In interepidemic periods, a sapronoses typically employs a variety of mechanisms for maintaining viability of its causative agent in terrestrial parasitic systems, associated with different adaptive strategies utilized by its populations to survive. Unlike spore-forming bacteria, causative agents of sapronoses use resistant cell forms, which is a viable but nonculturable (VBNC) state, and persistence. Implementation of these strategies is conditioned by effects of various stress factors of the habitat and is characterized by decreased metabolism, alteration of the morphology and physiology of bacterial cell, and cessation of its replication. It is important that the resistant forms of cells retain virulence and, as favorable conditions come, turn back into the active vegetative form again. The discovery of the genetic modules of bacterial toxin–antitoxin systems in recent years has made it possible to identify a number of complicated regulatory molecular mechanisms responsible for maintaining the pathogenic potential of resistant forms of causative agents of natural-focus sapronoses in interepidemic periods.

Discoveries in molecular biology made in recent decades enabled to estimate a key role of Toll-like receptors (TLRs) in initiating innate and acquired immunity in the pathogenesis of inflammatory and autoimmune reactions. The increasing clinical significance of infections associated with gram-negative flora, and structural peculiarity of their cell membranes determined the aim of the review -synthesis of modern ideas about molecular mechanisms of infections caused by microorganisms of this type. As an actual model for the implementation of these molecular strategies the authors considered temperature-dependent immunogenicity variations of pathogenic bacteria, yersinia species, depending on the number and types of acyl groups of lipid A of lipopolysaccharide of the outer membrane that has a modulating effect on the receptor TLR4 sensitivity, regulating the immune response of the body in infections caused by gram-negative bacteria. The results of numerous studies on molecular mechanisms of yersiniosis and other infections enabled to estimate that the patterns of pathogen associated molecules of gram-negative bacteria when interacting with recognizing the receptors transmit numerous signals to immune cells, and can therefore be used as a natural, innate adjuvants activating an adaptive immune response of the body. These low molecular weight natural adjuvants resembling molecular components of lipopolysaccharides are currently efficiently use to develop modern vaccines designed to activate the work of innate immune system and induce the production of inflammatory mediators.

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In the 2000s, with the development of scientific research on the uncultivated (dormant) state of pathogenic bacteria, the ideas about persistent, chronically recurrent infections, difficult to respond to antibiotic therapy have begun to shape. However, regarding human pseudotuberculosis (Far Eastern scarlet-like fever, FESLF), this question remains open. While analyzing the pathology of pseudotuberculosis, its clinical and epidemic manifestation as FESLF, we identified the etiopathogenetic prerequisites for the disease recurrence and development of persistent infection [3]. In this study, it was found that the strains of Yersinia pseudotuberculosis, which were in a dormant state, caused the development of a peculiar granulomatous inflammation in target organs with pronounced delayed-type hypersensitivity reactions in vivo. To reproduce the experimental infection, sexually mature white mice were inoculated with the strain 512 Y. pseudotuberculosis, serotype I sored for 10 years at the Museum of the Research Somov Institute of Epidemiology and Microbiology and transformed into a dormant state. For comparative studies, a dormant form from vegetative bacteria of the strain 512 Y. pseudotuberculosis was obtained by exposure to a large dose of kanamycin (the minimum antibiotic dose was exceeded 25 times). The infecting dose of both forms of bacteria was 108 µ/mouse. Samples of target organs (lung, liver, spleen) were collected for histological examination on days 3, 7, 10, 14, 21 and 32 after infection. Histological sections with 3-5 µm thickness were stained with hematoxylin and eosin according to standard techniques. It was established that strains of Y. pseudotuberculosis in dormant state caused in vivo development of a peculiar granulomatous inflammation due to delayed-type hypersensitivity reactions (DHR), which characterizes the protective reaction in infected host and reflects formation of local, tissue immunity in target organs. The peculiarities of granulomatous inflammation were revealed, in comparison with that of found during infection with vegetative ("wild") Y. pseudotuberculosis bacteria, namely: the granulomas were predominantly small in size, clearly delimited from the surrounding tissue, without destruction of central zone cells and formation of the so-called "granulomas with central karyorrhexis" (terminology proposed by A.P. Avtsyn) [4]; perivascular infiltrates and vasculitis consisted mainly of lymphocytes and often had a follicle-like appearance, resembling the follicles in lymphoid organs; in the lungs, a well-marked reaction of the bronchial-associated lymphoid tissue was observed, and in the spleen, a follicular hyperplasia, indicating a T-cell defense reaction, was observed. Thus, the causative agent of Y.pseudotuberculosis infection / FESLF, being in a dormant state, initiates the development of immunomorphological changes of a protective nature such as productive granulomatous inflammation with reactions of local tissue immunity in target organs and can contribute to the formation of persistent infection.