Bat-Borne Influenza A Viruses: An Awakening

Abstract

Influenza A viruses (IAVs) originating from aquatic waterfowl recurrently cross interspecies barriers, which is greatly facilitated by utilizing cell surface-exposed monosaccharide sialic acids located on vertebrate cells as a universal host cell receptor. These glycan structures are first bound by the viral hemagglutinin (HA) for cell entry and then cleaved by the viral neuraminidase (NA) for particle release. In contrast, viruses of the recently identified bat-borne IAV subtypes H17N10 and H18N11 encode HA and NA homologs unable to interact with sialic acid residues despite a high degree of structural homology with their conventional counterparts. However, the most recent findings show that bat IAV HAs make use of the major histocompatibility complex class II proteins of different vertebrate species to gain entry into host cells, potentially permitting a broader host tropism. This review recapitulates current progress in the field of bat IAV research including the first assessment of the spillover potential of these bat viruses into other mammals.

Figure 1.

Current model of the receptor-binding and -modulating function of conventional and bat influenza A virus (IAV) surface glycoproteins. To infect a host cell, H1 to H16 hemagglutinin (HA) proteins of conventional IAV bind to sialic acid moieties exposed on cell surface glycoproteins. Neuraminidases (NAs) of the N1 to N9 subtypes facilitate viral egress by catalyzing the hydrolysis of terminal sialic acids from glycan structures. In contrast, the HA subtypes H17 and H18 use major histocompatibility complex class II (MHC-II) molecules of various species for cell entry. However, the precise H17/H18 HA–MHC-II-binding interface is currently unclear. Preliminary data suggest a MHC-II-down-regulating function for the N11 NA. Therefore, similar to conventional NA proteins, bat IAV N10 and N11 NA could counteract the H17/H18 HA function to allow virus spread.

Figure 2.

Mutant variants of H18N11 lack the N11 neuraminidase (NA) head domain and encode compensating mutations in H18 hemagglutinin (HA). Cartoon depicting the principle structures of the wild-type (wt) H18N11 (left) and the mutant rP11 virus particle (right). rP11 encodes the amino acid substitutions K170R and N250S located in the H18 HA head domain together with a premature stop codon in N11 at position G107X, resulting in a truncated N11 NA protein lacking the ectodomain.

Figure 3.

Tissue tropism of H18N11 viruses in different mammalian species following intranasal inoculation. In mice, H18N11 replicates exclusively in the olfactory epithelium of the nasal cavity; in ferrets, especially the respiratory epithelium of the nasal cavity and the follicle-associated epithelium of the pharyngeal as well as the palatine tonsils, were identified as the sites of viral replication. In Jamaican fruit bats, H18N11 was found in the squamous epithelium of the palatine tonsils, the lamina propria of the small intestine, and the follicle-associated epithelium of the jejunal Peyer's patches. Representative images showing the detection of H18-specifc viral RNA for selected infected organs from either mice, ferrets, and Jamaican fruit bats are shown on the right. The magnification is indicated. (Images provided by Reiner Ulrich and Jan Schinköthe, Institute of Veterinary Pathology, Leipzig University.)