Common Strategies for Antigenic Variation by Bacterial, Fungal and Protozoan Pathogens
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REVIEWS Common strategies for antigenic variation by bacterial, fungal and protozoan pathogens Kirk W. Deitsch*, Sheila A. Lukehart‡ and James R. Stringer§ Abstract | The complex relationships between infectious organisms and their hosts often reflect the continuing struggle of the pathogen to proliferate and spread to new hosts, and the need of the infected individual to control and potentially eradicate the infecting population. This has led, in the case of mammals and the pathogens that infect them, to an ‘arms race’, in which the highly adapted mammalian immune system has evolved to control the proliferation of infectious organisms and the pathogens have developed correspondingly complex genetic systems to evade this immune response. We review how bacterial, protozoan and fungal pathogens from distant evolutionary lineages have evolved surprisingly similar mechanisms of antigenic variation to avoid eradication by the host immune system and can therefore maintain persistent infections and ensure their transmission to new hosts. Antigenic variation The evolution of mammalian species has resulted in the avoid recognition by the immune system through the Changes in the antigenic development of large, multicellular organisms that, in use of hypervariable surface molecules that allow them molecules of an invasive addition to replicating in their own right, also provide an to multiply undetected (at least temporarily) or, once organism exposed to the environment for the proliferation of many other species, recognized, they must be able to avoid destruction immune system over the course of an infection. This can particularly single-celled organisms that inhabit various by various components of the innate and acquired incorporate mechanisms of niches within, and on the surface of, mammals. It has immune response. This common need to evade the phase variation, DNA been estimated that the average human contains tenfold host immune system has resulted in the evolution of recombination, epigenetic more bacterial cells than human cells1. Although the remarkably similar survival strategies among pathogens, modifications or mutually relationship between the host organism and its resident even those from distant evolutionary lineages. One such exclusive expression. microorganisms is often commensal or symbiotic, many strategy is antigenic variation: the capacity of an infecting *Department of Microbiology microbial species have evolved to have a detrimental or organism to systematically alter the proteins displayed to and Immunology, Weill even lethal effect on their mammalian hosts. Mammals the host immune system, such that the host is confronted Medical College of Cornell have responded by developing an extremely complex, with a continually changing population that is difficult University, New York, multifaceted immune system that enables the infected or impossible to eliminate. The term antigenic variation New York 10021, USA. individual to recognize, control and, in some cases, erad- is generally used to encompass both phase variation (the ‡Departments of Medicine and Global Health, University icate detrimental microorganisms. The microorganisms on–off expression of a particular antigen) and true anti- of Washington, Seattle, have, in turn, evolved correspondingly complex methods genic variation (the expression of alternative forms of a Washington 98195, USA. for avoiding destruction, resulting in an intricate balance particular antigen). §Department of Molecular of host–pathogen interactions that we are only beginning Antigenic variation has been extensively studied in a Genetics, Biochemistry and Microbiology, University of to understand. number of microbial systems, leading to the generation Cincinnati College of Infectious microorganisms — viral, bacterial, fungal of several models of the mechanisms underlying this Medicine, Cincinnati, Ohio or protozoan — all face similar challenges when infect- phenomenon. In recent years, the availability of exten- 45267, USA. ing a susceptible host. First, they must avoid mechanical sive genome sequence data and improvements in the Correspondence to K.W.D. clearance to successfully colonize their preferred tissue tools available to study non-model pathogenic organ- e-mail: kwd2001@med. cornell.edu or niche, a process that frequently involves the produc- isms have shed new light on old paradigms, providing doi:10.1038/nrmicro2145 tion of specific adhesive molecules that use various greater insight into how pathogens avoid the immune Published online 8 June 2009 host ligands as anchors. In addition, they must either systems of their mammalian hosts. In this Review we NATURE REVIEWS | MICROBIOLOGY VOLUME 7 | JULY 2009 | 493 © 2009 Macmillan Publishers Limited. All rights reserved REVIEWS a 1 gene loci, occur frequently and are readily reversible; these features distinguish these systems from antigenic varia- 1 1 1 on tion caused by random spontaneous mutation, as is more Phase on 2 1 off or typical of some viruses, such as HIV-1. Phase off A simple form of antigenic variation is often termed b 2 genes phase variation because it was first recognized by observing switching between two alternative pheno- 1 1 1 on, 2 on types (phases) among the cells in a clonal population Phase on 2 1 off, 2 on of bacteria. In general, one phase variant differs from or 3 1 on, 2 off another by virtue of the particular cell surface markers Phase off 4 1 off, 2 off expressed (for example, pili), such that a cell surface marker is present in one phase and not in the alternative 2 phase. In some cases, more than one gene in a family can Phase on be regulated by phase variation, in which case each gene or switches on and off independently. The possible number Phase off of phenotypes that can be created by N phase-variable genes is therefore 2N (FIG. 1). c 3 genes Although as few as 7 phase-variable genes can pro- duce more than 100 different phenotypes, even more 1 1 1 on, 2 on, 3 on Phase on 2 1 off, 2 on, 3 on phenotypes can be generated by systems that use families or 3 1 on, 2 off, 3 on of related DNA sequences. Some of these systems dis- mutually exclusive expression Phase off 4 1 off, 2 off, 3 on play a phenomenon called Phase variation 5 1 on, 2 on, 3 off in which any family member can be expressed but only Regulation of gene expression 2 6 1 off, 2 on, 3 off one member of the family is expressed in a particular in which an individual gene Phase on 7 1 on, 2 off, 3 off microbial cell. The number of different phenotypes is switches between ‘on’ and ‘off’ or therefore at least as high as the number of family mem- states. This can be regulated at 8 1 off, 2 off, 3 off the level of either transcription Phase off bers. However, the number of possible phenotypes can initiation or RNA translation. be much greater than the number of family members 3 if recombination occurs among family members, as Epigenetic Phase on recombination can produce virtually unlimited diversity Inheritance of particular or through the production of chimeric sequences. patterns of gene expression that is not based on changes in Phase off DNA sequence. This Figure 1 | Relationship between the number of phase Mechanisms of phase variation phenomenon is often variant genes and the numberNatur ofe phenotypes.Reviews | Microbiolog An y Phase variation in bacteria was first identified in the associated with DNA increase in the number of phase variant genes can expression of flagella in Salmonella, and a DNA inversion modifications (in particular contribute to a large increase in the number of possible 2 DNA methylation) and/or with mechanism was implicated . Perhaps the most extensively alterations in chromatin phenotypes. The total number of phenotypes can be studied organisms that undergo phase variation, however, N structure. Post-translational calculated as 2 (N represents the number of are the pathogenic Neisseria spp., including Neisseria men- modifications to histones are a independently regulated genes), so in part a, where 1 gene ingitidis and Neisseria gonorrhoeae. Both of these species 1 well-studied example of is shown, the total number of phenotypes is 2 (2 ), in part b, produce surface proteins that function in adherence to chromatin marks associated where 2 genes are shown, the total number of phenotypes host cells and perhaps also in tissue tropism3–6, in particu- with epigenetic inheritance. is 4 (22) and in part c, where 3 genes are shown, the total number of phenotypes is 8 (23). lar pili and the Opa proteins. Antigenic variation mecha- Mutually exclusive nisms that were first defined in these bacteria, including expression phase variation by slipped-strand mispairing during DNA The expression of a single gene gene conversion from a multicopy gene family. highlight several recent examples in bacteria, protozoa replication and , have provided a conceptual Typically, switches in gene and fungi which illustrate common themes that are framework for many recent advances in our understanding expression do not require DNA repeatedly observed despite significant evolutionary of the mechanisms responsible for antigenic variation in recombination and are strictly distance between the various pathogens. other prokaryotes and eukaryotes. Several recent examples coordinated so that activation of phase variation mechanisms are described below. of one gene involves the simultaneous silencing of Gene families and variant phenotypes the previously active gene. Antigenic variation in microorganisms is created by Phase variation through transcriptional regulation. two general types of mechanism: genetic mechanisms Treponema pallidum, the causative agent of syphilis, is a Gene conversion and epigenetic mechanisms. Genetic events (muta- difficult organism to study owing to our inability to cul- Also called duplicative transposition. The copying of tion and recombination) change the DNA sequence of ture or genetically manipulate this bacterium. However, an entire gene or segment of a an antigen-encoding gene or its regulatory elements, recent work has shown that there are many parallels gene from one position in the thereby altering either the level of expression of the gene between T.