Numerous mollicute species appear to make up the commensal microbial flora of healthy persons, which complicates the association of these mollicutes with disease. There is considerable evidence of the pathogenicity of mollicutes in addition to their role as a commensal.² Mollicutes by themselves can cause acute and chronic disease at multiple sites with wide-ranging complications. They have been linked as a cofactor to AIDS pathogenesis and to malignant transformation, chromosomal aberrations, and other unexplained and complex illnesses, including chronic fatigue syndrome, Crohn's disease, and various arthritides. Rather than being simple organisms, they are evolutionarily advanced prokaryotes and necessitate new paradigms to understand their disease potential.

No other group of prokaryotes has been so embroiled in controversy in establishing a clear pathogenic niche as the mollicutes. Many clinicians think they should be regarded as commensals unless proved otherwise. The isolation or identification of a mollicute from a person does not necessarily prove its pathogenicity, but conversely the isolation of a mollicute from diseased tissue does not necessarily mean that the organism is merely a commensal.

Mycoplasma-like organisms (MLOs) have been detected in inflamed ocular tissues in a number of diseases; this is the reason for inclusion as a chapter in this text. This review will highlight the biology and pathogenesis of these prokaryotes and expand the recent controversies. This may lead to an increased appreciation of their role as human pathogens and possibly ocular pathogens. These data are preliminary, and further analysis is necessary before definitively establishing their role in ocular disease.

TABLE 59-1. Taxonomy and Properties of Mollicutes

TABLE 59-2. Mollicutes of Human Origin

TABLE 59-3. Diseases Attributed to Mycoplasmas or Ureaplasmas and Strength of the Association

In 1967, Japanese investigators reported that a chronic plant disease long thought to be viral in nature was caused by intracellular mollicutes.³ Cells parasitized by these mollicutes displayed dysfunction, destruction, or proliferation.^3,4 Despite many years of effort, these mollicutes have defied cultivation. Their bacterial nature and pathogenicity have been confirmed by transmission studies and their response to antibiotics.³ They have been designated MLOs. Using molecular biologic techniques, the phylogeny of these mollicutes has been elucidated and several subtypes have been identified;⁵ they have been related phylogenetically to Acholeplasma.⁶ The term “phytoplasma” has been recommended for the MLOs by the Subcommittee on the Taxonomy of Mollicutes of the International Organization for Mycoplasmology, based on phylogenetic analysis.^7,8rRNA and tRNA sequence analyses reveal that mollicutes are not at the root of the bacterial phylogenetic tree, but rather developed by degenerate evolution from gram-positive bacteria with a low molecular percentage of guanine plus cytosine content in their DNA. This loss of coding capacity is tolerated because of the parasitic lifestyle of the mollicutes. They have never been found as freely living organisms but, rather, depend on a host cell. The lack of a cell wall probably facilitates the close contact of mollicutes and their host cells and guarantees the exchange of essential components, which support the growth of the bacterium. As a consequence of this bacterial surface parasitism, the host cell is severely damaged. No specific toxic compounds have been detected.

Their small genome size (500 to 1000 megadaltons or 750 to 1500 kilobase pairs), small number of rRNA operons and tRNA genes, lack of a cell wall, fastidious growth, and limited metabolic activities are seen as the result of their evolution.⁹ Other properties, such as the anaerobiosis of their earliest evolving members (Anaeroplasmas and Asteroleplasmas), the high adenine-plus-thymidine content of their DNA, their lack of sensitivity to rifampin, and the regulatory signals for the transcription of their DNA have been inherited from their eubacterial ancestors. They have some unique properties. High adenine-thymine pressure has resulted in a particular codon usage, where, for instance, UGA is read as tryptophan and not as a stop.¹⁰ They have developed peculiar systems for pathogenicity, cell adhesion, antigenic variation, and (in the case of the spiroplasmas) helical morphology and motility.⁹

Mollicutes are pleomorphic, varying in size from 0.2 to 0.3 μm, thus being about the size of large viruses. They are contained only by a triple-layered “unit-membrane” that contains sterol and are incapable of synthesis of peptidoglycan and its precursors. Hence, they do not take up Gram stain and are resistant to antimicrobials that affect a cell wall. They are sensitive to osmotic shock, detergents, alcohols, and specific antibody plus complement. Individual organisms can assume various shapes, from round to filamentous, depending on the mollicute species and the constituents of the broth medium. Budding forms and chains of beads, as well as classic binary fission, may be observed by dark-field and phase-contrast microscopy. Usually nonmotile, some species show gliding motility on liquid-covered surfaces.

On agar media, the mollicutes multiply to form colonies that vary in diameter from 15 to 300 μm; the largest colonies can be seen by the naked eye and often have a typical “fried-egg” appearance because of the contrast between central growth in the depth of the agar and peripheral shallow growth on the surface. The smaller colonies of ureaplasmas require low-power magnification to be seen. Generation times vary from 1 to 6 hours. Colonies are detectable in 2 to 20 or more days. Yield of organisms in broth is small. Because of their small genomes, mollicutes are fastidious in their growth requirements. They need preformed nucleic acid precursors and enriched media containing cholesterol. Most mollicutes are categorized by their abilities to ferment glucose, utilize arginine, or hydrolyze urea.

The association between immunodeficiency and mollicute infections was first reported in the mid-1970s in patients with primary hypogammaglobulinemia and infections with U. urealyticum, M. pneumoniae, Mycoplasma salivarium, and M. hominis that localized in joint tissues, frequently with destructive arthritis.¹⁸ Mollicute infections after organ transplantation and immunosuppressive chemotherapy were observed in the early 1980s, with both M. hominis and U. urealyticum reported most often. Patients with antibody defects or those receiving immunosuppressive drugs appear to be the most susceptible to infections with mollicutes. They are present in healthy tissues, and emerging evidence indicates that contact with other mollicutes in the environment may be an important hazard.¹

A virus-like agent that arose through transfection of NIH3T3 cells with DNA from Kaposi sarcoma tissues of AIDS patients was later shown to be M. fermentans.¹ Independent laboratories have implicated M. fermentans as a cause of systemic infections and organ failure in AIDS patients.¹⁹ M. fermentans has been isolated from blood and urine samples of HIV-infected persons, detected by polymerase chain reaction (PCR) and immunochemistry in multiple tissue sites at various stages of AIDS, and is implicated as a cofactor in AIDS by virtue of its ability to stimulate lymphocytes and other immunomodulatory activities. M. fermentans acts synergistically with HIV to enhance cytopathic effects on human CD4+ lymphocytes. Mycoplasma penetrans has emerged as a potential cofactor in AIDS progression.²⁰ It has been isolated almost exclusively from the urine of HIV-infected patients and not in HIV-seronegative persons. It has the capacity to invade target cells and activate the immune system of HIV-infected patients at various stages of disease. The ability of mollicutes to establish persistent infections with concomitant activation of the immune system, their potential mitogenicity stimulation of cytokine production, and induction of oxidative stress correlate with increased HIV replication and disease production.¹ The proposed role of mollicutes as infectious agents and cofactors in AIDS-related disorders remains a stimulating hypothesis.

Mollicute-infected cell lines have been associated with chromosomal aberrations, altered morphologies, and cell transformation.²¹ Long-term persistent mollicute infection of mouse embryo cells initiated a multistage cellular process that resulted in irreversible cell transformation, karyotypic alterations, and tumorigenicity in nude mice.²² Their role in the ontogeny of human cancers remains speculative.

Several epidemiologic studies have correlated respiratory infections from Mycoplasma with exacerbation of Crohn's disease and other chronic inflammatory bowel diseases.²³ Acute-onset gastrointestinal symptoms in patients are accompanied by seroconversion to specific viral or M. pneumoniae antigens.

Various Mycoplasma and Ureaplasma species have been detected in joint tissues of patients with rheumatoid arthritis, sexually transmitted reactive arthritis, and other human arthritides.²⁴ In a review of 358 patients with primary antibody deficiency, mollicute infection was the most common cause of severe erosive arthritis.²⁵

In animals, mollicutes colonize mucous membranes and are therefore found in the ororespiratory and genitourinary tracts, often behaving as commensals. Mollicutes also infect the conjunctiva, the external ear, and the mammary glands of some animals. They tend to be host-specific. From their initial site of colonization, mollicutes may disseminate to various other body sites, particularly in immunodeficient patients.^27,28 In humans who are immunocompetent, some mollicutes are isolated almost entirely from a particular site (e.g., M. pneumoniae from the ororespiratory tract), whereas others have a preference for one site but are also found in another (see Table 2).

Several mollicutes are human commensals without proven pathogenicity. The association of these mollicutes with disease complicates the diagnosis and necessitates extensive corroborative and highly specific serologic, nucleic acid, and epidemiologic data. They have been implicated as causes of acute and chronic disease at multiple sites and as cofactors in other diseases. Among these are M. salivarium and Mycoplasma orale, found most commonly in the oropharynx. M. penetrans has been isolated from urine in homosexual men and isolated with HIV infection and with Kaposi sarcoma; its pathogenicity awaits further study.²⁹

Many mollicutes exhibit filamentous or flask-shaped appearances and display prominent and specialized polar tip organelles that mediate attachment to host target cells.¹ These tip structures are complex, composed of a network of interactive proteins, designated adhesins, and adherence-accessory proteins. These proteins cooperate structurally and functionally to mobilize and concentrate adhesins at the tip and permit mollicute colonization of mucous membranes and eukaryotic cell surfaces, probably through host sialoglycoconjugates and sulfated glycolipids. Mollicute cytadherence-related proteins represent a superfamily of genes and proteins that have been conserved through horizontal gene transfer from an ancestral gene family.

Other mollicute species lack distinct tip structures but are capable of cytadherence, and they may use related genes and proteins or alternative mechanisms of surface parasitism.¹ An interesting feature of specific M. pneumoniae and Mycoplasma genitalium adhesins is their multiple gene copy nature. Multiple truncated and sequence-related copies of the adhesin genes are dispersed throughout the genome, which could generate adhesin variation through homologous recombination. Despite their small genomes, pathogenic mollicutes facilitate DNA rearrangements through repetitive gene sequences, thus promoting genetic diversity and maximizing the coding potential of their limited genomes.¹

Another characteristic of the cytadherencerelated proteins is their proline-rich composition, which markedly influences protein folding and binding. One of the most unusual features of the adhesins is their extensive sequence homology to mammalian structural proteins, with this molecular mimicry possibly provoking an anti-self response that triggers immune disorders. Patients with documented M. pneumoniae respiratory infections demonstrate seroconversion to myosin, keratin, and fibrinogen and exhibit extrapulmonary manifestations (Table 4).³⁰ Mollicute adhesins exhibit amino acid sequence homologies with human CD4 and class II major histocompatibility complex lymphocyte proteins; this could generate attractive antibodies and trigger cell killing and immunosuppression.³¹ Mollicutes may serve as B-cell and T-cell mitogens and induce autoimmune disease through the activation of anti-self T cells or polyclonal B cells. The multiorgan, protean manifestations are consistent with the pathogenesis of autoimmunity and the induction of a broad range of immunoregulatory events, mediated by cytokine production. The direct effects on macrophages, B and T cells, and glial cells are evidence that mollicutes have the attributes of a primary mediator of disease.³²

TABLE 59-4. Extrapulmonary Sequelae of Mycoplasma pneumoniae Infection

System or Organ	Manifestations	Estimated Frequency
Cardiovascular	Myocarditis, pericarditis	<5%
Dermoid	Erythema multiforme, Stevens-Johnson syndrome, other rashes	Some skin involvement in ~25%
Gastrointestinal	Anorexia, nausea, vomiting, transient diarrhea	5%
	Hepatitis	?
	Pancreatitis	?
Genitourinary	Tubo-ovarian abscess	Very low (insignificant)
Hematologic	Cold hemagglutinin production	~50%
	Hemolytic anemia	?
	Thrombocytopenia	?
	Intravascular coagulation	Very low (few cases reported)
Musculoskeletal	Myalgia, arthralgia	45%
	Arthritis	?
Nervous	Meningitis, meningoencephalitis, ascending paralysis, transient myelitis, cranial nerve palsy, and poliomyelitis-like illness	6%–7%
Kidneys	Acute glomerulonephritis	?

Cytadherence is the initial step in the virulence process of pathogenic mollicutes and precedes a spectrum of subtle or overt host cell responses. In specific instances, distinct cytopathology correlates with the infecting mollicute species, the number of adherent mollicutes, the length of coincubation, the induction of proinflammatory cytokines, and the age and immune status of the patient; in other cases, however, there is no correlation of symptoms of disease and mollicute infection.^12,16

Potent toxins have not been associated with mollicutes. The biologic properties of mollicutes that have been implicated as virulence determinants include:

• Generation of hydrogen peroxide and superoxide radicals by adhering mollicutes, causing oxidative damage to the host cell membrane
  
• Competition for and depletion of nutrients or biosynthetic precursors by mollicutes
  
• Existence of capsule-like material and electron-dense surface layers or structures
  
• High-frequency phase and antigenic secretion, which results in surface diversity and avoidance of protective host immune defenses
  
• Secretion or introduction of mollicute enzymes, such as phospholipases, ATPases, hemolysins, proteases, and nucleases into the host cell milieu
  
• Intracellular residence, which sequesters mollicutes and may establish latent or chronic states.^1,33
  
• The close contact with human membranes may also lead to fusion or exchange of membrane components.
  

Whether pathogenic mollicutes enter and survive within mammalian cells has been debated for years. Two mycoplasmas are known to penetrate human cells (M. penetrans and M. fermentans). Sighting of intact mollicutes throughout the cytoplasm and the perinuclear regions of tissue cells from infected patients and in cell cultures and evidence that mollicutes are capable of long-term intracellular survival and replication in vitro offer an additional dimension to the pathogenic potential of mollicutes.^34,35

Although there are multiple virulence strategies that may be displayed by mollicutes, there is no obvious single or group of mollicute properties that inextricably correlates with disease manifestations. Further research, specific microbiologic, epidemiologic, and diagnostic criteria, and detailed descriptions of biochemical, genetic, and immunologic characteristics that distinguish virulent and avirulent mollicutes are required. The development of experimental animal models is also important. Until then, there will continue to be a debate as to whether mollicutes are singular agents of infectious diseases, putative cofactors in the progression of other diseases, or universal contaminants of cell cultures.

MYCOPLASMA PNEUMONIAE

In the 1930s, a nonbacterial pneumonia termed primary atypical pneumonia was described. The Eaton agent was isolated in fertile eggs³⁶ at that time, but it was not until the early 1960s that M. pneumoniae was confirmed by isolation, serologic findings, inoculation of volunteers, and vaccination.³⁷ M. pneumoniae infection occurs worldwide as a mild respiratory tract infection. It is more common in the late summer and early autumn; it is endemic in most areas, although epidemic peaks occur in some countries every 4 to 7 years. Spread from person to person occurs slowly and is fostered by continual contact or repeated close contact. M. pneumoniae may account for 15% to 20% of all cases of pneumonia, and in certain confined groups it has been responsible for 40% of cases of pneumonia.³⁸ M. pneumoniae affects both children and adults, and the consequence of infection depends on age and immune status. Infection rates are greatest among school-aged children and teenagers. The disease is more severe in the middle-aged and elderly than in the young. The organism attaches strongly to and invades the respiratory epithelial cells. A variety of extrapulmonary manifestations may occur during or after the respiratory infection, as shown in Table 4.

MYCOPLASMA HOMINIS

M. hominis was first isolated from a human Bartholin's duct abscess in 1937 and was formally named 18 years later. Studies in the 1960s confirmed that M. hominis caused respiratory tract disease.³⁹ M. hominis may be involved in approximately 5% of cases of acute pyelonephritis⁴⁰ and is involved in the pathologic processes in bacterial vaginitis and pelvic inflammatory disease.²M. hominis has been isolated from amniotic fluid samples from women with severe chorioamnionitis, perhaps related to its role in bacterial vaginitis. M. hominis has been isolated from the blood of approximately 10% of women with postabortion fever. M. hominis has been suggested as a possible cause of the respiratory distress syndrome or meningitis in newborns.

The extragenital infections of M. hominis have often been discovered fortuitously by growth of mycoplasmas on blood agar or in routine blood cultures. The infections fall into five categories: septicemia, joint infections, central nervous system infections, respiratory tract infections, and wound infections.⁴¹ M. hominis and U. urealyticum have been implicated in more than 38 cases of surgical infections.¹⁵ Experimental infections in animals lend some support to the observations made from humans.²

UREAPLASMA UREALYTICUM

Organisms that produced small colonies, referred to as tiny-form colonies, were first isolated from men with primary and recurrent nongonococcal urethritis in the early 1950s. These organisms were later called T mycoplasmas; they were distinguished because they metabolized urea.⁴² In 1974, it was proposed that they deserved a new classification, and it was discovered that there were other animal-specific species of ureaplasmas.

Although inoculation studies and observations on immunocompromised patients provide evidence that U. urealyticum is a cause of urethritis, the proportion of patients who have this disease is unknown. The organism may persist after causing asymptomatic untreated disease. Only certain serovars are pathogenic. Predisposing factors such as lack of mucosal immunity may be a prerequisite for those who develop disease. Ureaplasmas can gain access to the prostate and may be involved in acute urethroprostatitis. By virtue of their urease metabolism, ureaplasmas induce crystallization of phosphates in vitro in urine and produce calculi in animal models. They may have a role in the development of infection stones in humans.⁴³

Ureaplasmas have been isolated directly from the affected fallopian tubes of patients with pelvic inflammatory disease, but their significance remains speculative.⁴⁴ Ureaplasmas have been isolated from amniotic fluid samples from women with severe chorioamnionitis who subsequently went into premature labor; it remains unclear whether Ureaplasma infection has an abortion-inducing effect apart from that of bacterial vaginitis. Ureaplasmas have been isolated from the blood of a small proportion of women with postpartum fever, perhaps from endometritis.

Ureaplasmas occasionally cause respiratory disease in newborns; these organisms are often acquired in utero, but the role of other organisms, namely those associated with bacterial vaginitis, is debated. Infants weighing less than 1000 g in whom ureaplasmas have been isolated from tracheal aspirates within the first 24 hours of life have been found to be twice as likely to die or to develop chronic lung disease as are uninfected infants of similar birth weight or who weigh more than 1000 g.⁴⁵

The role of ureaplasmas in central nervous system infection in neonates is debated. Ureaplasmas, like M. hominis, can invade the cerebrospinal fluid and seem particularly liable to do so during the first few days of life in premature infants with respiratory disease or hydrocephalus.⁴⁶ Meningitis may occur and run a mild subclinical course in these infants, or there may be more severe neurologic damage.

Ureaplasmas have been isolated from the joints of hypogammaglobulinemia patients with suppurative arthritis; administration of specific high-titer antibody aids clinical recovery.¹⁸ The arthritis in hypogammaglobulinemic patients has sometimes been associated with subcutaneous abscesses, persistent urethritis, and chronic urethrocystitis or cystitis; in these cases, ureaplasmas have been isolated from all of the inflammatory sites involved. Ureaplasmas seem to be responsible less often than M. hominis for disease in patients receiving immunosuppressive therapy. There is no evidence that ureaplasmas are involved in AIDS.

M. hominis and U. urealyticum have been implicated in more than 38 surgical infections.¹⁵ Experimental infections in animals are consistent with the above clinical observations; they imply a role of ureaplasmas in some disease processes and a role as an enabler in some processes.²

MYCOPLASMA GENITALIUM

M. genitalium was originally recovered from the male urethra. It has biologic and structural properties similar to M. pneumoniae, including adherence to and invasion of epithelial cells. This mycoplasma appears to be strongly associated with nongonococcal urethritis. The organism may persist in the urethral tract in the same way that M. pneumoniae persists in the respiratory tract. The organism has also been associated with pelvic inflammatory disease, but again the association is not firmly defined. Studies in nonhuman male primates support the evidence that M. genitalium plays an important role in nongonococcal urethritis.²⁶

M. genitalium has been isolated from human nasopharyngeal throat specimens, but its role in human respiratory disease remains unknown. PCR assays specific for this organism have detected M. genitalium in throat specimens of patients infected with HIV-1.³⁰ M. genitalium has been implicated in human joint diseases.⁴⁷

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-kilodalton adhesin protein gene of M. genitalium were selected as targets in a PCR-based detection assay and provided evidence for the involvement of M. genitalium as an etiologic agent in acute nongonococcal urethritis.⁴⁸

MYCOPLASMA FERMENTANS

M. fermentans strains were first isolated from the lower genital tract of both adult men and women in the early 1950s. It was a frequent contaminant of cell cultures, so its role in human disease was tenuous.⁴⁹ In the 1970s, M. fermentans was found in the joints of rheumatoid patients⁵⁰ and the bone marrow of children with leukemia but was not adequately confirmed. M. fermentans has been recovered from the throats of approximately 16% of children with community-acquired pneumonia.⁵¹ Infection and associated disease are not necessarily linked with immunosuppression. M. fermentans has been detected by specific gene amplification techniques such as PCR in the synovial fluid of patients with inflammatory arthritis, but not in the joints of patients with juvenile or reactive arthritis.⁵²M. fermentans has been found by PCR in the joints of approximately 20% of patients with rheumatoid arthritis and some other inflammatory arthritic conditions⁵³; the significance is unknown. In two other studies using PCR, M. fermentans was identified in the upper respiratory tracts of 20% to 44% of both healthy and HIV-infected patients,^54,55 and was associated with acute respiratory distress syndrome in nonimmunocompromised persons.⁵⁶

M. fermentans has been detected intracellularly in various tissues of patients with AIDS by means of immunohistochemistry, DNA hybridization, and electron microscopy.⁵⁷ M. fermentans was later detected by PCR in the urine, the peripheral blood mononuclear cells, and the throats of 5%, 10%, and 20%, respectively, of HIV-infected persons, most of whom were homosexuals.⁵⁴ M. fermentans has been detected as the sole microbe in bronchoalveolar lavage specimens from 25% of patients with AIDS who had pneumonia, suggesting a role as an opportunistic pathogen.⁵⁸ The specific role of M. fermentans as a factor in the progression of HIV disease remains unresolved.

Inoculation of these MLOs from humans into the subcutaneous eyelids of young mice produced chronic ophthalmic inflammatory disease, including uveitis, cataract, and orbital inflammation; after a 3-month latent period, MLOs were demonstrated in the inflamed ocular tissues and accelerated death was noted.^65–67 Death was associated with chronic inflammatory disease in vital organs, with MLOs demonstrated in ophthalmic and visceral tissue.⁶⁸ Mouse-to-mouse passage was confirmed. Rifampin decreased the mortality rate when compared with controls, perhaps based on the active incorporation of rifampin into leukocytes.⁶⁸ Rifampin has been found to be highly effective against plant MLO disease,⁶⁹ but not against other mycoplasmal disease.

The pathobiologic features of MLO ocular disease are an initial microvasculitis of involved ocular tissues (orbit, uvea), with parasitization of leukocytes and endothelial cells and later granuloma formation. The authors hypothesized that the MLOs can parasitize lymphocytes, monocytes, and neutrophils in humans and subsequently replace the cytoplasm and destroy the organelles and later the nucleus, resulting in cell proliferation, cell destruction, or cell dysfunction. The same investigators subsequently identified MLOs in the vitreous of patients with the uveitis associated with Crohn's disease, with idiopathic inflammatory bowel disease, with sarcoidosis, and with juvenile rheumatoid arthritis, as well as in the orbital tissues of patients with nonspecific chronic orbital inflammatory disease.^61,63

MLOs have been found parasitizing (or at least in association with) retinal pigment epithelial cells by other observers.^70,71 MLO-parasitized leukocytes were also confirmed, suggesting that MLOs can parasitize a wide range of cells.⁶⁸

Mycoplasma gallisepticum has recently been identified as a pathogen of conjunctivitis in poultry.⁷² These birds manifested moderate to severe lymphoplasmacytic conjunctivitis with hyperplasia of associated lymphoid and epithelial tissues and rhinitis: there were occasional cases of keratitis and tracheitis. MLOs have also been detected by other investigators in the conjunctival epithelial cells in swine conjunctivitis⁷³ and the small bowel of children with chronic diarrhea.⁷⁴ M. penetrans and M. fermentans are both seen in patients with AIDS and are the first true mollicutes shown to be capable of penetrating human cells.⁷⁵

Healthy skepticism exists, with further research aimed at defining the role of mollicutes and MLOs as a causative infectious pathogen in ocular disease processes.⁷⁶

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