CLINICAL MICROBIOLOGY REVIEWS, Apr. 1997, p. 320–344 Vol. 10, No. 2 0893-8512/97/$04.0010 Copyright q 1997, American Society for Microbiology Bacterial Persistence and Expression of Disease 1 2 GERALD J. DOMINGUE, SR., * AND HANNAH B. WOODY Department of Urology, Department of Microbiology and Immunology,1 and Department of Pediatrics,2 Tulane University School of Medicine, New Orleans, Louisiana 70112 INTRODUCTION .......................................................................................................................................................320 CWDB AS PERSISTERS: SUMMARY OF BASIC BIOLOGY OF CWDB L-FORMS....................................321 History......................................................................................................................................................................321 Induction of a Wall-Deficient/Defective State and Spontaneous Change to L-Forms ..................................322 General Characteristics .........................................................................................................................................322 RELATIONSHIP OF THE L-FORMS TO MYCOPLASMAS .............................................................................323 EXPERIMENTAL STUDIES WITH LABORATORY-INDUCED CWDB: HOST-PATHOGEN INTERACTIONS.................................................................................................................................................323 Demonstration of the Phenomena of Bacterial Persistence and Reversion in Cell Culture .......................323 Dense Elementary Bodies Derived from Enterococcal L-Forms in Cell Culture ..........................................324 Proposed Developmental Stages in a Pathogenic Bacterium ...........................................................................324 Formation of Urinary Bladder Calculi in Experimental Animals by Proteus mirabilis L-forms .................324 Role of In Vitro-Induced L-Forms in Pyelonephritis ........................................................................................325 Persistence of Experimentally Induced L-Forms in Antibiotic-Treated and Untreated Animals ...............325 Phagocytosis of CWDB...........................................................................................................................................325 Host-Pathogen Interactions with CWDB in Germfree Animals.......................................................................326 SPONTANEOUS CONVERSION OF BACTERIA INTO CWDB........................................................................326 Transformation of Bacteria into CWDB In Vivo ...............................................................................................326 Transformation of Bacteria into CWDB in Cell Cultures ................................................................................327 L-Forms of Nocardia spp.: Host-Induced Cell Wall Modification of Nocardia spp. and Its Role in Pathogenesis ........................................................................................................................................................327 EXPERIMENTAL STUDIES WITH BACTERIAL VARIANTS DERIVED FROM HUMAN SPECIMENS.328 Ultrastructure of CWDB in Human Blood and Urine ......................................................................................328 Exaggerated Immune Responses and Toxic Responses in Guinea Pigs Sensitized with CWDB Derived from Human Blood Lysate and CWDB Culture Supernatants....................................................................331 CLINICAL RELEVANCE OF BACTERIAL PERSISTERS AND EXPRESSION OF DISEASE ...................332 Idiopathic Urinary Diseases..................................................................................................................................332 Renal Fanconi syndrome ...................................................................................................................................332 Nephrotic syndrome............................................................................................................................................333 Idiopathic hematuria..........................................................................................................................................335 Glomerulonephritis and Rheumatic Fever..........................................................................................................335 Aphthous Stomatitis ...............................................................................................................................................336 Whipple’s Disease ...................................................................................................................................................337 Crohn’s Disease.......................................................................................................................................................338 Mycobacterial Infection..........................................................................................................................................338 Miscellaneous Difficult-To-Culture Bacteria.......................................................................................................339 Bartonella spp ......................................................................................................................................................339 Unidentified hemotropic bacteria .....................................................................................................................339 Hypothesis for a Dormant Bacterial Phase of Treponema pallidum Resulting in Spirochetal Persistence in Syphilis: an Analog? .................................................................................................................340 CONCLUSION............................................................................................................................................................340 ACKNOWLEDGMENTS ...........................................................................................................................................340 REFERENCES ............................................................................................................................................................340 INTRODUCTION quences of their interaction with other microorganisms and their host (121, 122). When bacteria were first recognized as A review concerned with the pathology generated by the causing disease, they were seen to be relatively stable cell persistence of difficult-to-culture or nonculturable bacteria in wall-containing forms that grew and expressed their toxic me- human infections must necessarily take into account not only tabolites in vitro. These forms tended to be quite virulent, so their morphologic and metabolic diversity but also the conse- connecting them to particular diseases was not difficult. Since then, technologic developments have revealed a continuum of microbial agents, viruses (and smaller) to protozoa, each di- * Corresponding author. Mailing address: Tulane University School of Medicine, Department of Urology, 1430 Tulane Avenue SL-42, New verse and continually changing. The interaction of these or- Orleans, LA 70112. Phone: (504) 588-5162. Fax: (504) 588-5059. E- ganisms within the host can lead to the enhancement or de- mail: [email protected]. pression of their individual properties. Clinical expression of 320 VOL. 10, 1997 BACTERIAL PERSISTENCE AND EXPRESSION OF DISEASE 321 their presence in the host depends on the genetic vulnerability in recent years, many once idiopathic, chronic, debilitating of the host, the particular environmental stresses, and the disorders have been discovered to be caused by microbial number and location of such consortia. The clinician who faces agents. Cultural techniques available to most physicians fail to this tangled scenario must quantitate and define the dynamic reveal the pathogen. In such situations, when there is micro- that has led to the patient’s illness. scopic and/or molecular evidence for bacterial presence in Survival of a species requires that a reasonable identity be clinical specimens, the cautious use of antimicrobial agents can maintained. Over time, mechanisms to maintain “self” have be justified. Case presentations at the end of this review tend evolved. Because life must be nourished by life, it is inevitable to support this philosophy. that subtle parasitism should also evolve. Many such relation- ships have been so successful that both host and invading CWDB AS PERSISTERS: SUMMARY OF BASIC organism benefit. Such a process, which transiently reduces BIOLOGY OF CWDB L-FORMS immune competence, can occur episodically in healthy subjects in association with various stresses or in particular diseases, A considerable body of experimental and clinical evidence such as rubeola. As one ages, there tends to be an insidious supports the concept that cell wall-deficient/defective bacteria accumulation of intracellular microbial forms. Such quiescent (CWDB) may be agents of disease. Although the pathogenic organisms tend to be activated to a more toxic form when potential of CWDB for humans and laboratory animals has homeostatic disturbances threaten their cellular loci. The num- been the subject of many journal reports (26, 27, 50, 61, 64, bers and locations of cells involved with one or more types of 66–68, 83, 88, 96, 137, 139, 145, 181, 182) and several books organisms determine the clinical