Coupled Phase-Variable Expression and Epitope Masking of Selective Surface Lipoproteins Increase Surface Phenotypic Diversity in Mycoplasma hominis

Abstract

A new mechanism expanding mycoplasmal surface diversity is described. Exposure of surface epitopes on a constitutively expressed membrane protein (P56) of Mycoplasma hominis was subject to high-frequency phase variation due to phase-variable expression of the P120 antigen and its selective masking of P56 epitopes. Phase-variable masking may confer previously unrealized adaptive capabilities on mycoplasmas.Many species of mycoplasma are causative agents of infectious diseases in plants and animals, including humans. Due to the lack of cell walls and surface appendages common to other eubacteria, the membrane proteins of many mycoplasmas are directly involved in mycoplasma-host interaction and play crucial roles in mycoplasma pathogenesis (14,21). A common strategy utilized by pathogenic mycoplasmas for adaptation in a host appears to be the rapid diversification of surface protein expression and structure (22,26), as recently reviewed in reference 14. Such changes lead to a dynamic phenotypic variation that may contribute to successful infection. Differential expression of mycoplasma surface proteins, which to date has been found to occur by promoter mutation (5, 27), DNA inversion (1, 17), or frameshift mutation (20,29), has been widely implicated in phenotypic variation of mycoplasma populations. In addition, it has been indirectly suggested that variable expression of particular surface proteins may affect other membrane molecules (4,16,19).We have used Mycoplasma hominis, a human pathogen associated with clinically diverse diseases (including urogenital infections, postpartum fever, and arthritis) (8), as a model system with which to study adaptive mechanisms of pathogenic mycoplasmas in the human host. Several surface lipoproteins of M. hominis, including the Vaa adhesin, P120, and Lmp, have been characterized in previous studies by us and others. Vaa is subject to size, phase, and antigenic variations in clonal populations and among strains of M. hominis (2,6,28,29). We have shown in clinical isolate 1620 of M. hominis that (i) size variation of Vaa is caused by gain or loss of the tandem repetitive sequences in the central region of this protein; (ii) Cterminal sequence divergence of Vaa leads to antigenic variation among strains, as shown also by others in diverse isolates (2, 6); and (iii) single-nucleotide insertions or deletions in a polyadenine tract within the 5Ј end of the vaa coding region create reversible frameshift mutations causing variable expression of Vaa, with concurrent alterations of M. hominis adherence to human cells in vitro (29). The abundant P120 surface lipoprotein contains a hypervariable N-terminal region, two central semivariable domains, and a highly conserved C-terminal region (3, 12). The hypervariable domain of P120 is exposed on the mycoplasma surface and is the target of a strong humoral response in the human host, while the conserved C-terminal region is not. The role of P120 has not been determined. Lmp antigens, encoded by a multiple-gene family, are also surface exposed...

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“…The repetitive sequences function like interchangeable cassettes that can be deleted, inserted or recombined to form a rich variety of protein variants (Zheng et al, 1995;Zhang & Wise, 1996; Yogev et al, 1995;Lysnyansky et al, 1999Lysnyansky et al, , 2001aBoguslavsky et al, 2000;Boesen et al, 1998;Citti et al, 2000). Epitope masking is a phenomenon in which the epitopes of a constitutively expressed surface protein are subject to variable surface exposure, either due to a secondary protein that sterically blocks accessibility of the surface epitopes or as a consequence of size variation Zhang & Wise, 2001). Variable proteins are often subjected to both size and phase variation, and many are members of multigene families.…”

Variable Surface Protein Vmm ofMycoplasma mycoidessubsp.mycoidesSmall Colony Type

“…Anti-genic variation of proteins often involves DNA rearrangements of repetitive regions, thereby creating new combinations of structural domains and changes in size (12,13,24,60,61,93,95,98,99). Epitope masking (83,88,96) is another process that contributes to phase variation of proteins on the bacterial surface.…”

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