Antigenic variation in Mycobacterium tuberculosis

While it is still too early to attribute biological functions to the PE and PPE families, it is tempting to speculate that they could be important protein antigens that may represent a source of antigenic variation. A number of observations support this contention. It is known that one PGRS member, WHO antigen 22T, a 55 kDa protein present in culture filtrate and cell extracts capable of binding fibronectin (Abou-Zeid et al 1991), is produced during infection and disease, and elicits an antibody response. When sera from 14 different tuberculosis patients were screened for reactivity to a recombinant form of 22T, strongly positive responses were observed in eight cases, suggesting that either individuals mount different immune responses or that this PGRS protein may not be produced by all strains of M. tuberculosis. Indirect support in favour of the latter is provided by Southern blotting studies with a PGRS-specific probe as striking differences in the hybridization profiles were observed (Fig. 4).

Given the remarkably low level of nucleotide sequence variation in structural genes (Sreevatsan et al 1997), and hence the high degree of conservation of restriction sites, it is probable that the restriction fragment length polymorphisms observed with PGRS genes, as well as with MPTR genes, reflect physical differences such as repeat length or copy number. This could result from inter- or intragenic recombinational events between the repetitive sequences comprising the corresponding coding sequences or strand slippage during replication, as discussed previously for the PGRS members (Poulet & Cole 1995a,b). It is probably significant in this respect that the genes encoding PE and PPE proteins often occur in clusters on the chromosome of H37Rv.

Antigenic variation among the surface proteins of many intra- and extracellular pathogens is commonly observed, presumably reflecting the selective pressure of the host's immune system. This has been well documented for both eukaryotes

FIG. 4. Restriction fragment length polymorphism analysis of Mycobacterium tuberculosis using a polymorphic GC-rich sequence (PGRS)-specific probe hybridized to Alul digestions. Lane 1: M. tuberculosis H37Rv. Lane 2: strain 161. Lane 3: strain 133. Lane 4: strain 253. Lane 5: strain 272. Lane 6: strain 164. Lane 7: strain 205. The positions of size markers used to calibrate the gel are shown.

such as trypanosomes, and prokaryotes, well exemplified by Neisseria gonorrhoeae or Haemophilus influenzae. In one of the best studied cases, the pili of Neisseria spp., antigenic variation often involves recombinational events in which previously silent coding sequences are inserted into expression sites (Haas et al 1992, Robertson & Meyer 1992). In N. gonorrhoeae and H. influenzae, other means of achieving antigenic variation include RecA-independent recombination, or replication errors such as strand slippage, within simple sequence (penta- or tetranucleotide) repeats in genes coding for surface proteins, thereby culminating in the use of alternative reading frames (Hoodet al 1996). Recombination between copies of tandemly arranged, repetitive motifs that code for multiple surface-exposed domains of the M-protein of Streptococci is another well characterized mechanism of antigenic variability (Robertson & Meyer 1992). Given the many potential parallels between these systems and the PE/PPE structures, it is important that further studies be performed to investigate the molecular basis of the polymorphism associated with the genes comprising the PPE and PE families. If genetic alterations led to significant antigenic variability they could be important for understanding protective immunity in tuberculosis and explain the varied responses seen in different Bacillus Calmette—Guerin vaccination programmes (Bloom & Fine 1994).

Important contributions to the work described here were made by R. Brosch, K. Eiglmeier, T. Garnier, S.V. Gordon, S. Poulet, C. Churcher, D. Harris, K. Badcock, D. Basham, D. Brown, T. Chillingworth, R. Connor, R. Davies, K. Devlin, T. Feltwell, S. Holroyd, S. Gentles, K. Jagels, J. McLean, S. Moule, L. Murphy, K. Oliver, J. Osborne, J. Parkhill, M. Quail, M-A. Rajandream, J. Rogers, S. Rutter, K. Seeger, J. Skelton, R. Squares, S. Squares, J. Sulston, K. Taylor and S. Whitehead. Financial support from the Wellcome Trust and the Association Française Raoul Follereau is gratefully acknowledged.

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