Potentiation of nonspecific immunologic memory for induction of anti-infection resistance

Infectious diseases of farm animals are one of the most pressing problems of current livestock sector. The commonly used specific vaccine prophylaxis is not always effective due to the genetic variability and mutational variability of pathogen antigens ("antigenic drift"), the widespread prevalence of mixed polyetiological infections, heterogeneity of the immune response and reduced immune resistance. Existent specific vaccines are aimed at protecting against a specific pathogen or, in the case of multivalency, against several specific pathogens, and are based on the induction of long-term adaptive, i.e. antigen-specific immunity due to the formation of Tand B-memory cells. In the last decade, it has been established that vaccines containing microorganisms, such as BCG, provide resistance not only to a specific pathogen (for example, in the case of BCG – against M. tuberculosis), but also to a wide range of other pathogens. The main mechanism of this broad heterologous resistance is the increased reactivity of the innate immune system cells, primarily monocytes-macrophages. In response to the primary stimulus ("training"), these cells undergo a number of epigenetic and metabolic rearrangements, become "sensitized" and, when confronted with a second stimulus, the same or another pathogen, provide long-term protection against many viral and bacterial infections. Metabolites of the mevalonate metabolic pathway play an important role in the formation of non-specific or "trained" immunological memory (“trained immunity”, TI). In the present work, the hypothesis of the ability of the farnesyl pyrophosphate synthase inhibitor, aminobisphosphonate (a blocker of the mevalonate pathway at the farnesyl pyrophosphate level), to potentiate BCG-induced TI was verified in in vitro and in vivo experiments. It has been found that the aminobisphosphonate zoledronate induces the TI phenotype in monocytes and causes nonspecific protection against staphylococcal infection in mice. In addition, zoledronate significantly enhances BCG-induced TI, causing a synergistic protective effect. The phenomenon of potentiated TI that we have discovered can form the basis for the development of fundamentally new powerful universal vaccines.

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