Key Points
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Mammals have evolved an elaborate, multifaceted immune system to respond to the ever-present threat of infection by pathogenic microorganisms. Bacterial, protozoan and fungal pathogens have responded by evolving equally elaborate systems to avoid destruction by their hosts. This process of coevolution has resulted in the development of complex genetic systems that underlie antigenic variation by numerous pathogenic microorganisms.
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The process of antigenic variation is focused at the host–pathogen interface, and in particular at the cell surface of the infectious organisms. Molecules displayed on the cell surface of pathogens often mediate adhesion within specific niches and are frequently virulence determinants.
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Some systems of antigenic variation involve the activation and silencing of genes that encode molecules exposed to the immune system of the infected host. In its simplest form, this entails changes in the expression of genes that are regulated individually, an on–off process referred to as phase variation.
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In other organisms, a single expression site is present for a key protein, with multiple silent gene copies or cassettes present elsewhere in the genome. The sequence of the expressed gene changes by gene conversion (or duplicative transposition) of large or small DNA sequences from the silent pseudogenes into the expression site.
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In more sophisticated systems, the pathogen has evolved large, multicopy gene families, with each copy encoding a different form of the surface antigen. In these organisms, each individual gene has all of the elements necessary for expression, and each undergoes silencing and activation as described above; however, there is an additional layer of regulation to ensure that only a single gene is active at any particular time. Gene silencing and activation within the family is therefore coordinated and strictly mutually exclusive.
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Although many of the genetic systems underlying antigenic variation — for example, slipped-strand mispairing or gene conversion — involve alterations to the genome, in several organisms changes in gene expression do not involve any alterations in the primary DNA sequence. These systems instead rely on epigenetic modifications to control gene activation and silencing, the hallmarks of which include histone modifications, the use of modified nucleotides, changes in chromatin structure and nuclear organization.
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In a few cases, the order in which specific antigen variants are expressed over the course of an infection is determined by the sequence of the encoding genes. This can help to extend the length of an infection or the infectious stage, thereby increasing the likelihood of transmission to a new host.
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Antigenic variation also enhances the capacity of a pathogen to infect a host that has resolved (or been cured of) prior infection (reinfection), or is persistently infected with the same organism (superinfection). This both expands the population of susceptible hosts and permits genetic exchange between organisms.
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.
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Acknowledgements
The authors thank S. Frank for valuable discussions concerning the possible role of antigenic variation in the duration of infectious syphilis lesions. Work in the laboratory of K.W.D. is supported by a grant from the US National Institutes of Health (AI 52390) and the United States–Israel Binational Science Foundation. The Department of Microbiology and Immunology at Weill Medical College of Cornell University acknowledges the support of the William Randolph Hearst Foundation. K.W.D. is a Stavros S. Niarchos Scholar. Work in the laboratory of S.A.L. is supported by the National Institutes of Health (AI42143 and AI63940) and work in the laboratory of J.R.S. is supported by a grant from the National Institute of Allergy and Infectious Diseases (5R01AI036701-14).
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Glossary
- Antigenic variation
-
Changes in the antigenic molecules of an invasive organism exposed to the immune system over the course of an infection. This can incorporate mechanisms of phase variation, DNA recombination, epigenetic modifications or mutually exclusive expression.
- Phase variation
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Regulation of gene expression in which an individual gene switches between 'on' and 'off' states. This can be regulated at the level of either transcription initiation or RNA translation.
- Epigenetic
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Inheritance of particular patterns of gene expression that is not based on changes in DNA sequence. This phenomenon is often associated with DNA modifications (in particular DNA methylation) and/or with alterations in chromatin structure. Post-translational modifications to histones are a well-studied example of chromatin marks associated with epigenetic inheritance.
- Mutually exclusive expression
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The expression of a single gene from a multicopy gene family. Typically, switches in gene expression do not require DNA recombination and are strictly coordinated so that activation of one gene involves the simultaneous silencing of the previously active gene.
- Gene conversion
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Also called duplicative transposition. The copying of an entire gene or segment of a gene from one position in the genome to a different position in the genome. The silent copy of the gene is often referred to as the donor, and gene conversion results in its duplication within the genome.
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Deitsch, K., Lukehart, S. & Stringer, J. Common strategies for antigenic variation by bacterial, fungal and protozoan pathogens. Nat Rev Microbiol 7, 493–503 (2009). https://doi.org/10.1038/nrmicro2145
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DOI: https://doi.org/10.1038/nrmicro2145
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Investigation of the immune escape mechanism of Treponema pallidum
Infection (2023)
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Antibodies to variable surface antigens induce antigenic variation in the intestinal parasite Giardia lamblia
Nature Communications (2023)