- Email: [email protected]
Microbial genomics
COMMENT
Orme raises several issues that I intentionally simplified in my recent review2 for the purposes of space and continuity. I agree that the organization of granulomas is complex, and depends on the concerted action of various cell types, cytokines and chemokines. I also agree that the number of bacteria in and around granulomas is often small; however, granulomas continue to grow. I stressed that the presence of antigen was the key event. One possibility is that bacterial antigens find their way to the draining lymph nodes of the
lung and drive a continual dendriticcell-mediated expansion and trafficking of T cells to and from lung granulomas. However, the resilience of the bacteria frustrates the immune system in a cyclical fashion. The validity of these models needs to be tested in an in vivo setting. I agree with Orme with regard to the growth state of bacteria. I consider a ‘quiescent’ phase of bacterial growth unlikely for the same reasons and also because of the considerable genetic investment required to participate in multiple growth phases. The simple question
of whether bacteria are growing, or not growing, offers ample opportunity for experimentation.
Peter J. Murray Dept of Infectious Diseases, St Jude Children’s Research Hospital, 332 North Lauderdale St, Memphis, TN 38103, USA References 1 Ting, L-M. et al. (1999) J. Immunol. 163, 3898–3906 2 Murray, P.J. (1999) Trends Microbiol. 7, 366–372
Horizons Varying the rifins
M
any pathogens evade the host immune response or adapt to their environment by expressing surface proteins that undergo rapid switching. In the case of the principal human malaria parasite, Plasmodium falciparum, products of a multigene family known as var [variants of P. falciparum erythrocyte membrane protein 1 (PfEMP1)] are expressed on the surface of infected erythrocytes. Here, they undergo clonal antigenic variation and contribute to malaria pathogenesis by mediating adherence to a variety of host endothelial receptors and to uninfected erythrocytes. PfEMP1 is therefore considered a major virulence factor, but its presence alone has not been sufficient to explain all the parasite-induced changes in surface phenotype. Now, Kyes et al.1 have discovered a second gene family, rif (repetitive interspersed family), which is associated with var at subtelomeric sites in the genome, and which encodes clonally variant proteins – rifins – that are expressed on the infected erythrocyte surface. The high copy number, high level of sequence diversity and erythrocyte location of rifins are consistent with their being subject to immune selection, and imply an important role for these polymorphic proteins in the host–parasite interaction underlying malaria pathogenesis and host protective immunity. As the surface of the infected erythrocyte
is the major interface between the host and the parasite during bloodstage P. falciparum infection, the fact that two distinct sets of clonally variable proteins are expressed at this site suggests that an important evolutionary advantage is conferred by their presence. The next step will be to elucidate the function of rifins.
Microbial genomics Sequencing sister genomes A few years ago, when bacterial genome sequencing was new, it was often said that it would only ever be feasible to fund the sequencing of the genome of just one species in a genus. It is thus heartening to see the Sanger Centre (http://www.sanger. ac.uk/Projects/) turn its attentions to sequencing the genomes of several species whose sisters have already been sequenced. Thanks to funding from the UK Ministry of Agriculture, Fisheries and Food (MAFF) and Beowulf Genomics, shotgun sequencing of the genome of Mycobacterium bovis is now under way, even though it is known to be 99.9% identical to Mycobacterium tuberculosis, one strain of which has already been sequenced by the Sanger and the sequence of a second is nearing completion at The Institute for Genomic Research
1 Kyes, S.A. et al. (1999) Rifins: a second family of clonally variant proteins expressed on the surface of red cells infected with Plasmodium falciparum, Proc. Natl. Acad. Sci. U. S. A. 96, 9333–9338
Andrew Taylor-Robinson [email protected]
(TIGR) (http://www.tigr. org/tdb/CMR/gmt/htmls/ SplashPage.html). Similarly, shotgun sequencing and library testing are now in progress at the Sanger for Bordetella bronchiseptica and Bordetella parapertussis, just as the Bordetella pertussis sequence is nearing completion. The trend seems set to continue, with two more Yersinia species (in addition to the nearly completed Yersinia pestis) and two more clostridial species (in addition to the nearly completed Clostridium difficile) listed as future targets for genome sequencing on the Sanger Centre’s web site. It is now perfectly conceivable that within a few years at least one genome will have been sequenced from every significant bacterial pathogen of humans, plants and animals. Mark Pallen [email protected]
0966-842X/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved. TRENDS
IN
MICROBIOLOGY
479
VOL. 7
NO. 12
DECEMBER 1999
Orme raises several issues that I intentionally simplified in my recent review2 for the purposes of space and continuity. I agree that the organization of granulomas is complex, and depends on the concerted action of various cell types, cytokines and chemokines. I also agree that the number of bacteria in and around granulomas is often small; however, granulomas continue to grow. I stressed that the presence of antigen was the key event. One possibility is that bacterial antigens find their way to the draining lymph nodes of the
lung and drive a continual dendriticcell-mediated expansion and trafficking of T cells to and from lung granulomas. However, the resilience of the bacteria frustrates the immune system in a cyclical fashion. The validity of these models needs to be tested in an in vivo setting. I agree with Orme with regard to the growth state of bacteria. I consider a ‘quiescent’ phase of bacterial growth unlikely for the same reasons and also because of the considerable genetic investment required to participate in multiple growth phases. The simple question
of whether bacteria are growing, or not growing, offers ample opportunity for experimentation.
Peter J. Murray Dept of Infectious Diseases, St Jude Children’s Research Hospital, 332 North Lauderdale St, Memphis, TN 38103, USA References 1 Ting, L-M. et al. (1999) J. Immunol. 163, 3898–3906 2 Murray, P.J. (1999) Trends Microbiol. 7, 366–372
Horizons Varying the rifins
M
any pathogens evade the host immune response or adapt to their environment by expressing surface proteins that undergo rapid switching. In the case of the principal human malaria parasite, Plasmodium falciparum, products of a multigene family known as var [variants of P. falciparum erythrocyte membrane protein 1 (PfEMP1)] are expressed on the surface of infected erythrocytes. Here, they undergo clonal antigenic variation and contribute to malaria pathogenesis by mediating adherence to a variety of host endothelial receptors and to uninfected erythrocytes. PfEMP1 is therefore considered a major virulence factor, but its presence alone has not been sufficient to explain all the parasite-induced changes in surface phenotype. Now, Kyes et al.1 have discovered a second gene family, rif (repetitive interspersed family), which is associated with var at subtelomeric sites in the genome, and which encodes clonally variant proteins – rifins – that are expressed on the infected erythrocyte surface. The high copy number, high level of sequence diversity and erythrocyte location of rifins are consistent with their being subject to immune selection, and imply an important role for these polymorphic proteins in the host–parasite interaction underlying malaria pathogenesis and host protective immunity. As the surface of the infected erythrocyte
is the major interface between the host and the parasite during bloodstage P. falciparum infection, the fact that two distinct sets of clonally variable proteins are expressed at this site suggests that an important evolutionary advantage is conferred by their presence. The next step will be to elucidate the function of rifins.
Microbial genomics Sequencing sister genomes A few years ago, when bacterial genome sequencing was new, it was often said that it would only ever be feasible to fund the sequencing of the genome of just one species in a genus. It is thus heartening to see the Sanger Centre (http://www.sanger. ac.uk/Projects/) turn its attentions to sequencing the genomes of several species whose sisters have already been sequenced. Thanks to funding from the UK Ministry of Agriculture, Fisheries and Food (MAFF) and Beowulf Genomics, shotgun sequencing of the genome of Mycobacterium bovis is now under way, even though it is known to be 99.9% identical to Mycobacterium tuberculosis, one strain of which has already been sequenced by the Sanger and the sequence of a second is nearing completion at The Institute for Genomic Research
1 Kyes, S.A. et al. (1999) Rifins: a second family of clonally variant proteins expressed on the surface of red cells infected with Plasmodium falciparum, Proc. Natl. Acad. Sci. U. S. A. 96, 9333–9338
Andrew Taylor-Robinson [email protected]
(TIGR) (http://www.tigr. org/tdb/CMR/gmt/htmls/ SplashPage.html). Similarly, shotgun sequencing and library testing are now in progress at the Sanger for Bordetella bronchiseptica and Bordetella parapertussis, just as the Bordetella pertussis sequence is nearing completion. The trend seems set to continue, with two more Yersinia species (in addition to the nearly completed Yersinia pestis) and two more clostridial species (in addition to the nearly completed Clostridium difficile) listed as future targets for genome sequencing on the Sanger Centre’s web site. It is now perfectly conceivable that within a few years at least one genome will have been sequenced from every significant bacterial pathogen of humans, plants and animals. Mark Pallen [email protected]
0966-842X/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved. TRENDS
IN
MICROBIOLOGY
479
VOL. 7
NO. 12
DECEMBER 1999