Antigenic variation

Antigenic variation or antigenic alteration refers to the mechanism by which an infectious agent such as a protozoan, bacterium or virus alters the proteins or carbohydrates on its surface and thus avoids a host immune response. It is related to phase variation. Antigenic variation not only enables the pathogen to avoid the immune response in its current host, but also allows re-infection of previously infected hosts. Immunity to re-infection is based on recognition of the antigens carried by the pathogen, which are 'remembered' by the acquired immune response. If the pathogen's dominant antigen can be altered, the pathogen can then evade the host's acquired immune system. Antigenic variation can occur by altering a variety of surface molecules including proteins and carbohydrates. Antigenic variation can result from gene conversion, site-specific DNA inversions, hypermutation, or recombination of sequence cassettes. The result is that even a clonal population of pathogens expresses a heterogeneous phenotype. Many of the proteins known to show antigenic or phase variation are related to virulence. Antigenic variation or antigenic alteration refers to the mechanism by which an infectious agent such as a protozoan, bacterium or virus alters the proteins or carbohydrates on its surface and thus avoids a host immune response. It is related to phase variation. Antigenic variation not only enables the pathogen to avoid the immune response in its current host, but also allows re-infection of previously infected hosts. Immunity to re-infection is based on recognition of the antigens carried by the pathogen, which are 'remembered' by the acquired immune response. If the pathogen's dominant antigen can be altered, the pathogen can then evade the host's acquired immune system. Antigenic variation can occur by altering a variety of surface molecules including proteins and carbohydrates. Antigenic variation can result from gene conversion, site-specific DNA inversions, hypermutation, or recombination of sequence cassettes. The result is that even a clonal population of pathogens expresses a heterogeneous phenotype. Many of the proteins known to show antigenic or phase variation are related to virulence. Antigenic variation in bacteria is best demonstrated by species of the genus Neisseria (most notably, Neisseria meningitidis and Neisseria gonorrhoeae, the gonococcus); species of the genus Streptococcus and the Mycoplasma. The Neisseria species vary their pili (protein polymers made up of subunits called pilin which play a critical role in bacterial adhesion, and stimulate a vigorous host immune response) and the Streptococci vary their M-protein. In the bacterium Borrelia burgdorferi, the cause of Lyme disease, the surface lipoprotein VlsE can undergo recombination which results in antigenic diversity. The bacterium carries a plasmid that contains fifteen silent vls cassettes and one functional copy of vlsE. Segments of the silent cassettes recombine with the vlsE gene, generating variants of the surface lipoprotein antigen. Antigenic variation is employed by a number of different protozoan parasites. Trypanosoma brucei and Plasmodium falciparum are some of the best studied examples. Trypanosoma brucei, the organism that causes sleeping sickness, replicates extracellularly in the bloodstream of infected mammals and is subjected to numerous host defense mechanisms including the complement system, and the innate and adaptive immune systems. To protect itself, the parasite decorates itself with a dense, homogeneous coat (~10^7 molecules) of the variant surface glycoprotein (VSG). In the early stages of invasion, the VSG coat is sufficient to protect the parasite from immune detection. The host eventually identifies the VSG as a foreign antigen and mounts an attack against the microbe. However, the parasite’s genome has over 1,000 genes that code for different variants of the VSG protein, located on the subtelomeric portion of large chromosomes, or on intermediate chromosomes. These VSG genes become activated by gene conversion in a hierarchical order: telomeric VSGs are activated first, followed by array VSGs, and finally pseudogene VSGs. Only one VSG is expressed at any given time. Each new gene is switched in turn into a VSG expression site (ES). This process is partially dependent on homologous recombination of DNA, which is mediated in part by the interaction of the T. brucei BRCA2 gene with RAD51 (however, this is not the only possible mechanism, as BRCA2 variants still display some VSG switching). In addition to homologous recombination, transcriptional regulation is also important in antigen switching, since T. brucei has multiple potential expression sites. A new VSG can either be selected by transcriptional activation of a previously silent ES, or by recombination of a VSG sequence into the active ES (see figure, 'Mechanisms of VSG Switching in T. brucei'). Although the biological triggers that result in VSG switching are not fully known, mathematical modeling suggests that the ordered appearance of different VSG variants is controlled by at least two key parasite-derived factors: differential activation rates of parasite VSG and density-dependent parasite differentiation. Plasmodium falciparum, the major etiologic agent of human malaria, has a very complex life cycle that occurs in both humans and mosquitoes. While in the human host, the parasite spends most of its life cycle within hepatic cells and erythrocytes (in contrast to T. brucei which remains extracellular). As a result of its mainly intracellular niche, parasitized host cells which display parasite proteins must be modified to prevent destruction by the host immune defenses. In the case of Plasmodium, this is accomplished via the dual purpose Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 is encoded by the diverse family of genes known as the var family of genes (approximately 60 genes in all). The diversity of the gene family is further increased via a number of different mechanisms including exchange of genetic information at telomeric loci, as well as meiotic recombination. The PfEMP1 protein serves to sequester infected erythrocytes from splenic destruction via adhesion to the endothelium. Moreover, the parasite is able to evade host defense mechanisms by changing which var allele is used to code the PfEMP1 protein. Like T. brucei, each parasite expresses multiple copies of one identical protein. However, unlike T. brucei, the mechanism by which var switching occurs in P. falciparum is thought to be purely transcriptional. Var switching has been shown to take place soon after invasion of an erythrocyte by a P. falciparum parasite. Fluorescent in situ hybridization analysis has shown that activation of var alleles is linked to altered positioning of the genetic material to distinct “transcriptionally permissive” areas.