Molecular Biology and Pathogenicity of Mycoplasmas 1st
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Molecular Biology
and Pathogenicity
of Mycoplasmas
Edited by
Shmuel Razin
The Hebrew University-Hadassah Medical School
Jerusalem, Israel
and
Richard Herrmann
University of Heidelberg
Heidelberg, Germany
KLUWER ACADEMIC PUBLISHERS
NEW YORK, BOSTON, DORDRECHT, LONDON, MOSCOW
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Foreword: From the Enigmatic Pleuropneumonia-like
Organisms to the Paradigmatic Mycoplasma
Over a century ago, Edmond Nocard and Pierre Roux were engaged in
the study of infectious bovine pleuropneumonia. The etiological agents were
filterable, like the recently discovered viruses but could be cultured in sterile
growth media similar to bacterial culture.1 When related taxa were
discovered, they were designated pleuropneumonia-like organisms (PPLO).
The driving force for the first half of the century or more of PPLO research
was the interest in a number of animal diseases associated with these
organisms and the possibility of their involvement in human diseases.
In 1960, Volume 79 Article 10 of the Annals of the New York Academy
of Sciences2 presented the proceedings of a previous year's meeting entitled,
"Biology of the Pleuropneumonia-like Organisms." Among the authors were
several of the pioneers in the description of these still incompletely
characterized microbes. The papers in this volume reveal great uncertainty
about the relation of the PPLO to bacteria, newly discovered bacterial L
forms, viruses, and other infectious agents such as the rickettsia. Of course,
1959 was less than a century after the founding of microbiology by Koch
and Pasteur. Most of the papers in the Academy volume focus on
pathogenicity with particular reference to animal diseases of importance to
agriculture. A few papers began to probe the biochemical characterization
of these organisms.
In the late 1950s, efforts were underway, from the perspective of
biophysics, to seek the lower limit of life, the smallest, autonomous, self-
replicating organisms. This began as a search for microbial oddities and
seemed to lead relentlessly toward the pleuropneumonia-like organisms,
which might therefore have a special role to play in molecular biology.
This second domain of interest in the PPLO resulted in the "Conference
on the Molecular Biology of the Pleuropneumonia-like Organisms" held
June 14-16, 1962, at the University of Connecticut. The site of the meeting
v
vi Foreword
was the result of the efforts of Robert Cleverdon. The rapidly developing
discipline of molecular biology and the rapidly expanding knowledge of the
PPLO were brought together at this meeting. In addition to the PPLO
specialists, the conference invited Julius Marmur to compare PPLO DNA to
DNA of other organisms; David Garfinkel, who was one of the first to
develop computer models of metabolism; Cyrus Levinthal to talk about
coding; and Henry Quastler to discuss information theory constraints on very
small cells. The conference was an announcement of the role of PPLO in the
fundamental understanding of molecular biology.
Looking back 40-some years to the Connecticut meeting, it was a rather
bold enterprise. The meeting was international and inter-disciplinary and
began a series of important collaborations with influences resonating down
to the present. If I may be allowed a personal remark, it was where I first
met Shmuel Razin, who has been a leading figure in the emerging
mycoplasma research and a good friend. This present volume is in some
ways the fulfillment of the promise of that early meeting. It is an example of
the collaborative work of scientists in building an understanding of
fundamental aspects of biology.
In the three years between the 1959 New York Academy meeting and the
University of Connecticut meeting, the problem of establishing the structural
nature of PPLO cellularity had been approached in many ways. The first
Academy meeting had left uncertainty about whether we were dealing with
normal cells, syncitia, or some other form of biological organization, perhaps
a novel method of structure. In retrospect the uncertainties resulted from
small size and absence of a rigid cell wall. From a physiological point of
view, we regarded a cell as an aqueous core surrounded by a membrane with
limited conductivity for polar molecules and ions, but this required proof.
This type of problem could be studied by a biophysical method going
back to J. Clerk Maxwell in 1873.3 It involved dielectric dispersion
measurements on a packed suspension of cells between two platinum plates.
We solicited the collaboration of Herman Schwan of the University of
Pennsylvania, who was a specialist in dielectric dispersion studies. This led
to the experimental conclusion4 that the organization was indeed cellular
with membranes having a capacitance of which is a normal
value for other living cells. These results allowed us to speak more
definitely of the smallest living cells. In subsequent years, S. Razin and
others have carried out detailed characterization of the membrane that gave
rise to the electrical properties. Although the dielectric work is seldom cited,
the dielectric dispersion studies were to me of enormous significance. They
established the nature of the mycoplasma. Robert Cleverdon and I in 1959
had posited another feature of the organism, the small amount of DNA per
cell or minimum genome.5 Our experimental value was misleadingly small,
which I believe was due to errors in our method of determining cell number.
In 1962 Mark Tourtellotte and I explored the question, "What are the
Foreword vii
smallest dimensions compatible with life?"6 We were driven by the
assumption that mycoplasma were primitive organisms. Another mea culpa:
Carl Woese, Jack Maniloff, and L. B. Zablen later showed from molecular
taxonomic arguments that, rather than being primitive, mycoplasma are the
ultimate parasites and saprophytes.7 I would now argue that primitive
organisms must be autotrophs, and mycoplasma are the ultimate
heterotrophs. Nonetheless, I believe that the taxon is of importance in the
basic study of all living cells.
In May 1966, a second meeting of the New York Academy of Sciences
brought together a considerably larger group to discuss "Biology of the
Mycoplasma".8 The impressive volume is 824 pages. In the opening
remarks, Leonard Hayflick notes, "Since the first conference dedicated to
them seven years ago, taxonomic dignity has been obtained by replacing the
name PPLO with proper Linnean terminology."
The major subject of the 1966 volume is microbiology and
characterization of mycoplasma. Much of what we now call molecular
biology was in the section called physiology and pathogenicity. It divided
according to the host taxon. In any case, from our point of view, the
fundamentals of the material discussed in this volume had been laid down.
The 1966 publication also included a report on Hans Bode's work on
unambiguously determining the genome size and configuration of
mycoplasma DNA.9 This was an important normalizing of this taxon among
the prokaryotes. In the absence of methods for determining the sequence of
DNA nucleotides, other methods were then undertaken, such as John Ryan's
analysis of t-RNA and r-RNA coding regions.10 This ultimately led to the
studies on gene organization of Mycoplasma capricolum by Akira Muto and
his coworkers and by Shmuel Razin and his coworkers.
In the 60s and 70s, mycoplasma also turned out to be a taxon of choice
for certain basic membrane studies for two reasons. First, the small size
resulted in a high surface-to-volume ratio and a large fraction of the cell's
mass as membrane. Secondly, the absence of a cell wall facilitated the
preparation of membrane. In addition, varying the fatty acid composition of
the growth medium permitted considerable control in the membrane fatty
acid composition. As a result, a series of physical chemical studies of
bilayer-phase transitions was carried out on purified membrane and whole
cells.11,12 It is doubtful that these fundamental membrane experiments could
have been done with any other taxon. In a sense, all of this was serendipity.
Cells that were being studied for other reasons turned out to be ideal for
basic biophysical characterizations of cellularity and fundamentals of
membrane structure and function.
The science that is the subject of this volume has covered about a century
from the discovery of the etiological agent of bovine pleuropneumonia to the
sequencing of the genome of Mycoplasma genitalium and other species. It is
rooted in the bacteriology of Pasteur and Koch, expands in the biochemistry
viii Foreword
of Watson and Crick, matures into present day genomics and looks ahead to
proteomics and physiomics.
Starting as a sideshow of early microbiology, mycoplasma have become
central to modern computational and theoretical biology and the
understanding of infectious disease. To look ahead, I'm confident that the
first decade of the century will lead to a complete computer model of
mycoplasma cell function. As the biology of the century unfolds, I
suspect that the minimal cell concept as embodied in the mycoplasma will
continue to be central to the understanding of life. The publishers and
editors have chosen an appropriate moment in time for this volume.
HAROLD J. MOROWITZ
Robinson Professor,
Krasnow Institute for Advanced Studies,
George Mason University,
Fairfax, Virginia 22030, USA
1
Nocard, E., E. R. Roux, Mm. Borrel, Salimbeni & Dujardin-Beaumetz. 1989. Le microbe
de la péripneumonie. Ann. Inst. Pasteur 12: 240.
2
Biology of the Pleuropneumonia-like Organisms. Volume 79, Art. 10, Pages 305-758.
Annals of the New York Academy of Sciences, 1960.
3
Maxwell, J. C., A Treatise of Electricity and Magnetism, 1973, Oxford University Press.
4
Schwan, H. P. and Morowitz, J. H. Electrical Properties of the Membranes of
Pleuropneumonia-like Organisms, A5969, 1962, Biophysical Journal 2, 295-407.
5
Morowitz, H. J. and Cleverdon, R. C., An Extreme Example of the Coding Problem, 1959,
Avian PPLO 5969. Biochim. Biophys. Acta 34, 578-579.
6
Morowitz, H. J. and Tourtellotte, M. E., The Smallest Living Cells, 1962, Scientific
American 206, 117-126.
7
Woese, C. R., J. Maniloff and L. B. Zablen, 1980, Phylogenetic Analysis of the
Mycoplasmas. Proc. Nat. Acad. Sci., USA, 77, 494-498.
8
Biology of the Mycoplasma, 1967, Volume 143, Art 1, Pages 1-824, Annals of the New York
Academy of Sciences.
9
Bode, H. R. and Morowitz, H. J., 1967, Size and Structure of the Mycoplasma hominis H39
Chromosome, J. Mol. Biol., 23, 191-199.
10
Ryan, J. L. and Morowitz, H. J., 1969, Partial Purification of Native r-RNA and t-RNA
Cistrons from Mycoplasma SP. (Kid), Proc. Nat Acad. Sci. 73, 1282-1289.
11
Stein, J. M., Tourtellotte, M. E., Reinhert, J. C., McElhaney, R. N. and Rader, R. L., 1969,
Calorimetric Evidence of Liquid-Crystalline State of Lipids in Biomembrane, Proc. Nat.
Acad. Sci. USA, 63, 104-109.
12
Melchior, D. L., Morowitz, H. J., Sturtevant, J. M. and Tsong, T Y., 1970, Phase
Transitions in Membrane Lipids, Biochim. Biophys. Acta, 219, 114-122.
Preface
The mycoplasmas (class Mollicutes) represent a wide spectrum of
phylogenetically related parasitic bacteria. They have already served in the
past as models for basic research but in many cases these studies were
hindered by the lack of efficient methods for genetic transformation and by
the fastidious growth of many mollicute species. The newly developed or
improved methods of molecular biology and bioinformatics helped to
overcome these problems to some extent. High through-put DNA
sequencing, handling of large data sets, the PCR technology with the
possibility to mutate DNA with relative ease and express mycoplasmal genes
in foreign hosts have contributed to the success of many research projects
summarized in the present book. The recent sequencing of the entire
genomes of Mycoplasma genitalium, M. pneumoniae, M. pulmonis and
Ureaplasma urealyticum has marked a turning point in the molecular genetic
analysis of these organisms. Studying gene expression with complete cells
at the level of transcription (transcriptome analysis) and at the level of
translation (proteome analysis) and relating the products to genes or ORFs
defined by total genome sequences promises to provide us with the
definition of the total protein complement of a cell. The Mollicutes group
includes the smallest known self-replicating organisms carrying the smallest
number of genes. There is no wonder, therefore, that mycoplasmas have a
special appeal to those interested in the definition of the minimal set of genes
essential for life considering this as an important step on the way of reaching
the goal of defining in molecular terms the entire machinery of a self-
replicating cell.
ix
x Preface
The application of molecular markers has also pushed forward our
understanding of the phylogeny of Mollicutes, placing their taxonomy on a
sound molecular basis. The use of molecular markers and comparative
genomics in taxonomy has extended the scope of mycoplasmology by
enabling the classification of uncultivable mycoplasmas, such as the plant
pathogenic phytoplasmas, and the recent inclusion in Mollicutes of the
Eperythrozoon and Haemobartonella species, classified previously as
rickettsia.
Considerable advances were also made towards better understanding of
mycoplasma pathogenesis. Most impressive are the findings concerning the
interaction of mycoplasmas with the immune system, macrophage
activation, cytokine induction, mycoplasma cell components acting as
superantigens, and autoimmune manifestations. Evasion of the host immune
system by antigenic variation of mycoplasmal surface components is another
subject that has gained much attention recently, as well as the molecular
definition of mycoplasmal adhesins. The recent demonstration of the ability
of mycoplasmas to enter host cells, cause fusogenic, apoptotic and
oncogenic effects, as well as the possible association of mycoplasmas with
activation of arthritis, and several other human diseases of unknown
aetiology had their share in intensifying research on mycoplasma
pathogenesis, bringing more researchers into the circle of those interested in
this group of organisms.
The last multi-authored treatise on mycoplasmas: “Mycoplasmas:
Molecular Biology and Pathogenesis” (J. Maniloff, R.N. McElhaney, L.R.
Finch, and J.B. Baseman, eds.) was published in 1992. Large parts of this
book are now out of date. Several reviews covering different aspects of
mycoplasmology have been published during the last decade. Clearly, these
reviews could not fill the gap created by the lack of a comprehensive, up-to-
date multi-authored treatise including the new advances in the molecular
aspects of mycoplasma research. The need for such a book has been felt for
quite a while, not only by mycoplasmologists, but also by molecular
biologists and the many researchers newly attracted to the study of
Mollicutes as excellent models in genomics and proteomics.
Some comments as to the nomenclature used in the book: While the
trivial terms “mycoplasmas” or “mollicutes” are used interchangeably to
denote any species included in Mollicutes, the names ureaplasmas,
entomoplasmas, mesoplasmas, spiroplasmas, acholeplasmas,
asteroleplasmas, and anaeroplasmas are routinely used for members of the
corresponding genera, and the term phytoplasmas is reserved for the
uncultivable plant mycoplasmas.
Preface xi
Considering the relatively large number of chapters and contributors,
keeping to the deadline set by the publisher is an achievement by itself.
Obviously, this could not be accomplished without the cooperation of the
many contributors. We express our gratitude and appreciation for their
friendly collaboration in this endeavor. We thank also the Senior Publishing
Editor (Biosciences) Joanna Lawrence, for her prompt and most efficient
help in facilitating the fast publication of this book.
Shmuel Razin
Richard Herrmann
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Contents
MYCOPLASMA DIVERSITY AND CELL BIOLOGY
1. Taxonomy of Mollicutes 1
Karl-Erik Johansson and Bertil Pettersson
2. Phylogeny and Evolution 31
Jack Maniloff
3. Mycoplasmas of Humans 45
Alain Blanchard and Cécile M. Bébéar
4. Mycoplasmas of Animals 73
Joachim Frey
5. Mycoplasmas of Plants and Insects 91
Erich Seemüller, Monique Garnier, and Bernd Schneider
6. Cell Division 117
Makoto Miyata
7. The Cell Membrane and Transport 131
Åke Wieslander and Maria Rosén
8. Central Carbohydrate Pathways: Metabolic Flexibility and
the Extra Role of Some "Housekeeping" Enzymes 163
J.Dennis Pollack
xiii
xiv Contents
9. Database Systems for the Analysis of Biochemical Pathways 201
Isabel Rojas-Mujica and Erich Bornberg-Bauer
MOLECULAR GENETICS
10. Mycoplasmas and the Minimal Genome Concept 221
Clyde A. Hutchison III and Michael G. Montague
11. Comparative Genome Analysis of the Mollicutes 255
Thomas Dandekar, Berend Snel, Steffen Schmidt, Warren
Lathe, Mikita Suyama, Martijn Huynen, and Peer Bork
12. Transcriptome and Proteome Analysis of Mollicutes 279
January Weiner Carl-Ulrich Zimmermann, Barbara Ueberle,
and Richard Herrmann
13. DNA Replication, Repair and Stress Response 303
Nianxiang Zou and Kevin Dybvig
14. Transcription and Translation 323
Akira Muto and Chisato Ushida
15. Extrachromosomal Elements and Gene Transfer 347
Joël Renaudin
16. Restriction-Modification Systems and Chromosomal
Rearrangements in Mycoplasmas 371
Ramakrishnan Sitaraman and Kevin Dybvig
PATHOGENESIS
17. Invasion of Mycoplasmas into and Fusion with Host Cells 391
Shlomo Rottem
18. Apoptotic, Antiapoptotic, Clastogenic and Oncogenic Effects 403
Shyh-Ching Lo
19. Genetic Mechanisms of Surface Variation 417
David Yogev, Glenn F. Browning and Kim S. Wise
20. Immunomodulation by Mycoplasmas: Artifacts, Facts and Active
Molecules 445
Peter F. Muhlradt
Contents xv
21. Mycoplasma arthritidis Pathogenicity:
Membranes, MAM and MAV1 473
Leigh R. Washburn and Barry C. Cole
22. Cytadherence and the Cytoskeleton 491
Mitchell F. Balish and Duncan C. Krause
23. Mycoplasma pneumoniae Disease Manifestations and
Epidemiology 519
Enno Jacobs
24. Diagnosis of Mycoplasmal Infections 531
Shmuel Razin
25. Antimycoplasmal Agents 545
Cécile M. Bébéar and Christiane Bébéar
Index 567
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Chapter 1
Taxonomy of Mollicutes
KARL-ERIK JOHANSSON* and BERTIL PETTERSSON#
*
Department of Bacteriology, National Veterinary Institute, SE-751 89 Uppsala, Sweden;
#
Division of Molecular Biotechnology, Department of Biotechnology, Stockholm Centre for
Physics, Astronomy and Biotechnology (SCFAB), Royal Institute of Technology (KTH),
Roslagstullsbacken 21, SE-106 91 Stockholm, Sweden
1. INTRODUCTION
Many commonly used bacteriological terms are far from being well
defined and in scientific papers these terms may be used with different
meanings15,89. One of the purposes of bacterial taxonomy is to avoid
confusion by creating a database with a common language for
bacteriologists. The word taxonomy is derived from the Greek words taxis
and nomos, which mean arrangement or order and law, respectively.
Microbial taxonomy includes three different, but related areas, namely
classification, nomenclature and identification2. Taxonomy can be regarded
as a complete system for organisation of information about organisms and
classification is defined as the theories and principles for arranging
organisms into hierarchic groups of the above database. Taxon (pl. taxa) is
defined as a group of organisms of any rank in the taxonomic hierarchy62.
For instance, species, family and domain are taxa and these taxa are ranked
according to their level of inclusiveness. Nomenclature refers to the process
of naming taxa on the basis of similarities or relations, which for bacteria is
regulated by the so-called Bacteriological Code72. Identification is the
practical application of a classification scheme to establish the identity of an
isolate. Systematics is sometimes used as a synonym for taxonomy, but
phylogenetic aspects are often also included in systematics74. Scientists have
always been interested in classifying organisms and for higher animals and
Molecular Biology and Pathogenicity of Mycoplasmas, Edited by Razin and
Herrmann, Kluwer Academic/Plenum Publishers, New York, 2002 1
2 Karl-Erik Johansson and Bertil Pettersson
plants this has been a comparatively easy and straightforward procedure,
because of the useful and easily observable morphological characters. To
avoid confusion, taxonomy should be as stable as possible to be useful, but
when the amount of information about an organism has increased to a certain
level, it may be necessary to accept a revised taxonomy. Bacterial taxonomy
has traditionally been regarded as a rather conservative branch of
bacteriology12, but after the introduction of molecular techniques into
taxonomy, the situation has changed and taxonomy has been transformed
into an exciting and rapidly developing field in bacteriology27. Phylogeny
plays a pivotal role in modern bacterial taxonomy, evident in the new
edition of Bergey’s Manual on Systematic Bacteriology23. Phylogeny is,
therefore, also discussed in this chapter, but at a more detailed and specific
level than in the chapter “Phylogeny and Evolution”, by J. Maniloff.
2. TAXONOMY
Classification can be based on many different principles, but a useful
system should have a predicative potential. In other words, if the taxon to
which an organism belongs is known, it should be possible to predict many
properties of that organism. A classification system based on the
evolutionary history (phylogeny) of the organisms will have the potential to
be very predicative. Classification of animals and plants have traditionally
been based on morphological characters, which sometimes also reflects their
evolutionary history. For unicellular organisms it is much more difficult to
find common morphological characters, which mirror their phylogeny and
which are easy to measure. Introduction of molecular methods has, therefore,
resulted in a revolution in the fields of bacterial taxonomy.
2.1 General concepts
Traditional classification can be divided into special purpose clas-
sification and natural classification. Special purpose classification is in
general only useful within particular areas and is often based on a few
characteristics only. Special purpose classification can be regarded as
artificial (in contrast to natural) and a classical example is the placement of
Escherichia coli and Shigella dysenteriae in different genera, because of the
more serious disease caused by the latter organism. Strains within these two
taxa are phenotypically very similar, they show high DNA-DNA
hybridisation values and they would normally be regarded as belonging to
the same species. In natural classification the aim is to arrange organisms in
a system which should be useful within as many areas as possible. For
