Evolutionary patterns in the antiviral immune response

Early characterization of the immune response focused primarily on antimicrobial defence. Antiviral defence is at least partially distinct from that against microbes, and currently is only poorly understood. Both the Toll and Imd pathways are activated during the course of some viral infections; however, only the Toll pathway seems to confer protection (Lemaitre and Hoffmann, 2007). RNAi provides an independent mechanism of defence that is specific against RNA viruses (Wang et al., 2006). Viruses are formidable opponents for the immune system. They are capable of rapid evolution owing to their fast generation times, large population sizes, high mutation rates and obligate pathogen lifestyles. These factors hint that the evolutionary patterns of antiviral defence genes will be different from those described previously for the antimicrobial defence.

Short-term evolution of an antiviral defence gene has been studied at the D. melanogaster locus ref(2) P, which is proposed to function in the Toll pathway (Avila et al., 2002). This locus is polymorphic for alleles that explain a large component of the variation in susceptibility or resistance to the rhab-dovirus Sigma (Contamine et al, 1989; Bangham et al, 2007, 2008). A single domain, termed PB1, of ref(2)P is required for viral replication (Carre-Mlouka et al., 2007). Sigma is infective if a permissive allelic variant of this domain is present, but not with a restrictive allele or genetic knock-out of the domain. This domain has an excess of amino acid polymorphisms (Wayne et al, 1996), consistent with natural selection acting to maintain allelic diversity. A random sample of 10 phenotypically random alleles identified six amino acid polymorphisms in the PB1 domain (Wayne et al., 1996). A single complex mutation, with a single glycine residue substituted for glutamine and asparagine residues, was found on restrictive but not permissive alleles. The remaining polymorphisms are shared by both restrictive and permissive alleles. The frequency of the complex mutation varies between populations, ranging from absent in some African and European populations to 23% in some North American populations (Bangham et al, 2007). There is greatly reduced variation in the restrictive haplotype in a North American population, suggesting that it has recently risen to high frequency by directional selection (Box 13.1). This indicates that selection is acting on localized spatial scales, likely in concert with Sigma virus, which also varies in frequency and genotype between populations (Carpenter et al, 2007).

The fact that there is an excess of non-synonymous polymorphism in ref(2)P PB1 domain but that only a single complex mutation separates restrictive and permissive alleles suggests that current Sigma virus populations have become adapted to some of the remaining polymorphisms. Indeed, analysis of all combinations of polymorphisms on the restrictive allele in artificially generated constructs indicates that no fewer than two of the three mutations are required to create a restrictive allele (Carre-Mlouka et al., 2007). These data suggest a model wherein novel mutations have been driven to high frequency by directional selection, but that the sweeps are incomplete because the virus quickly adapts to the increasingly common allele before it fixes in the population. Host resistance then requires the repeated reintroduction of novel restrictive mutations. The most escalated rates of evolution are expected when host and pathogen are co-evolving, such that host adaptations to escape infection are met by a gene-for-gene pathogen adaptation to maintain virulence (Dawkins and Krebs, 1979). Over the evolutionary long term, there is evidence for elevated amino acid substitution at this domain, with more adaptive mutations becoming fixed in D. melanogaster when compared with D. simulans, a species in which Sigma infection is rare or absent (Wayne et al., 1996). Restrictive polymorphisms that are driven to high frequencies during partial selective sweeps will fix by genetic drift more often than mutations that are selectively neutral over their entire evolutionary history, which may lead to elevated amino acid divergence between species.

A distinct pathway using RNAi presents an important defence against RNA viruses. In D. mel-anogaster, double-stranded viral RNA (dsRNA) is recognized and cleaved into small interfering RNA (siRNA) by Dicer-2 (Wang et al, 2006). These siRNAs then guide cleavage of matching RNA via formation of an RNA-induced silencing complex (RISC). Some viruses produce proteins that suppress RNA silencing. For example, Drosophila picornavirus C produces a dsRNA-binding protein that interferes with Dicer-2 activity and promotes viral establishment and proliferation (van Rij et al., 2006). Dicer-2, along with RISC genes R2D2 and Argonaute-2, are among the most rapidly evolving genes in the D. melanogaster genome. These antiviral genes, but not their paralogues with housekeeping regulatory function, show indications of adaptive evolution by recurrent fixation of novel amino acid mutations (Obbard et al., 2006).

The unique patterns of evolution of antiviral defence yield a useful system for integrating measures of short- and long-term evolution. In the case of ref(2)P in D. melanogaster, rapid evolution is driven by a gene-for-gene interaction between host and virus, and is evidenced by reduced genetic variation within the selectively favoured allele in the short term and increased amino acid divergence in the long term. Rates of long-term evolution in RNAi antiviral genes in D. melanogaster are dramatically higher than the genome average. Evidence suggests that the selective pressures are different from those that act on antimicrobial defence, leading to elevated rates of evolution. This may reflect either rapid viral evolution or high host specificity in viruses, either of which would facilitate co-evolution. Like humoral signalling pathways in the antimicrobial defence, RNAi pathways are also subject to pathogen interference to overcome host defences, indicating that they too are a potential site of direct conflict. Thus, evidence from both types of defence suggests that sites of pathogen interference display elevated evolutionary rates. As antiviral defence becomes better characterized at the molecular level, this system will yield further insights into genetic adaptation to pathogen pressures and serve as a comparison for evolutionary patterns observed in antimicrobial defence.

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