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Competition-Colonization Dynamics in an RNA Virus

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Competition-Colonization Dynamics in an RNA Virus Competition-colonization dynamics in an RNA virus Samuel Ojosnegrosa,b, Niko Beerenwinkelb, Tibor Antalc, Martin A. Nowakc, Cristina Escarmísa, and Esteban Domingoa,d,1 aCentro de Biología Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid. Campus de Cantoblanco, 28049 Madrid, Spain; bDepartment of Biosystems Science and Engineering, Eidgenössische Technische Hochschule Zurich, 4058 Basel, Switzerland; cProgram for Evolutionary Dynamics, Harvard University, Cambridge, MA 02138; and dCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, 08036 Barcelona, Spain Edited by Peter Schuster, University of Vienna, Vienna, Austria, and approved November 16, 2009 (received for review September 7, 2009) During replication, RNA viruses rapidly generate diverse mutant populations at passages 200, 219, 225 and 240 were subjected to progeny which differ in their ability to kill host cells. We report three low-MOI passages (0.006–0.02 PFU/cell) to obtain the corre- that the progeny of a single RNA viral genome diversified during sponding populations termed 200p3d, 219p3d, 225p3d, and 240p3d, hundreds of passages in cell culture and self-organized into two respectively, as detailed in Materials and Methods. The four pop- genetically distinct subpopulations that exhibited the competition- ulations and their 3d derivatives were analyzed phylogenetically colonization dynamics previously recognized in many classical (Fig. 1A). The results show that the sequence of the initially dominant ecological systems. Viral colonizers alone were more efficient in populations is similar to the consensus sequence of passage 200 killing cells than competitors in culture. In cells coinfected with (p200), although the sequence of the p3d derivatives is similar to both competitors and colonizers, viral interference resulted in MARLS, a MAb-escape mutant isolated from the same viral lineage reduced cell killing, and competitors replaced colonizers. Mathe- (14), and previously characterized as a high-fitness and high-virulence matical modeling of this coinfection dynamics predicted selection variant (10, 15). To ascertain that the viral population included in- to be density dependent, which was confirmed experimentally. dividual infectious particles that were either p200 or MARLS, a total Thus, as is known for other ecological systems, biodiversity and of 16 biological clones derived from the populations at passages 219, even cell killing of virus populations can be shaped by a tradeoff 225, and 240 were isolated and their genomic RNA analyzed by nu- between competition and colonization. Our results suggest a cleotide sequencing. The phylogenetic analysis showed that indeed model for the evolution of virulence in viruses based on internal two subclasses of genomes were present and that they segregated into interactions within mutant spectra of viral quasispecies. p200 and MARLS sequences (Fig. 1B). These phylogenetic com- parisons suggest that MARLS clones might be suppressed by p200 evolution | quasispecies | self-organization | virulence variants replicating in the same population and that the MARLS variants could become dominant after the three low-MOI passages NA viruses replicate as complex mutant distributions termed (Fig. 1). Therefore, limiting coinfection of cells by MARLS and Rviral quasispecies (1–4). Viral clones diversify upon replication p200 genomes permitted the former to attain dominance in the −3 −5 because of mutation rates in the range of 10 to 10 substitutions viral population. per nucleotide copied, due to absence (or low efficiency) of proof- reading-repair functions in viral RNA dependent RNA polymerases Competitor and Colonizer FMDV Subpopulations. To further analyze (5–7). Little is known of the evolution of virulence when a viral clone the interaction between p200 and MARLS, the two viral sub- diversifies to produce a broad mutant distribution. Large population populations were characterized phenotypically. The MARLS passages result in fitness gain (8, 9). However, fitness and virulence population and its derived clones killed BHK-21 cells faster than are not necessarily correlated traits, as shown with clones of the the p200 population and its derived clones in a cell killing assay important picornaviral pathogen foot-and-mouth disease virus that compared the time needed to kill 104 BHK-21 cells as a (FMDV) using cell killing as a marker for virulence (10), or using function of the initial number of PFU (10) (Fig. 2 A and B). To Tobacco Etch virus and reduction in seed production in planta as a further evaluate this difference, viruses were tested in cell killing- marker for virulence (11). interference assays (see Materials and Methods). Cells coinfected FMDV has been used as a model system to study quasispecies by fast-killing MARLS and slow-killing p200 viruses died at a dynamics (12). A biological clone of FMDV of serotype C similar rate as cells infected only by slow p200 viruses, either termed C-S8c1 was extensively passaged in BHK-21, resulting in using whole populations or individual clones (Fig. 2 C–D). A genetic diversification and fitness increase (13, 14). At passage possible dose effect was excluded because no alteration of the 143, a monoclonal antibody (MAb) SD6-resistant mutant termed cell killing time was observed when cells were infected by twice MARLS was isolated (14). This mutant differed in 32 mutations the amount of fast viruses. The delay of cell killing could be from its parental C-S8c1 virus and displayed high fitness and a fi 3 attributed speci cally to slow (p200) viruses because cells in- 10 -fold greater ability to kill cells than C-S8c1 (10, 15). In the fected by two fast (MARLS) viruses experienced no delay (Fig. present study we have examined the mutant composition of the 2E). A tradeoff between higher cell killing and lower progeny population that resulted after 240 serial passages of FMDV C- production was also rejected because MARLS clone 240c2 fi S8c1 (Fig. 1). The clonal population diversi ed into two geno- production was statistically indistinguishable from p200 clones typically and phenotypically distinct classes of FMDV genomes that correspond to competitors and colonizers, as previously recognized in ecological systems (16, 17). We provide evidence Author contributions: S.O., N.B., T.A., M.A.N., C.E., and E.D. designed research; S.O. per- that cell killing is the result of a compromise between the two formed research; S.O., N.B., T.A., M.A.N., and E.D. analyzed data; and S.O., N.B., and E.D. phenotypes that coexist in the populations and develop a wrote the paper. mathematical model for the competition-colonization dynamics. The authors declare no conflict of interest. This article is a PNAS Direct Submission. Results Data deposition: The sequence reported in this paper has been deposited in the GenBank High Fitness FMDV Clones Were Suppressed by the Dominant database (accession nos. NC002554, FJ824812, and AF274010). Population. A biological clone of FMDV was passaged in BHK-21 1To whom correspondence should be addressed. E-mail: [email protected]. – cells at a multiplicity of infection (MOI) of 1 20 plaque-forming-units This article contains supporting information online at www.pnas.org/cgi/content/full/ per cell (PFU/cell) for a total of 240 passages (see SI Appendix).The 0909787107/DCSupplemental. 2108–2112 | PNAS | February 2, 2010 | vol. 107 | no. 5 www.pnas.org/cgi/doi/10.1073/pnas.0909787107 Downloaded by guest on September 29, 2021 p0 MARLS viruses when coinfecting the same cell. We refer to A B p200 p0 97 225c6 p200 p200 p200 viruses as competitors because of their intracellular com- 98 219c2 p219 99 240c13 100 100 240c1 petitive advantage and to MARLS viruses as colonizers because p225 219c5 100 p240 219c4 96 219c3 of their higher cell killing capacity, which entails a faster dis- p219p3d 240c15 p200p3d 225c8 persal upon completion of the infectious cycle. 100 MARLS MARLS p225p3d 240c6 MARLS 100 240c7 p240p3d 91 91 240c10 Mathematical Model of Viral Coinfection Dynamics. To pinpoint the 240c11 240c8 240c12 coevolutionary dynamics of competitors and colonizers, and to 240c2 generate testable hypotheses, we developed a mathematical Fig. 1. Genetic characterization of p200 and MARLS viruses. (A) Maximum model of virus dynamics (18, 19) in cell culture that accounts for likelihood reconstruction of consensus nucleotide sequences (nucleotides intracellular interactions. Two different viruses, whose abun- 1033 through 1154 and 1570 through 3853, see Materials and Methods)of dances are denoted by v1 and v2, compete for an uninfected cell populations before and after three sequential low-MOI infections (indicated x by “p3d”). (B) Maximum likelihood reconstruction [nucleotides 1033 through pool of size and give rise to singly infected and coinfected cell y y y 3853; residue numbering is as described in (10)] of biological clones. Clones are populations of size 1, 2, and 12, respectively. The dynamics are identified by passage number and clone number (e.g., 225c6). Consensus given by the ordinary differential equations (ODE) reference sequences at passages 0, 200 (p0, p200), and of MARLS virus are included. Confidence values higher than 80% are indicated. _ x ¼ − βxv1 − βxv2 y_ ¼ βxv − βy v − a y 1 1 1 2 1 1 P > SI Appendix y_ ¼ βy v þ βy v − a y 240c1 and 240c13 (KS-test, 0.05, ). MARLS 12 1 2 2 1 1 12 y_ ¼ βxv − βy v − a y clone 240c12 production was slightly higher than that of both 2 2 2 1 2 2 _ p200 clones (KS-test, P < 0.05). These results demonstrate that v1 ¼ k1y1 þ ck1y12 − uv1 _ slow p200 viruses directly interfere with the replication of fast v2 ¼ k2y2 þð1 − cÞ k1y12 − uv2 A B 107 7 6 106 10 10 5 5 10 10 4 4 10 10 3 3 10 10 2 2 PFU/ml 10 10 101 101 100 100 51520 25 30 3540 51520 25 30 3540 Time for killing (h) CD 5 5 10 * 10 * EVOLUTION 104 104 * * 103 103 centers Infecctious 2 2 10 10 Fig.
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