Toxoplasma gondii is a common protozoan parasite that infects up to one-third of the world’s population. Notably, very little is known about innate immune-sensing mechanisms for this obligate intracellular parasite by human cells. Here, by applying an unbiased biochemical screening approach, we have identified that human monocytes recognized the presence of T. gondii infection via detection of the alarmin S100A11 protein, which is released from parasite-infected cells via caspase-1-dependent mechanisms. S100A11 induced a potent chemokine response to T. gondii via engagement of its receptor RAGE and regulated monocyte recruitment in vivo by inducing expression of the chemokine CCL2. Our experiments have revealed a sensing system for T. gondii by human cells that is based on detection infection-mediated release of alarmin S100A11 and RAGE-dependent induction of CCL2, a crucial chemokine required for host resistance to the parasite.

Paneth cells constitutively produce antimicrobial peptides and growth factors that allow for intestinal homeostasis, host protection and intestinal stem cell replication. Paneth cells rely heavily on the glycolytic metabolic program, which is in part controlled by the kinase complex Mechanistic target of rapamycin (mTORC1). Yet, little is known about mTOR importance in Paneth cell integrity under steady state and inflammatory conditions. Our results demonstrate that IFN-γ, a crucial mediator of the intestinal inflammation, acts directly on murine Paneth cells to alter their mitochondrial integrity and membrane potential, resulting in an mTORC1-dependent cell death mechanism distinct from canonical cell death pathways including apoptosis, necroptosis, and pyroptosis. These results were established with the purified cytokine and a physiologically relevant common Th1-inducing human parasite Toxoplasma gondii. Given the crucial role for IFN-γ, which is a cytokine frequently associated with the development of inflammatory bowel disease (IBD) and compromised Paneth cell functions, the identified mechanisms underlying mTORC1-dependent Paneth cell death downstream of IFN-γ may provide promising novel approaches for treating intestinal inflammation.

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Relevance. Against the background of epidemiological well-being for diphtheria infection, the formation of the optimal structure of the population post-vaccination antitoxic immunity remains an urgent problem. Aims. The review is devoted to anti-toxic antidiphtheria immunity and the possibility to form the optimal structure of post-vaccination anti-toxic population immunity using the small booster doses of anatoxin. Results. Special attention is paid to the formation of antitoxic population immunity in a natural way during the pre-vaccination period. It is proposed to pay attention to the immunosuppressive characteristics of anatoxin and the immune response to booster its small doses. Natural decrease in the concentration indicators of post-vaccination antitoxic IgG in the blood of adults has been demonstrated. A mathematical analysis of determining the structure of post-vaccination population immunity in all age groups of the population is proposed. Conclusions. The small booster personalized doses of anatoxin in adolescents and adults will contribute to the creation of optimal population anti-diphtheria protection of these age groups of the population.

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