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, 7 (1), 289

A Permanent Host Shift of Rabies Virus From Chiroptera to Carnivora Associated With Recombination

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A Permanent Host Shift of Rabies Virus From Chiroptera to Carnivora Associated With Recombination

Nai-Zheng Ding et al. Sci Rep.

Abstract

Bat virus host shifts can result in the spread of diseases with significant effects. The rabies virus (RABV) is able to infect almost all mammals and is therefore a useful model for the study of host shift mechanisms. Carnivore RABVs originated from two historical host shifts from bat viruses. To reveal the genetic pathways by which bat RABVs changed their host tropism from bats to carnivores, we investigated the second permanent bat-to-carnivore shift resulting in two carnivore variants, known as raccoon RABV (RRV) and south-central skunk RABV (SCSKV). We found that their glycoprotein (G) genes are the result of recombination between an American bat virus and a carnivore virus. This recombination allowed the bat RABV to acquire the head of the G-protein ectodomain of the carnivore virus. This region is involved in receptor recognition and binding, response to changes in the pH microenvironment, trimerization of G proteins, and cell-to-cell transmission during the viral infection. Therefore, this recombination event may have significantly improved the variant's adaptability to carnivores, altering its host tropism and thus leading to large-scale epidemics in striped skunk and raccoon.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Recombination analysis of SCSKV and bat and skunk RABVs. (A) Variable site comparison of the G genes of SCSKV and carnivore and bat RABV representatives, A09-0255, CA, and LAH60. SCSKV A09-0255 was used as a query. The y-axis gives the percent identity between A09-0255 and two representatives of the parental lineages. (B) A bootscan plot of A09-0255 with a sliding window of 350 bp and a width of 20 bp using the complete G gene. The y-axis represents the percentage of permuted trees. Two Lagos bat viruses, 8619NGA and 0406SEN, were used as an outgroup. Analyses were performed using Simplot software. Vertical lines represent crossover sites. (C) Statistical analysis of the recombination event in the A09-0255 G gene using RDP 3.0. P-values of seven statistical methods implemented in RDP 3.0 to identify recombination are listed. (D) Analysis of informative sites for identification of potential recombination breakpoints. Three sites with maximum χ2 values are indicated by three vertical lines. The χ2 value and P-value of Fisher’s exact test are shown near the vertical lines. The Lagos virus isolate 8619NGA is used as the outgroup.
Figure 2
Figure 2
Phylogenetic patterns of the different regions of the G gene delimited by the putative breakpoints. (A) Phylogenetic history of the G gene region from positions 601 to 1347. (B) Phylogenetic history of G gene regions from positions 1 to 600 and 1347 to 1515 of the alignment. The evolutionary history was inferred using maximum likelihood (ML) methods. Bayesian Information Criterion within MEGA6 was used to find the best nucleotide substitution model for ML analyses. ML trees were constructed using the Tamura 3-parameter nucleotide substitution model. Among-site rate variation was gamma-distributed with invariant sites (G + I) (A) or gamma-distributed (G) (B) with four rate categories (Γ4). Bootstrap values (>70%) are listed above the branches. Evolutionary analyses were conducted in MEGA v6. G2, G3, and G7 indicate genotypes 2, 3, and 7 of Lyssavirus; NCSK, north-central skunk; SCSK, south-central skunk; Rac, raccoon. Cosmopolitan and Arctic-like RABVs are also included.
Figure 3
Figure 3
Analysis of convergent evolution in the recombinant region. Phylogenetic histories of the G gene recombinant region inferred from codon position 3 (based on the Kimura 2-parameter + invariable sites models) (A) and positions 1 and 2 (based on Tamura 3-parameter + Γ4 models) (B). These trees were reconstructed using the ML method implemented in MEGA v6. Please refer to Fig. 4 for detailed descriptions. NCSK, north-central skunk; SCSK, south-central skunk; Rac, raccoon.
Figure 4
Figure 4
Estimation of the age of the recombination event using Bayesian Markov chain Monte Carlo (MCMC). (A) Bayesian tree based on the region outside the two breakpoints. (B) Bayesian tree based on the region between the two breakpoints. The scale axis shows the years to 2013. The dotted line indicates the time to the most recent common ancestor (tMRCA) of the recombinant lineage.
Figure 5
Figure 5
Schematic representation showing the different origins of the recombinant glycoprotein. (A) Schematic representation of the mosaic glycoprotein. Light and dark colors indicate regions descended from bat and carnivore RABVs, respectively. Different colors represent the different functional regions of the G protein: lateral domain (domain I), pink; trimerization domain (domain II), yellow; pH domain (domain III), purple; fusion domain (domain IV), red; C-terminal region, green; transmembrane region, black. The main antigenic sites/epitopes and functional sites corresponding to host tropism also are listed. Amino acid numbering is derived from the mature protein minus the signal peptide. (B) The ball and stick model of 3D structure of the mosaic trimeric G protein ectodomain. The 3D structure is inferred from that of vesicular stomatitis virus G protein (PDB ID: 5I2M). The amino acid residues obtained from skunk RABV and bat RABV are displayed in bright green and black, respectively. (C) Schematic diagram of the origin of the recombinant. On the left, the two parent viruses are shown with red and black denoting regions derived from the skunk and bat RABVs, respectively. In the center, the two viruses come into contact and recombine inside a skunk cell. On the right, the mosaic offspring with a carnivore RABV-derived G-protein head circulates in carnivores.

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