MYCOPLASMAS: SOPHISTICATED, REEMERGING, AND BURDENED BY THEIR NOTORIETY

Authors: Joel B. Baseman, The University of Texas Health Science Center at San Antonio; and Joseph G. Tully, National Institute of Allergy and Infectious Diseases

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 challenge the host differently from typical bacterial pathogens. Recently, mycoplasmas have been linked as a cofactor to AIDS pathogenesis and to malignant transformation, chromosomal aberrations, the Gulf War Syndrome, and other unexplained and complex illnesses, including chronic fatigue syndrome, Crohn's disease, and various arthritides. The earliest reports of mycoplasmas as infectious agents in humans appeared in the 1930s and 1940s.

Reports in the 1970s of M. fermentans in the joints of rheumatoid arthritis patients and in the bone marrow of children with leukemia raised expectations for its pathogenic potential; these findings have not been adequately confirmed. Sufficient evidence, however, has accumulated recently to establish 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 reactive arthritis.

M. genitalium has been implicated as an etiologic agent in certain human joint diseases. This clinical correlation began with the observation of a mixed infection of M. pneumoniae and M. genitalium in synovial fluid specimens of a nonimmunocompromised patient after an acute respiratory infection. 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.

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 hypogammaglobulinemic patient with septic arthritis was recently reported, with suspected transmission occurring through a cat bite 6 months before the onset of arthritis. Other examples include fatal septicemia caused by M. arginini, a common animal mycoplasma, from blood and multiple tissue sites in a slaughter house employee who had advanced non-Hodgkin's lymphoma and hypogammaglobulinemia, and a septicemic infection with a canine mycoplasma (M. edwardii) in a patient with advanced AIDS (M.K.York, pers. comm.).

One of the most critical aspects of mycoplasmal 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 ability to mount a strong antibody response. 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 antibiotics; expeditious administration of the antibiotic by the most appropriate route (intravenously, if warranted); prolonged therapy terminated only if there is no rapid clinical or microbiological response; and possibly administration of intravenous immunoglobulin.

Molecular mimicry is especially interesting since it has been suggested for decades that mycoplasmas provoke an antiself response that triggers immune disorders, although the basis for the induction has been elusive. A classic example of bacteria-mediated autoimmune disorders is the development of acute rheumatic fever following streptococcal infection.

The Latest Controversies: Food for Thought or the Twilight Zone

Gulf War Syndrome

One of the most controversial current medical issues is whether the multiple acute and chronic symptoms found in veterans of the Persian Gulf War were caused by chemical exposure, infectious agents, or psychological problems, or whether a Gulf War Syndrome exists at all. The clinical illness comprises a collection of symptoms, including chronic fatigue, joint pain, headaches, and skin rashes. One study suggests that pathogenic mycoplasmas are responsible for a large number of cases among veterans, on the basis of DNA hybridization and the responsiveness of veterans to prolonged antibiotic treatment. Even though the experimental evidence is sparse and incomplete and well-controlled and detailed studies by independent laboratories are needed, if the Gulf War Syndrome has infectious causes, mycoplasmas with their requisite biological credentials are potential candidates.

Crohn's Disease

Several epidemiologic studies correlate respiratory infections with exacerbation of Crohn's disease and other chronic inflammatory bowel diseases. Acute onset gastrointestinal symptoms in patients with these diseases are accompanied by seroconversion to specific viral or M. pneumoniae antigens. As indicated earlier, mycoplasmas can elicit pleiotropic immune responses and are difficult to eliminate in patients despite appropriate antibiotic treatment. Steroid therapy to control gastrointestinal symptoms in these patients, along with the multifaceted biological properties associated with pathogenic mycoplasmas, may precipitate the onset of acute exacerbations of chronic inflammatory bowel disease.

Rheumatoid Arthritis and Other Human Arthritides

The occurrence of various Mycoplasma and Ureaplasma species in joint tissues of atients with rheumatoid arthritis, sexually transmitted reactive arthritis, and other human arthritides can no longer be ignored [8]. A clinical trial of longterm (6 to 12 months) antibiotic (doxycycline) therapy before cartilage destruction might prove beneficial in managing such frequent and often debilitating infections.

Extensive clinical and microbiological evidence indicates that mycoplasmas alone can elicit a spectrum of illness for which no other agents are incriminated. The eradication of these pathogenic mycoplasmas from various tissue sites requires an intact and functional immune system, although persons with fully competent immune systems may have difficulty eliminating mycoplasmas, even with recommended prolonged drug therapy. Nonetheless, mycoplasmas are still viewed as subordinates to other infectious agents and are relegated to a category of commensals that unwittingly cause disease in patients whose immune systems offer little resistance to microbial stress and overload.

The fundamental importance of mycoplasmas in specific diseases of humans, animals, insects, and plants is irrefutable, and their unique biological properties are consistent with their intimate association with host target cells. These remarkable bacteria must continue to receive the scientific attention of mycoplasmologists, cell culturists, clinicians, immunologists, and DNA sequencers who most recently are compiling extensive databases that may eventually dissect every approachable mycoplasmal element that defines their biological and genetic being. Nonetheless, mycoplasmas remain mysterious and enigmatic, and the available data and proposed hypotheses that correlate mycoplasmas with disease pathogenesis range from definitive, provocative, and titillating to inconclusive, confusing, and heretical. Controversy seems to be a recurrent companion of mycoplasmas, yet good science and openmindedness should overcome the legacy that has burdened them for decades.

About the Authors

Dr. Baseman is professor and chair, Department of Microbiology, University of Texas Health Science Center, San Antonio. His research focuses on pathogen-host cell interactions with special interest in defining the biology and virulence determinants of mycoplasmas pathogenic for humans.

Dr. Tully heads the Mycoplasma Section, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Frederick, Maryland. His interest covers the host distribution, pathogenicity, and taxonomy of mollicutes.

Address for correspondence: Joel B. Baseman, Department of Microbiology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7758; fax: 210-567-6491; e-mail: baseman@uthscsa.edu.

Acknowledgments
This study was supported in part by NIH grants AI 27873, AI 32829 and AI 41010.


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