Species-Specific Host-Virus Interactions: Implications for Viral Host Range and Virulence

Abstract

A growing number of studies indicate that host species-specific and virus strain-specific interactions of viral molecules with the host innate immune system play a pivotal role in determining virus host range and virulence. Because interacting proteins are likely constrained in their evolution, mutations that are selected to improve virus replication in one species may, by chance, alter the ability of a viral antagonist to inhibit immune responses in hosts the virus has not yet encountered. Based on recent findings of host-species interactions of poxvirus, herpesvirus, and influenza virus proteins, we propose a model for viral fitness and host range which considers the full interactome between a specific host species and a virus, resulting from the combination of all interactions, positive and negative, that influence whether a virus can productively infect a cell and cause disease in different hosts.

Keywords: PKR; herpesvirus, influenza virus; host–pathogen interactions; poxvirus; viral fitness interactome.

Figure 1. Consequences of host-virus molecular arms races for cross-species transmission

(I) Good inhibition of an antiviral protein in species 1 (PKR allele a) by an inhibitor from virus 1 exerts selective pressure and leads to the selection for the resistant allele b, which was present in the population at low frequency (II). This variant cannot be inhibited by virus 1 and thus prevents virus infection. (III) The provided selective advantage leads to the fixation of this allele in the population. (IV) The inhibitor of virus 1 is unable to inhibit PKR from species 2, which precludes virus replication. (V) An inhibitor of virus 2 suboptimally inhibits PKR from species 2, which leads to limited virus replication, (VI) allowing the virus to evolve a better inhibitor, which results in good virus replication. (VII) By chance, the evolved inhibitor from virus 2, is also a good inhibitor for the PKR b allele from species 1, which enables virus 2 to gain a foothold in species 1 and results in successful cross-species transmission of the virus.

Figure 2. Key host interaction partners of influenza A virus NS1 are highly divergent between relevant host species.

The amino acid identities between pig (Sus scrofa), waterfowl (mallard duck (Anas platyrhynchos) or goose (Anser anser domesticus)), ferret (Mustela putorius furo) and human (Homo sapiens) for PKR, RIG-I (DDX58), TRIM25, RNF135/RIPLET and NOLC1 are shown in colored boxes. For waterfowl, mallard duck proteins were analyzed, except for PKR (goose), because a high-quality mallard PKR sequence is not available. Sequence identities shown were determined from psi-blast searches and are very similar to sequence identities obtained from multiple sequence alignments. Accession numbers for PKR (eIF2aK2): NP_002750.1; NP_999484.1; XP_012918395.1 (first 39 aa missing from sequence); AXJ21467.1. RIG-I (DDX58): NP_055129.2; NP_998969.2; XP_004765417.2; BAO25514.1. TRIM25: NP_005073.2; XP_005657028.3; XP_012909123.1; XP_012948210.2. RNF135 (Riplet): NP_115698.3; XP_003131783.1; XP_004747119.1; XP_027327216.1 (contains a unique 97 aa N-terminal extension, which was excluded from analyses). NOLC1: NP_001271317.1; XP_005671467.1; XP_004749466.1; XP_027316116.1.

Figure 3. Host-specific Viral Fitness Interactome.

The Viral Fitness Interactome (VFI) results from the combinatory effects of all interactions between viral molecules with antiviral and pro-viral host factors. The VFI varies between different hosts and cell types. In this model, viral fitness (VF) of a single virus, as indicated by the size of the plus sign, is the result of interactions of a viral protein (VP) with the orthologs of four different host proteins (HP1–4). The relative strength of the interactions is indicated by the thickness of the lines connecting VP and HP. In species A, one strong interaction (with HP1, as indicated by the thickness of the line), one intermediate interaction (HP2) and two weaker interactions contribute to high VF. In species B, the interactions between VP and HPs are different, yet the combinatorial effects result in the same VF as found in species A. In species C, intermediate or weak interactions occur with HP1, 2 and 3, and there is no interaction with the antiviral HP4, resulting in low VF. In species D, the interactions between VP and HP1–3 are the same as species C; however, HP4 is not present, so the VF is therefore higher than in species C.