W1 FM664LH
`V.3 (cid:9)
`NO.1 (cid:9)
`1997
`C.01 -------- SEO: SE0083700
`TI: EMERGING INFECTIOUS
`DISEASES (cid:9)
`04/01/97
`
`ring trends and analyzing new and reemerging
`tious disease issues around the world
`
`FECTIullst A1Spa81;%
`
`A peer-reviewed journal published by the National Center for Infectious Diseases (cid:9)
`
`Vol. 3, No. 1, Jan-Mar 1997
`
`International Regulations
`
`Syphilis Spirochetes
`
`Mycoplasmas
`
`Fluoroquinolone Resistance
`
`CM in Canada
`
`C. pseudodiphtheritkum
`
`S.
`
`PROPERTY OF TH L
`
`NATIONAL
`LIBRARY OF
`MEDICINE
`
`U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service
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`C DC
`CENTERS FOR DISEASE CONTROL
`ANC) PREVENTION
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`

`

`Emerging Infectious Diseases
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`National Center for Infectious Diseases
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`The Rockefeller University
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`

`

`Emerging Infectious Diseases
`
`Con tents
`
`Volume 3 • Number 1
`
`January—March 1997
`
`Perspective
`Designing an International Policy and Legal Framework for
`the Control of Emerging Infectious Diseases: First Steps
`Synopses
`Surface Antigens of the Syphilis Spirochete and Their
`Potential as Virulence Determinants
`Mycoplasmas: Sophisticated, Reemerging, and Burdened
`by Their Notoriety
`Fluoroquinolone Resistance in Neisseria gonorrhoeae
`
`Infectious Diseases and Immunity: Special Reference to Major
`Histocompatibility Complex
`Cryptosporidiosis: An Emerging, Highly Infectious Threat
`Dispatches
`Isolation and Phylogenetic Characterization of Ebola Viruses
`Causing Different Outbreaks in Gabon
`
`The Epidemiology of Creutzfeldt-Jakob Disease in Canada:
`A Review of Mortality Data
`Exudative Pharyngitis Possibly Due to Corynebacteriuin
`pseudodiptheriticum, a New Challenge in the Differential
`Diagnosis of Diphtheria
`Mycoplasmal Conjunctivitis in Wild Songbirds: The Spread
`of a New Contagious Disease in a Mobile Host Population
`Knowledge-Based Patient Screening for Rare and Emerging
`Infectious/Parasitic Diseases: A Case Study of Brucellosis
`and Murine Typhus
`Letters
`Emergence of Epidemic O'nyong-nyong Fever in
`Southwestern Uganda, After an Absence of 35 Years
`
`Prostatitis and Benign Prostatic Hyperplasia: Emerging
`Infectious Diseases?
`Risk Factors for Severe Leptospirosis in the Parish
`of St. Andrew, Barbados
`Electronic Communication and the Rapid Dissemination
`of Public Health Information
`News and Notes
`Emerging Infectious Diseases Conference
`"Emergent Illness and Public Scholarship" Fellowships
`International Workshop on Molecular Epidemiology
`and Evolutionary Genetics
`
`1 (cid:9)
`
`B.J. Plotkin and A.M. Kimball
`
`D.R. Blanco, J.N. Miller, and
`M.A. Lovett
`J.B. Baseman and J.G. Tully
`
`J.S. Knapp, K.K. Fox, D.L. Trees,
`and W.L. Whittington
`N. Singh, S. Agrawal, and A.K. Rastogi
`
`R. L. Guerrant
`
`M-C. Georges-Courbot, A. Sanchez, C-Y
`Lu, S. Baize, E. Leroy, J. Lansout-
`Soukate, C. Tevi-Benissan, A.J.Georges,
`S.G. Trappier, S.R. Zaki, R. Swanepoel,
`P.A. Leman, P.E. Rollin, C.J. Peters,
`S.T. Nichol, and T.G. Ksiazek
`E. Stratton, M.N. Ricketts, and
`P.R. Gully
`H.S. Izurieta, P.M. Strebel, T.
`Youngblood, D.G. Hollis, and T. Popovic
`
`J.R. Fischer, D.E. Stallknecht, M.P.
`Luttrell, A.A. Dhondt, and KA Converse
`C.N. Carter, N.C. Ronald, J.H. Steele,
`E. Young, J.P. Taylor, L.H. Russell, Jr.,
`A.K. Eugster, and J.E. West
`
`E.B. Rwaguma, J.J. Lutwama, S.D.K.
`Sempala, N. Kiwanuka, J. Kamugisha,
`S. Okware, G. Bagambisa, R. Lanciotti,
`J.T. Roehrig, and D.J. Gubler
`B. Hennenfent
`
`C.P. Douglin, C. Jordan, R. Rock,
`A. Hurley, and P.N. Levett
`C.B. Dalton, P.M. Griffin, and
`L. Slutsker
`
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`Cover photo: Immunostaining of Huila virus antigens within subepithelial vascular endothelial cells in a skin biopsy from a chimpanzee that died
`' during, the 19% Gabon outbreak; Dr. Sherif' R. Zaki, ('enters for Disease Control and Prevention, Atlanta, GA.
`
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`Ex. 1040 - Page 3
`
`

`

`Synopses
`
`Mycoplasmas: Sophisticated, Reemerging, and
`Burdened by Their Notoriety
`
`Joel B. Baseman* and Joseph G. Tullyt
`'The University of Texas Health Science Center at San Antonio,
`San Antonio, Texas, USA; -I-National Institute of Allergy and Infectious
`Diseases, Frederick Cancer Research and Development Center,
`Frederick, Maryland, USA
`
`"Sit down before fact as a little child, be prepared to give up every
`preconceived notion, follow humbly wherever and to whatever
`abysses nature leads, or you shall learn nothing."
`Thomas Henry Huxley
`
`Mycoplasmas are most unusual self-replicating bacteria, possessing very small
`genomes, lacking cell wall components, requiring cholesterol for membrane function
`and growth, using UGA codon for tryptophan, passing through "bacterial-retaining"
`filters, and displaying genetic economy that requires a strict dependence on the host for
`nutrients and refuge. In addition, many of the mycoplasmas pathogenic for humans and
`animals possess extraordinary specialized tip organelles that mediate their intimate
`interaction with eucaryotic cells. This host-adapted survival is achieved through surface
`parasitism of target cells, acquisition of essential biosynthetic precursors, and in some
`cases, subsequent entry and survival intracellularly. Misconceptions concerning the role
`of mycoplasmas in disease pathogenesis can be directly attributed to their biological
`subtleties and to fundamental deficits in understanding their virulence capabilities. In
`this review, we highlight the biology and pathogenesis of these procaryotes and provide
`new evidence that may lead to increased appreciation of their role as human pathogens.
`
`No other group of procaryotes has been so
`embroiled in controversy and in establishing a
`clear pathogenic niche as the mycoplasmas. Their
`virulence determinants are undeniably complex,
`and their unique biological properties likely chal-
`lenge the host differently from typical bacterial
`pathogens (1,2). Also, numerous Mycoplasma
`species appear to comprise the commensal micro-
`bial flora of healthy persons (3), and the association
`of these mycoplasmas with disease complicates
`the diagnosis and necessitates extensive and
`highly specific serologic, nucleic acid, and epide-
`miologic data. Nonetheless, mycoplasmas by
`themselves can cause acute and chronic diseases
`at multiple sites with wide-ranging complications
`and have been implicated as cofactors in disease.
`Recently, mycoplasmas have been linked as a
`
`Address for correspondence: Joel B. Baseman, Department of
`Microbiology, The University of Texas Dealt h Science Center
`at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX
`78284-7758; fax: 210-567-6491; e-mail: baseman@uthscsa.edu,
`
`cofactor to AIDS pathogenesis and to malignant
`transformation, chromosomal aberrations, the
`Gulf War Syndrome, and other unexplained and
`complex illnesses, including chronic fatigue syn-
`drome, Crohn's disease, and various arthritides
`(4-8). Even with mounting evidence of their
`pervasive and pathogenic potential, mycoplasmas
`still evoke the image of a group of obscure or
`impotent microorganisms. Yet they are evolu-
`tionarily advanced procaryotes (9-11), and their
`elite status as "next generation" bacterial patho-
`gens necessitates new paradigms in fully under-
`standing their disease potential.
`Mycoplasmas, which lack cell walls but
`possess distinctive sterol-containing plasma mem-
`branes, are taxonomically separated from other
`bacteria and belong to the class Mollicutes
`(mollis, soft; cutis, skin). Mollicutes, a term that
`includes the cell wall-less procaryotes assigned to
`numerous genera under the class Mollicutes and
`is frequently used interchangeably with myco-
`plasmas, are unusual for other biological reasons
`
`Mil. 3, No. I lanuot Pvlarch 1997
`
`This mate2alwascortie-d
`atthe NLM anti may be
`Subject US Copyright Laws
`
`Emerging Infections Diseases
`
`Ex. 1040 - Page 4
`
`(cid:9)
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`

`

`Synopses
`
`as well. They are evolutionary descendants of the
`low G+C containing gram-positive bacteria and,
`through chromosome reduction, represent the
`smallest self-replicating life forms. Their stream-
`lined genome size, which illustrates extreme bio-
`logical gene economy, imposes complex nutritional
`requirements, such as dependence on external sup-
`plies of biosynthetic precursors, including amino
`acids, nucleotides, fatty acids, and sterols. This
`limited coding capacity dictates for mycoplasmas
`a parasitic way of life that few pathogenic micro-
`organisms can claim. Therefore, the view that
`pathogenic mycoplasmas can grow "independently"
`requires an appreciation of their fastidious
`nature and their intimate dependence upon the
`host. Because of these properties, pathogenic
`mycoplasmas are among the most difficult micro-
`organisms to grow from clinical specimens and
`remain frequent contaminants of primary and
`continuous eucaryotic cell lines and tissue cul-
`tures (12). In some instances, mycoplasma con-
`tamination is obvious since infected eucaryotic
`cells exhibit aberrant growth, metabolism, and
`morphology. However, mycoplasmas often estab-
`lish covert and chronic infections of target cells
`that lead to either invalid and misleading data or
`introduction of mycoplasmas or their products into
`reagents dedicated to therapeutic or research pur-
`poses. The recent emphasis on isolating viral agents,
`such as human immunodeficiency virus (HIV)-1,
`from human primary lymphocytic cells has also
`demonstrated the frequent cocultivation of myco-
`plasmas of human origin. Often, the unwanted
`sources of exogenous mycoplasmas are serum
`products and filter-"sterilized" (450 mn ) solutions;
`cross-contamination by already infected cel l cul-
`tures, viral stocks, or immunologic preparations;
`breaks in technique, including aerosols from the
`respiratory tract or by mouth pipetting; ignorance
`of the mycoplasma problem; or scientific indifference.
`Detailed up-to-date reviews describing the
`biological and pathogenic properties of myco-
`plasmas have been published (1,2,13,14). Our
`intention here is to provide a concise historical
`perspective of the role of mycoplasmas in human
`disease; highlight the discoveries of new Myco-
`plasma species and their association with human
`illness and host conditions that present problems
`in detection and treatment; describe selected
`biological properties of mycoplasmas consistent
`with their intimate host relationship and pos-
`sible mechanisms of pathogenicity; and address
`recent controversies associated with mycoplasmas
`
`as emerging infectious agents. Renewed attention
`to these issues may provide the impetus to
`demystify mycoplasmas and improve their standing
`as genuine, card-carrying pathogens.
`
`Historical Perspectives
`The earliest r, ports of mycoplasmas as infec-
`„
`tious
` agents in humans appeared in the 193”,
`and 1940s. At that time, primary atypical
`p
`neumonia was associated with an infectious
`
`that because of its minute size and innate bio-
`logical properties unknown at that time, Passed
`through bacteria-retaining filters, resisted penicillin
`and sulfbnamide therapies, and adapted to growth
`in embryonated eggs and tissue culture cells.
`Correlations between the etiologic agent of
`"walking pneumonia" with viruses, 1,-fbrnIs' and
`pleuropneum on ial ike agents (referred to as PPLOS
`in publications and textbooks of that era) were
`frequent and often misleading. Finally, definitive
`studies in the early 1960s established M.YcoPlasnict
`pneumoniae as the singular cause of cold agglu-
`tinin-associated primary atypical pneumonia (2).
`'Podgy M.imerimoiriae remains an important cause
`of pneumonia and other airway disorders, such as
`tracheobronchitis arid pharyngitis (1.3,14), and is
`associated with extrapulmonary manifestations,
`such as hematopoietic, exanthematic, joint, cen-
`tral nervous system, liver, pancreas, and
`cardiovascular syndromes (15).
`The confusion associated with M. pneumontae-
`mediated infections has recurred many times
`with other mycoplasmas, whose detection in clini-
`cal specimens through culture, antibody, or
`DNA-based testing is frequently dismissed as
`"only mycoplasmas" even when they appear to be
`the primary pathogens. Two mycoplasmas com-
`monly Ibund in the urogenital tracts of healthy
`persons are Mycoplasma hominis and Ureaplasma
`urealyticum. However, over the years, the patho-
`genic roles of these mycoplasmas have been proven
`in adult urogenital tract diseases, neonatal res-
`piratory infections, and a range of other diseases
`usually in immunocompromised patients (2).
`Several recent examples illustrate the
`increasing impact of Mycoplasma species on emer-
`ging diseases. Mycoplasma fermentans strains
`were first isolated from the lower genital tract of
`both adult men and women in the early 1950s,
`but their role in classic lower genital tract disease
`has not been established (16). Reports in the 1970s
`of M. fermentans in the joints of rheumatoid,
`arthritis patients and in the bone marrow of
`
`Emerging Infections Divacc-; (cid:9)
`
`22
`This material was copied
`at the NLM and may be
`
`Vol ;. No. I Imo, Marrlr 1997
`
`Ex. 1040 - Page 5
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`(cid:9)
`

`

`Synopses
`
`children with leukemia raised expectations for its
`pathogenic potential (17,18); these findings have
`not been adequately confirmed. Sufficient evi-
`dence, however, has accumulated recently to estab-
`lish an important and emerging role for M.
`fermentans in human respiratory and joint diseases.
`For example, M. fermentans has been detected by
`specific gene amplification techniques such as
`polymerase chain reaction (PCR) in the synovial
`fluid of patients with inflammatory arthritis, but
`not in the joints of patients with juvenile or reac-
`tive arthritis (19). In two other studies using
`PCR, M. fermentans was identified in the upper
`respiratory tract of 20% to 44% of both healthy
`and HIV-infected patients (20,21) and was asso-
`ciated with acute respiratory distress syndrome
`in nonimmunocompromised persons (22).
`Mycoplasma genitalium was detected in the
`urogenital tract of two patients with non-
`gonococcal urethritis in 1981 (23), but for more
`than a decade, very little was known about its host
`distribution and pathogenicity. Early experi-
`mental studies established that the organism
`caused lower genital tract infections in both male
`and female chimpanzees, with extensive urethral
`colonization in males and apparent tissue inva-
`sion, eventually leading to overt bacteremia (24).
`However, the fastidious growth requirements of
`M. genitalium from human hosts severely limited
`further study until the advent of molecular
`detection techniques. Specific sequences in the
`140 kDa adhesin protein gene of M. genitalium
`were selected as targets in a PCR-based detection
`assay (25,26). Subsequent application of these
`techniques in cases of acute nongonococcal
`urethritis, not including those of patients colo-
`nized or infected with Chlamydia trachomatis,
`has provided mounting evidence for the involve-
`ment of M. genitalium as an etiologic agent of
`this disease (27-29). Also, M. genitalium has been
`suspected in chronic nongonococcal urethritis and
`pelvic inflammatory disease (30).
`The discovery in 1988 of M. genitalium
`strains in human nasopharyngeal throat specimens,
`where they were frequently mixed with strains of
`M. pneumoniae, not only changed dramatically
`the concept of host distribution of M. genitalium
`but also prompted critical questions about the
`role of this mycoplasma in human respiratory
`disease (31). However, the immunologic cross-
`reactivity between M. genitalium and M. pneu-
`moniae and the inability of most conventional
`diagnostic serologic tests to conclusively identify
`
`M. genitalium have complicated its delineation in
`acute human respiratory disease. PCR assays
`specific for the organism have detected M. genita-
`lium in throat specimens of patients infected
`with HIV-1(32). However, these probes have not
`been applied to control groups and patients in
`outbreaks of acute respiratory disease and/or pneu-
`monia to determine whether M. genitalium alone
`is an etiologic agent in respiratory infections.
`M. genitalium has been implicated as an
`etiologic agent in certain human joint diseases.
`This clinical correlation began with the obser-
`vation of a mixed infection of M. pneumoniae and
`M. genitalium in synovial fluid specimens of a
`nonimmunocompromised patient after an acute
`respiratory infection (33). A predominant role was
`not established for either Mycoplasma species in
`the initial respiratory disease or in the joint
`manifestations, although evidence to implicate
`postinfectious autoimmunity to both organisms
`was described. These findings prompted a PCR
`assay on synovial fluids from patients with
`various arthritic syndromes, which presented
`case reports on two of 13 patients with M.
`genitalium detected in joint fluids (34).
`Another area of emerging mycoplasmal
`infections concerns immunodeficiency. Although
`patients with congenital or acquired disorders of
`antibody production are susceptible to a wide
`variety of microbial infections, the unique suscep-
`tibility of such patients to mycoplasmal infections
`is a growing concern, especially considering the
`number of occurrences, the types of mycoplasmas
`involved, and the difficulties posed in the thera-
`peutic management of such infections. In addition,
`the increased use of prolonged or permanent
`immunosuppressive chemotherapy required for
`patients undergoing tissue or organ transplan-
`tation or treatment of various malignant diseases
`has also increased the risk for mycoplasmal
`infections—from mycoplasmas that are part of
`the normal human mollicute flora to those
`acquired through animal contact.
`The association between immunodeficiency
`and mycoplasmal infections was first reported in
`the mid 1970s in patients with primary hypogam-
`maglobulinemia and infection with U. urealyticum,
`M. pneumoniae, Mycoplasma salivarium, and M.
`hominis that localized in joint tissue, frequently
`with destructive arthritis. Similar joint infections
`in hypogammaglobulinemic patients with these
`mycoplasmal species continue to be reported (35).
`Since most of these mollicutes, with the possible
`
`Vol. .3, No. I Iniluary-March 1997
`
`This mate23 was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`Emerging Infectious Diseases
`
`Ex. 1040 - Page 6
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`

`

`Synopses
`
`exception of M. pneumoniae, occur as part of the
`normal human flora, the origin of such joint
`infections is considered endogenous. Patients
`with hypogammaglobulinemia and other antibody
`deficiencies are also especially susceptible to
`mycoplasmal infections of the upper respiratory
`and urinary tracts caused most frequently by M.
`pneumoniae or U. urealyticum, respectively (36).
`Mycoplasmal infections following organ trans-
`plantation and immunosuppressive chemotherapy
`were observed in the early 1980s, with both M.
`hominis and U. urealyticum reported most often
`(37-39). Although these infections most likely origi-
`nated from the patient's normal microbial flora, a
`recent report of donor transmission of M. hominis
`to two lung allograft recipients (40) suggests that
`donor tissue may be a more important factor in
`transplant infections than currently recognized.
`While patients with antibody defects or those
`receiving immunosuppressive drugs appear to be
`the most susceptible to infections with mycoplasmas
`present in healthy tissues, emerging evidence
`indicates that contact with other mycoplasmas in
`the environment is an important hazard. For
`example, the direct isolation of a feline mycoplasma
`(M. felis) from the joint of a hypogamma-
`globulinemic patient with septic arthritis was
`recently reported (41), with suspected transmis-
`sion occurring through a cat bite 6 months befbre
`the onset of arthritis. Other examples include
`fatal septicemia caused by M. arginini, a common
`animal mycoplasma, from blood and multiple tis-
`sue sites in a slaughter house employee who had
`advanced non-Hodgkin's lymphoma and hypoga in-
`maglobulinemia (42), and a septicemic infection
`with a canine mycoplasma (M. cclrc crr cliff) in a patient
`with advanced AIDS (M.K. York, pers. comm.).
`One of the most critical aspects of myco-
`plasmal infections in immunodeficient patients
`is the frequent inability to control such infections
`with appropriate broad spectrum antibiotics.
`Although the tetracyclines and erythromycins
`are effective chemotherapeutic agents for many
`mycoplasmal infections, M. fermentans and M.
`hominis strains are usually resistant to
`erythromycin, and tetracycline-resistant strains
`of M. hominis and U. urealyticum have been
`reported from the lower urogenital tract of
`patients. However, these antibiotics and most
`other broad spectrum agents have limited
`mycoplasmacidal activity in vivo, and their
`efficacy eventually depends on an intact host
`immune system to eliminate the mycoplasmas.
`
`Most, hypogammaglobulinemic patients lack the e
`
` ;
`ability to mount a strong antibody respells
`
`Guidelines for managing such mycoplasmal
`infections in patients with immune defects
`
`should include immediate in vitro testing of the
`isolated mollicute against a wide range of ant!_
`biotics; expeditious administration ofthe
`by the most appropriate route ( intravenously, 1.1,
`warranted ); prolonged therapy terminated only'',
`there is no rapid clinical or microbiologlea..1
`response; and possibly administration of intra-
`venous
`venous immunoglobulin (35,36). Clinical manage.
`ment of mycoplasmal infections in transplant
`s
`patients is more difficult since i m munoglebulT
`
`the
`may enhance graft or organ rejection. In
`absence of suitable mycoplasmacidal chemothera-
`peutic
`agents, vigorous and sustameci
`
`chemotherapy with the most active antibiotic is
`the current method of choice.
`
`Mechanisms of Pathogenicity
`.
`Many mycoplasmal pathogens exhibit
`filamentous or flask-shaped appearances and
`display prominent and specialized polar tip
`organelles that mediate attachment to hest
`target cells (43,44). These tip structures are
`e
`complex, composed of a network of interactiv
`-
`proteins, designated adhesins, and adherence
`accessory proteins ( Figure 1, 114,431). These
`proteins cooperate structurally and functionally
`to mobilize and concentrate adhesins at the tip
`and permit, mycoplasmal colonization of mucous
`membranes and eucaryotic cell surfaces, probably
`through host sialoglycoconjugates and sulfated
`glycol i pids ( Figure 2, 114,43,451). It appears that
`mycoplasmal cytadherence-related proteins
`represent a superkunily of genes and proteins
`that have been conserved through horizontal
`gene transfer from an ancestral gene family. This
`protein network resembles a specialized cyto-
`skeleton like apparatus, which may represent the
`precursor to mammalian cytoskeletal and
`extracellular matrixlike complexes (14). Other
`Mycoplasma species lack distinct tip structures
`yet are capable of cytadherence, and they may
`use related genes or proteins or alternative
`mechanisms of surface parasitism.
`The family of mycoplasmal genes and proteins
`involved in cytadherence has been studied most
`( 14,43,46-48).
`extensively in M. pneumoniae
`Noncytadhering phenotypes that arise through
`spontaneous mutation at high frequency have
`been categorized into mutant classes on the basis
`
`11111tr,,,ill:e, Ill/CO/MI • I )i .01 ,',
`
`This material wascal
`at the NLM and may be
`Subject US Copyright Laws
`
`111)1, a, N'. 1 (cid:9)
`
`Januar (cid:9)
`
`h
`
`Ex. 1040 - Page 7
`
`

`

`Synopses
`
`'igure I. Transmission electron photomicrographs of the specialized tip organelle of cytadherence-positive M. pneumoniac demon-
`strating a) truncated structure with nap, b) clustering of cytadherence-related proteins (PI, B, C, P30) at the tip based on immunolabeling
`with ferritin and colloidal gold and crosslinking studies, and c)Triton X- I 00—resistant, cytoskeleton-like, structure with distinct bleb
`and parallel filaments (14,43,45,46).
`
`Figure 2. Transmission electron
`photomicrograph of a hamster
`trachea ring infected with M.
`pneumoniac (43). Note the
`orientation of the mycoplasmas
`through their specialized Liplike
`organelle, which permits close
`association with the respiratory
`epithelium. M, mycoplasma; m,
`microvillus; C, cilia.
`
`Vol. 3, No. I lan ru March 1997 (cid:9)
`
`This mate2a5wasuppiad
`atthe NLM and may ba
`Subject USCopyright Laws
`
`Emerging Infectious Diseases
`
`Ex. 1040 - Page 8
`
`(cid:9)
`

`

`Synopses
`
`of distinct protein profiles. These noncytadhering
`mycoplasmas cannot synthesize specific cytad-
`herence-related proteins or are unable to stabilize
`them at the tip organelle, which leads to abnormal
`anatomical tip structures and avirulence (43).
`Spontaneous reversion to the cytadhering pheno-
`type is accompanied by the reappearance of the
`implicated proteins, restoration of structurally
`and functionally intact tips, and return of full
`infectivity (43). Similar cytadherence-related
`genes and proteins have been reported for M.
`genitalium on the basis of biochemical, immuno-
`logic, and genetic analyses (25,49,50). Furthermore,
`striking similarities exist in the order of operons
`that comprise the cytadherence-related genes and
`the organization of these genes within each operon
`of M. pneumoniae and M. genitalium (14,50,51).
`These similarities reinforce the unexpected coiso-
`lations of M. genitalium, along with M. pneu-
`moniae, from the nasopharyngeal throat swabs of
`patients with acute respiratory diseases and
`from synovial fluids of patients with arthritis as
`described in the previous section (31,33). The
`isolation of M. pneumoniae from the human
`urogenital tract (52) further suggests that these
`mycoplasmas have evolved parasitic strategies
`that include overlapping tissue tropisms as
`determined by the genetic and chemical related-
`ness of their cytadherence genes and proteins
`(14,25,43,50,51). The recent use of transposon
`mutagenesis to generate M. pneumoniae and M.
`genitalium transformants displaying cytadherence-
`deficient phenotypes should further clarify the
`relationships between the cytadherence-related
`genes and proteins and identify additional sites
`previously unlinked to cytadherence (46,53).
`An interesting feature of specific M.
`pneumoniae and M. genitalium adhesins is their
`multiple gene copy nature (14,43,54,55,56).
`Although only one full-length copy of the adhesin
`structural genes exists in adhesin-related
`operons, precise regions of these adhesin genes
`are detected as single genomic copies, while other
`regions occur as closely homologous, but not
`identical, multiple copies. In other words,
`multiple truncated and sequence-related copies
`of the adhesin genes are dispersed throughout
`the genome, which could gene