Oncogenic potential of human mycoplasmas was studied using cultured mouse embryo cells, C3H/10T1/2 (C3H). Mycoplasma fermentans and Mycoplasma penetrans, mycoplasmas found in unusually high frequencies among patients with AIDS, were examined. Instead of acute transformation, a multistage process in promotion and progression of malignant cell transformation with long latency was noted; after 6 passages (1 wk per passage) of persistent infection with M. fermentans, C3H cells exhibited phenotypic changes with malignant characteristics that became progressively more prominent with further prolonged infection. Up to at least the 11th passage, all malignant changes were reversible if mycoplasmas were eradicated by antibiotic treatment. Mycoplasma fermentans and Mycoplasma penetrans are the most common mycoplasmas associated with AIDS (1-3). M penetrans infects male homosexuals and is seroepidemiologically associated with Kaposi sarcoma (4). Wall-free mycoplasmas are among the few prokaryotes that can grow symbiotically and have a close interaction with mammalian cells for long periods of time without causing acute cytopathic effects. Thus, infections in cell culture are commonly unrecognized, and many persistent parasitic infections in humans or in animals are clinically silent (5,6). But what is the potential effect on mammalian hosts parasitically infected by the prokaryotes with seemingly low virulence? Can mycoplasmas, the simplest organisms capable of self-replication, alter significantly and permanently the biological properties of mammalian cells during the long course of persistent infection?In the 1960s, two studies reported that infection of mycoplasmas (Mycoplasma orale and one unspeciated) caused chromosomal changes (7,8). But the studies did not reveal that the cells underwent transformation. A separate study reported that introduction of mycoplasmas into cultures of baby hamster kidney (BHK) cells produced immediate morphological transformation with a higher soft agar cloning efficiency (9). Unfortunately, the BHK cells had a high rate of spontaneous transformation. In the 1980s, one article reported that an arthropod spiroplasma could rapidly transform mouse and monkey cells (10). Most scientists thought mycoplasmas simply introduced confusing artifacts that mimic cell transformation (11).Since the question of whether mycoplasmas can induce malignant transformation of mammalian cells may have great significance in general biology, tumor biology, as well as direct clinical implications, we have examined mycoplasmal transforming effects in the murine embryonic C3H/10T½/2 (C3H) cell system, pne of the few standard test systems available for studying potential carcinogenic agents or factors in animals or humans (12)(13)(14)(15). Using this model system with low inherent spontaneous transformation (12), we did not find mycoplasmas induced acute mammalian cell transformation described in the earlier studies. Instead, we found mycoplasma-mediated oncogenesis had a long latency and required a chronic pe...

Orientia tsutsugamushi is the etiologic agent of scrub typhus, a chigger-borne zoonosis that is a highly prevalent, life-threatening illness of greatest public health importance in tropical Asia and the islands of the western Pacific Ocean. The target cell of this bacterium is poorly defined in humans. In this study, O. tsutsugamushi were identified by immunohistochemistry using a rabbit polyclonal antibody raised against O. tsutsugamushi Karp strain in paraffin-embedded archived autopsy tissues of three patients with clinical suspicion of scrub typhus who died during World War II and the Vietnam War. Rickettsiae were located in endothelial cells in all of the organs evaluated, namely heart, lung, brain, kidney, pancreas, and skin, and within cardiac muscle cells and in macrophages located in liver and spleen. Electron microscopy confirmed the location of rickettsiae in endothelium and cardiac myocytes.

Histopathologic examination of lymph nodes from 39 patients with clinical and pathological criteria for cat scratch disease revealed delicate pleomorphic Gram-negative bacilli in 34 of the 39 nodes. They were within the walls of capillaries in or near areas of follicular hyperplasia and within microabscesses. They were best seen with the Warthin-Starry silver impregnation stain. Organisms in lymph node sections exposed to convalescent serum from three patients and to immunoperoxidase stained equally well with all three samples. The organisms did not react with hyperimmune sera to Legionella pneumophila nor to several species of Rickettsia. These bacilli appear to be the causative agents of cat scratch disease.

Mycoplasma penetrans, a novel mycoplasma isolated from HIV-1-infected patients with AIDS, has pathogenic properties associated with in-vivo virulence. Enzyme-linked immunosorbent assay and western blotting detected a more than 100 times higher frequency of antibodies to the mycoplasma in serum from HIV-1-infected patients with AIDS (40%) than from HIV-negative controls (0.3%). Serum from 20% of HIV-1-infected, symptom-free individuals also had M penetrans specific antibodies. The antibodies' major immunoreactivity was directed against P35 and P38, the two main lipid-associated membrane protein antigens of the organism. Patients attending sexually transmitted disease clinics had a low frequency of antibody (0.9%). None of 178 HIV-negative patients with different non-AIDS diseases, many associated with immune dysfunction and/or low white cell counts, tested positive for the antibodies. M penetrans, apparently not a commensal and not a simple opportunist, is uniquely associated with HIV-1 infection and AIDS.

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Over a seven-year period, we identified 23 patients who had prolonged or recurrent, severe, systemic, cat-scratch disease (CSD). Compared with the usual, benign course in 1,038 patients with typical CSD, the course in these 23 patients included prolonged (two or more weeks) morbidity (fever, malaise, fatigue, myalgia, arthralgia, skin eruptions, weight loss, and splenomegaly). Five patients with systemic CSD had either neuroretinitis, pleurisy, arthralgia or arthritis, splenic abscesses, and mediastinal masses or enlarged nodes of the head of the pancreas. Recurrent CSD in two of three adults was confirmed by finding typical CSD bacilli in lymph nodes removed during separate episodes. The majority of patients were adult males, and all patients recovered completely without sequelae. Histopathologic studies of five skin and 18 lymph node biopsy specimens were diagnostic. CSD bacilli were detected in lymph nodes from 15 patients and in the primary skin lesions of four patients. CSD bacilli were found in both skin and lymph nodes of three patients.

Antibodies to Mycoplasma penetrans were found at an unusually high frequency in male homosexuals with AIDS (55 of 149; 37%) and in human immunodeficiency virus (HIV)-infected asymptomatic homosexuals (13 of 49; 26.5%) but not in intravenous drug users (3 of 308; 1%) and hemophiliacs (1 of 165; 0.6%) with or without HIV-1 infection. Thus, both M. penetrans and Kaposi's sarcoma (KS) occur primarily in male homosexuals and rarely in other groups of patients at high risk of AIDS. Among 414 HIV-1-infected patients, statistical analysis revealed those with M. penetrans antibody were 11.7 times more likely to develop KS. Furthermore, among 198 HIV-infected homosexuals (149 with AIDS and 49 without AIDS), those with KS had M. penetrans-specific antibody at a significantly higher frequency (28 of 47; 59.6%) than did those without KS (27 of 102 with AIDS [26.5%] as well as 13 of 49 without AIDS [26.5%]; odds ratio = 4.1, P < .001). M. penetrans is apparently transmitted sexually through homosexual activity and is epidemiologically linked to formation of KS in homosexual men with AIDS. Parallel tests with M. genitalium revealed no similar link to KS in the same study sample.

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