evolutionary tree based on the nucleotide sequences of the IDV HEF segment. More than 50 % of the bootstrap values are shown next to the branches. The scale bars indicate the number of substitutions per site. Red, IDV in North America; purple, IDV in Asia; green, IDV in Europe.

Fig. 3.

Schematic illustration of the HA/HEF. Linear order of the sequence fragments in HA/HEF with each individual functional domain indicated in a different monochromatic colour scheme: fusion domain (F1, F2 and F3, red); esterase domain (E1, E1’ and E2 in the HEF, blue; only E1’ in the HA, grey); receptor domain (R, green); fusion peptide (FP, black); and transmembrane region (TM, grey). The functional form of the HA/HEF is a homotrimer.

Fig. 4.

Strategies used by influenza viruses to produce the NS1, NS2, M1 and M2 proteins. The NS1 protein of four types of influenza viruses is encoded by an unspliced mRNA transcript from the first initiation codon of the NS segment, while the NS2 protein is encoded by a spliced mRNA transcript from the NS segment by using the splicing mechanism. In IAV the M1 and M2 proteins are produced in a similar way to to the NS1 and NS2 proteins. In IBV, M1 protein is encoded by a colinear transcript, whereas the M2 protein is generated via a translational stop–start mechanism. In ICV and IDV, the unspliced and spliced mRNAs from the M segment encode the P42 and M1, respectively. The cleavage of the P42 by a signal peptidase produces the M1’ and M2 proteins. ICV M1 mRNA needs to be spliced to create a termination codon, while the splicing of the IDV M segment produces an additional 4-amino-acid peptide added into the preceding exon of the M1. The boxes represent different coding regions and the shapes filled with grey strips represent introns in the mRNAs. The filled cycles at the 5′ end of the mRNAs represent the 5′ cap, and the A(n) at the 3′ end represents the poly(A) tail. Other lines at both ends of the mRNAs represent noncoding regions. Modified from [95].