Refugia and the evolutionary epidemiology of drug resistance.

Drug resistance is a long-standing economic, veterinary and human health concern in human and animal populations. Efficacy of prophylactic drug treatments targeting a particular pathogen is often short-lived, as drug-resistant pathogens evolve and reach high frequency in a treated population. Methods to combat drug resistance are usually costly, including use of multiple drugs that are applied jointly or sequentially, or development of novel classes of drugs. Alternatively, there is growing interest in exploiting untreated host populations, refugia, for the management of drug resistance. Refugia do not experience selection for resistance, and serve as a reservoir for native, drug-susceptible pathogens. The force of infection from refugia may dilute the frequency of resistant pathogens in the treated population, potentially at an acceptable cost in terms of overall disease burden. We examine this concept using a simple mathematical model that captures the core mechanisms of transmission and selection common to many host-pathogen systems. We identify the roles of selection and gene flow in determining the utility of refugia.

Superinfection reconciles host-parasite association and cross-species transmission.

Parasites are either dedicated to a narrow host range, or capable of exploiting a wide host range. Understanding how host ranges are determined is very important for public health, as well as wildlife, plant, livestock and agricultural diseases. Our current understanding of host-parasite associations hinges on co-evolution, which assumes evolved host preferences (host specialization) of the parasite. Despite the explanatory power of this framework, we have only a vague understanding of why many parasites routinely cross the host species' barrier. Here we introduce a simple model demonstrating how superinfection (in a heterogeneous community) can promote host-parasite association. Strikingly, the model illustrates that strong host-parasite association occurs in the absence of host specialization, while still permitting cross-species transmission. For decades, host specialization has been foundational in explaining the maintenance of distinct parasites/strains in host species. We argue that host specializations may be exaggerated, and can occur as a byproduct (not necessarily the cause) of host-parasite associations.

Ecological and inhost factors promoting distinct parasite life-history strategies in Lyme borreliosis.

Understanding the ecology and evolution of tick-borne parasites is the foundation for preventing and managing tick-borne diseases. Tick-borne diseases such as Lyme borreliosis, are an emerging health threat in America, Europe, and Asia. Certain strains of Borrelia burgdorferi (the etiological agent of Lyme borreliosis) sampled in nature appear to be rapidly cleared by murine hosts. These strains, unlike their inhost-persistent counterparts, are unlikely to manifest severe disease. Their emergence and abundance in North America is unclear. Understanding why strains adopt a persistent or rapid-clearing phenotype is a crucial question in Lyme biology. Using dynamic, data-driven infectivity profiles in a competitive, two-strain mathematical model, we show that these phenotypes are differentially favored under distinct ecological conditions (i.e. vector phenology). We argue these two phenotypes represent distinct parasite life-history strategies, impacting regional Lyme disease severity across North America.

Pervasive recombination and sympatric genome diversification driven by frequency-dependent selection in Borrelia burgdorferi, the Lyme disease bacterium.

How genomic diversity within bacterial populations originates and is maintained in the presence of frequent recombination is a central problem in understanding bacterial evolution. Natural populations of Borrelia burgdorferi, the bacterial agent of Lyme disease, consist of diverse genomic groups co-infecting single individual vertebrate hosts and tick vectors. To understand mechanisms of sympatric genome differentiation in B. burgdorferi, we sequenced and compared 23 genomes representing major genomic groups in North America and Europe. Linkage analysis of >13,500 single-nucleotide polymorphisms revealed pervasive horizontal DNA exchanges. Although three times more frequent than point mutation, recombination is localized and weakly affects genome-wide linkage disequilibrium. We show by computer simulations that, while enhancing population fitness, recombination constrains neutral and adaptive divergence among sympatric genomes through periodic selective sweeps. In contrast, simulations of frequency-dependent selection with recombination produced the observed pattern of a large number of sympatric genomic groups associated with major sequence variations at the selected locus. We conclude that negative frequency-dependent selection targeting a small number of surface-antigen loci (ospC in particular) sufficiently explains the maintenance of sympatric genome diversity in B. burgdorferi without adaptive divergence. We suggest that pervasive recombination makes it less likely for local B. burgdorferi genomic groups to achieve host specialization. B. burgdorferi genomic groups in the northeastern United States are thus best viewed as constituting a single bacterial species, whose generalist nature is a key to its rapid spread and human virulence.

Fast, adaptive evolution at a bacterial host-resistance locus: the PFam54 gene array in Borrelia burgdorferi.

Microbial pathogens have evolved sophisticated mechanisms for evasion of host innate and adaptive immunities. PFam54 is the largest paralogous gene family in the genomes of Borrelia burgdorferi, the Lyme disease bacterium. One member of PFam54, the complement-regulator acquiring surface proteins 1 (BbCrasp-1), is able to abort the alternative pathway of complement activation via binding human complement-regulator factor H (FH). The gene coding for BbCRASP-1 exists in a tandem array of PFam54 genes in the B. burgdorferi genome, a result apparently of repeated gene duplications. To help elucidate the functions of the large number of PFam54 genes, we performed phylogenomic and structural analyses of the PFam54 gene array from ten B. burgdorferi genomes. Analyses based on gene tree, genome synteny, and structural models revealed rapid adaptive evolution of this array through gene duplication, gene loss, and functional diversification. Individual PFam54 genes, however, do not show high intra-population sequence polymorphisms as genes providing evasion from adaptive immunity generally do. PFam54 members able to bind human FH are not monophyletic, suggesting that human FH affinity, however strong, is an incidental rather than main function of these PFam54 proteins. The large number of PFam54 genes existing in any single B. burgdorferi genome may target different innate-immunity proteins of a single host species or the same immune protein of a variety of host species. Genetic variability of the PFam54 gene array suggests that universally present PFam54 lineages such as BBA64, BBA65, BBA66, and BBA73 may be better candidates for the development of broad-spectrum vaccines or drugs than strain-restricted lineages such as BbCRASP-1.

An update on carotenoid biosynthesis in algae: phylogenetic evidence for the existence of two classes of phytoene synthase.

Carotenoids play crucial roles in structure and function of the photosynthetic apparatus of bacteria, algae, and higher plants. The entry-step reaction to carotenoid biosynthesis is catalyzed by the phytoene synthase (PSY), which is structurally and functionally related in all organisms. A comparative genomic analysis regarding the PSY revealed that the green algae Ostreococcus and Micromonas possess two orthologous copies of the PSY genes, indicating an ancient gene duplication event that produced two classes of PSY in algae. However, some other green algae (Chlamydomonas reinhardtii, Chlorella vulgaris, and Volvox carteri), red algae (Cyanidioschyzon merolae), diatoms (Thalassiosira pseudonana and Phaeodactylum tricornutum), and higher plants retained only one class of the PSY gene whereas the other gene copy was lost in these species. Further, similar to the situation in higher plants recent gene duplications of PSY have occurred for example in the green alga Dunaliella salina/bardawil. As members of the PSY gene families in some higher plants are differentially regulated during development or stress, the discovery of two classes of PSY gene families in some algae suggests that carotenoid biosynthesis in these algae is differentially regulated in response to development and environmental stress as well.