This lecture, the following one and the two accompanying seminars (see below) focus on the particularities of infections by intracellular microorganisms and the modalities of the immune response. Four microorganisms were discussed: Salmonella, mycobacteria, Brucella and Listeria.
Salmonella are Gram-negative bacteria that are facultative parasites of macrophages. Depending on their type (typhi/paratyphi and non-typhi), they cause typhoid fever and infectious intestinal diseases respectively. Salmonella typhi is endocytosed by intestinal epithelial M cells and by the epithelial cells themselves. This is followed by extracellular dissemination and infection (by phagocytosis) of macrophages and dendritic cells associated with the intestinal immune system. Immune responses involve innate immunity via receptors of the TLR and NLR (inflammasome) families. These are activated by bacterial products, including flagellin, in the cytosol of epithelial cells. In addition to the inflammatory response, the inflammasome leads to the expulsion of infected cells into the intestinal lumen. Experimental infection models in mice have demonstrated the importance of this defense mechanism in controlling Salmonella infection. Adaptive immunity is also involved, leading to the induction of Salmonella cell death mechanisms in macrophages via the secretion of interferon γ by TH1 lymphocytes and the recruitment of neutrophils by IL17 produced by TH17 lymphocytes. Experimental models have also demonstrated the essential role played by T lymphocytes and these populations in infection control. In humans, a genetic defect in IL12p40 or in the b1 chain of the IL12 receptor (among other things) predisposes to Salmonella infections, due to a joint defect in the activation of TH1 (interferon γ production) and TH17 lymphocytes.
An essential element of protection against Salmonella infection is competition with commensal intestinal flora. It has recently been shown that the flora of adult mice (but not newborns) protects against Salmonella infection thanks to the presence of Clostridium, which creates an unfavorable environment for Salmonella. Like all microorganisms, Salmonella has developed multiple resistance factors to effectors of innate and adaptive immunity in the course of co-evolution with man. Salmonella can "benefit" from horizontal transfer by infection with a phage that confers a virulence factor. Paradoxically, the inflammatory response favours phage production and transfer, which is conducive to the acquisition of virulence. One of the interests of studying the immune response to Salmonella is to address the hypothesis of the role of chronic infection as a factor in the induction of chronic inflammatory pathology of the intestine. Experimentally, a molecular mechanism likely to account for such a link has been demonstrated.
