Evolution of Eukaryotic Microbial Pathogens Via Covert Sexual Reproduction

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Evolution of Eukaryotic Microbial Pathogens Via Covert Sexual Reproduction View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Cell Host & Microbe Review Evolution of Eukaryotic Microbial Pathogens via Covert Sexual Reproduction Joseph Heitman1,2,3,* 1Department of Molecular Genetics and Microbiology 2Department of Pharmacology and Cancer Biology 3Department of Medicine Center for Microbial Pathogenesis, Duke University Medical Center, Durham, NC 27710, USA *Correspondence: [email protected] DOI 10.1016/j.chom.2010.06.011 Sexual reproduction enables eukaryotic organisms to reassort genetic diversity and purge deleterious muta- tions, producing better-fit progeny. Sex arose early and pervades eukaryotes. Fungal and parasite pathogens once thought asexual have maintained cryptic sexual cycles, including unisexual or parasexual reproduction. As pathogens become niche and host adapted, sex appears to specialize to promote inbreeding and clonality yet maintain outcrossing potential. During self-fertile sexual modes, sex itself may generate genetic diversity de novo. Mating-type loci govern fungal sexual identity; how parasites establish sexual identity is unknown. Comparing and contrasting fungal and parasite sex promises to reveal how microbial pathogens evolved and are evolving. Introduction that promote mating, we now appreciate that a parasexual cycle How microbial pathogens evolve, develop drug resistance, and is extant (Bennett and Johnson, 2003). Recently, C. albicans was interact with the host involves both genetic change and also discovered to reproduce unisexually, illustrating a remark- exchange. In bacteria, genetic exchange occurs largely via hori- able convergence in modes of sexual reproduction in two zontal gene transfer (HGT); in the fungal and parasite eukaryotic divergent successful human fungal pathogens (Alby et al., microbial pathogens, sexual reproduction drives genetic 2009). Studies of other pathogenic Candida sp. have converged exchange. We review here how sexual identity is defined and to illustrate a marked plasticity in specification of sexual identity, modes and roles of sexual reproduction in virulence, production meiotic machinery, and the generation of aneuploid progeny with of infectious propagules, and generation of diversity. In fungi and the capacity for phenotypic diversity (Butler et al., 2009; Reedy parasites once thought asexual, genomics reveals they have et al., 2009). Finally, an extant sexual cycle was uncovered for retained machinery for sex, and laboratory studies uncovered A. fumigatus, a species previously thought to be asexual, extant sexual cycles that enable but limit genetic exchange, requiring specialized media and culture conditions (O’Gorman generating populations with clonal features. et al., 2009). Thus, rather than being asexual, pathogenic fungi In fungi, sex commonly involves two cells of opposite mating have retained cryptic, modified sexual cycles that enable both type (a, a) that secrete mating pheromones to trigger cell-cell inbreeding and outcrossing and generate diversity in novel fusion (heterothallism). Other fungi are self-fertile, and a single ways. This includes the potential of sex itself to serve as isolate can undergo sexual reproduction (homothallism). Transi- a mutagen that generates genetic diversity de novo, analogous tions between these sexual reproduction modes, outcrossing to the model fungus Aspergillus nidulans in which parasexual versus selfing/inbreeding, commonly occur throughout the reproduction generates phenotypic plasticity during experi- fungal kingdom. Recent studies of the three most common mental evolution (Schoustra et al., 2007). systemic human fungal pathogens (Cryptococcus neoformans, Our understanding of sexual reproduction in pathogenic fungi Candida albicans, Aspergillus fumigatus) reveal novel mating parallels recent advances in defining extant sexual cycles of paradigms that differ substantially from model species like human parasite pathogens. In the protozoan Giardia, the S. cerevisiae. discovery of a novel sexual reproduction mode involving nuclear C. neoformans has an a-a opposite sex mating cycle that has fusion, meiotic gene expression, and genetic exchange illus- been defined in the laboratory for more than 30 years, and yet the trates a novel form of self-fertility, similar to unisexual mating natural population is largely unisexual, predominantly a mating of fungal pathogens (Poxleitner et al., 2008). In the protozoan type, and had therefore been thought to be asexual. Instead, parasite Leishmania, coinfections in the sand fly vector reveal a novel form of self-fertility evolved in which cells of one mating an extant capacity for genetic exchange with parallels to the type (a) can complete a unisexual cycle without an opposite C. albicans parasexual cycle (Akopyants et al., 2009). In the ki- partner, and population genetics studies suggest this may be netoplastid Trypanosoma, an extant sexual cycle involving the predominant form of sexual reproduction in nature meiosis and intraclonal and interclonal mating mirrors the out- (Bui et al., 2008; Lin et al., 2005, 2007, 2009). C. albicans was crossing/self-fertile duality of human fungal pathogens (Heitman, thought to be asexual for more than a century, but with the 2006). In Plasmodium a well-defined sexual cycle is essential for discovery of the MTL locus, isolation of a and a mating compe- vertebrate-insect transmission, and an outline for this develop- tent strains, and the discovery of genetic and host conditions mental cascade is emerging from proteomic and molecular 86 Cell Host & Microbe 8, July 22, 2010 ª2010 Elsevier Inc. Cell Host & Microbe Review Figure 1. Sex and Virulence of Fungal Ascomycete Basidiomycetes Pathogens Candida albicans Malassezia globosa Cryptococcus neoformans Ustilago maydis Four major human and plant fungal pathogens are illustrated to compare and contrast features of Human pathogen Plant pathogen sexual reproduction and links to virulence (adap- ted from Hsueh and Heitman, 2008). genetic diversity, and the a-mating type has been linked to virulence. • Obligate diploid • Haploid yeast • Haploid yeast found • Haploid yeast that only The structure and evolution of a large, commensal and commensal of human world-wide in trees, soil, infects the plant host pathogen that causes skin associated with and pigeon guano. (corn) as a filamentous complex mating type (MAT) locus that mucosal and systemic eczema and dandruff. • Plants or pigeon guano, dikaryon. governs sexual identity and promotes infections. • Conservation of MAT stimulate mating, • Mating and sexual virulence has been defined (Fraser et al., • Retains opposite-sex and mating and producing spores recently reproduction occurs only and same-sex meiotic genes shown to represent in association with the 2004). Studies have also shown that a-a parasexual cycles, and suggests sex may infectious propagules. plant and the yeast form opposite sex occurs in environmental mating can occur on occur on human skin • Opposite-sex mating has is not infectious. niches (pigeon guano, plants) and is the skin or in response and could produce been geographically to CO2/anaerobic GI novel antigens to restricted. extant in sub-Saharan Africa (Litvintseva tract conditions. provoke immune • Same-sex mating likely et al., 2003; Nielsen et al., 2007; Xue responses. occurs globally to enable et al., 2007), and document that sexually generation of diversity. produced spores are infectious (Giles et al., 2009; Velagapudi et al., 2009). Moreover, an unusual sexual mode has studies (Khan et al., 2005). Yet in all of the parasite pathogens, been discovered involving only one mating type that generates we know nothing about how their sexual identities are specified. infectious spores and diversity within unisexual populations Insights from fungal sex and MAT evolution might lay the founda- (Lin et al., 2005). tion to approach this question and suggest models by which C. neoformans mating involves two opposite haploid mating parasite sexual identity is specified. partners, a and a, which secrete pheromones that trigger cell- These studies of sex evolution and its impact throughout cell fusion (McClelland et al., 2004). The resulting dikaryon fungi and parasites illuminate paradigms for generating and harbors two congressed, unfused nuclei, and undergoes maintaining genetic diversity in microbial pathogens with impli- a dimorphic transition from budding yeast to filamentous cations for multicellular eukaryotes. Reviews on fungal sex and hyphae. The hyphae produce a specialized structure (basidia) the meiotic toolkit have recently appeared to which the inter- where nuclear fusion and meiosis occur, and repeated rounds ested reader is referred (Butler, 2010; Lee et al., 2010; Lin, of mitosis/budding decorate the basidium surface with long 2009; Morrow and Fraser, 2009; Schurko and Logsdon, 2008; spore chains. Spores are readily aerosolized, and their small Schurko et al., 2009; Sherwood and Bennett, 2009). Parallels size promotes alveolar deposition following inhalation. Similar between fungal and parasite sexual reproduction were reviewed to yeast cells, these sexually produced spores are infectious in earlier (Heitman, 2006); advances since 2006 are the focus here. murine inhalation models; unlike yeast cells, spores do not require opsonization for phagocytosis by alveolar macrophages (Giles et al., 2009; Velagapudi et al., 2009). Sex in Fungi Sexual reproduction and identity are governed by the MAT Cryptococcus neoformans locus, which
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