Demystifying pleomorphic forms in persistence and expression of disease: Are they bacteria, and is peptidoglycan the solution?

There is considerable circumstantial evidence linking tissue pleomorphic forms of unknown origin with idiopathic chronic inflammatory, collagen, lymphoproliferative, nephro-urological (including interstitial cystitis and prostatodynia), and neoplastic diseases. Although these forms have been observed in stained tissue histopathologic specimens for many decades, most are ignored and generally regarded as diagnostically insignificant staining artifacts or debris. It is hypothesized that these pleomorphic forms are not staining artifacts/cellular debris, but instead represent various stages in the life cycle of stressed bacteria: cell wall-deficient/defective (often called L-forms) that are difficult-to-culture or nonculturable. Essential to the thesis is that small, electron dense, non-vesiculated L-forms are the central (core) element in bacterial persistence. Depending on the stimulus received, these dense forms might be considered as undifferentiated cells, with the capacity to develop along several different routes. Hence, these altered forms created in vivo take up intracellular and/or extracellular residence; possibly establishing a sort of immune protected parasitic relationship, resisting/surviving phagocytic action, and creating subtle pathologic changes in the host during a prolonged period of tissue persistence. This might translate into an etiology for chronic inflammatory diseases, when the stressed bacteria increase in numbers and overwhelm the normal biological functions of the host. In the last few decades, an increasing percentage of the population has become immunosuppressed. Some mechanisms for this increase are aging; autoimmunity; congenital, metabolic and degenerative disorders; and AIDS. The life of a patient so affected is prolonged by therapy with hormones, antimicrobials, and immunosuppressants. It is therefore not surprising that pleomorphic, dormant, and mutant bacterial populations arise in vivo when bacteria are exposed to agents that interfere with structural components and metabolic processes necessary to survival of the microbe. Recent provocative, microbiological data lend credence to the hypothesis and corroborate the multiplicity of pleomorphic forms that develop during reproduction of L forms in vitro. It is proposed that in vivo persistence of these bacterial elements escape immune surveillance partially, completely, or may integrate with host cell organelles to create bacteria-host-cell-antigen complexes which could provoke immunopathologic consequences. Highly relevant, newly published data on modifications of gene expression, modes of division for stressed bacteria, and the paradoxical finding of peptidoglycan in L-forms are pertinent to the hypothesis that atypical, pleomorphic bacteria are the organisms operative in persistence and expression of pathology over a wide spectrum of diagnostically troublesome human diseases.