Common strategies for antigenic variation by bacterial, fungal and protozoan pathogens

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.

Figure 1

Example of how increasing numbers of phase variant genes can contribute to large numbers of phenotypes. Observe how the total number of phenotypes can be calculated as 2ⁿ, where N represents the number of independently regulated genes.

Figure 2

Schematic diagram showing phase variation through slipped strand mispairing. During DNA replication, tandem DNA repeats can “slip”, leading to changes in the number of repeats and consequent changes in the transcription or translation of the gene product. A. Some tpr genes of Treponema pallidum (left) are regulated at the level of transcription through changes in the number of Gs found upstream of the transcription start site. B. Similar mispairing of CTCTT repeats within the open reading frame can regulated Opa expression in Neisseria at the level of translation.

Figure 3

Examples of phase variation regulated at the level of mRNA translation in two eukaryotic pathogens. A. The var2csa gene of Plasmodium falciparum is transcribed into an mRNA with two open reading frames (ORFs). The mRNA is bound by the large and small subunits of the ribosome (gray circles), which then moves along the transcript (arrows) until it initiates translation at a start codon. The first ORF (uORF) is translated when the parasites infect children, men or nonpregnant women, however the ribosome is thought to dissociate from the mRNA prior to reaching the second ORF, thus preventing expression of the encoded form of PfEMP1. The second ORF is only translated when parasites infect pregnant women and the encoded form of PfEMP1 only functions in the presence of a placenta. B. Mutually exclusive expression of the vsp gene of Giardia lamblia is achieved through the RNAi pathway. Small RNAs (red strands) target the RNAi degradation machinery (scissors) to mRNAs from all but a single vsp gene. Only mRNA from one gene escapes degradation and is translated into protein, although the mechanism that enables this escape is unknown.

Figure 4

Antigenic variation through mechanisms that rely on DNA recombination. A. Gene conversion resulting in the duplication of a segment of a silent gene into an active expression site. The duplicated segment can include an entire open reading frame or small portions, creating a chimeric gene as illustrated here. B. Promoter inversion. As shown for M. pulmonis, inversion of a single promoter leads to expression of one vsa gene at a time (top panel). Inversion occurs by recombination between regions of sequence similarity (black boxes). In the mpl genes of M. penetrans (bottom panel), tandem arrays of genes are each regulated by separate promoters. In one orientation, a promoter drives the expression of a short transcript (ended by a transcriptional terminator, red box) that does not encode protein. When inverted, the promoter drives transcription through the mpl open reading frame, leading to expression of the encoded protein.

Figure 5

A loose order of expression can be programmed into large multi-copy gene families. vmp gene expression in Borrelia is an example. A. The active vmp gene contains two elements that contribute to expression switching called the UHS and the DHS. These elements are also found within the silent genes, with varying degrees of sequence identity (displayed here as differing degrees of dark red color). In addition, the distance between the DHS and the vmp coding region is also variable. B. In a mouse infection, waves of bacteria arise as antigenically distinct populations cause relapses. C. Examination of the expressed vmp gene in each wave shows that the order of expression is determined by the degree of sequence identity within the UHS and the distance between the DHS and the coding region.