engleski

Host Immune Response to Listeria monocytogenes Infection

Listeria monocytogenes is a gram-positive facultative anaerobic rod that is a well-known pathogen in neonates, pregnant women and others with impaired cell-mediated immunity. The general goal of our research is to understand how Listeria interfaces with the host, with particular emphasis on perinatal group, including mother, her fetuses and newborns. To achieve this, we use a variety of experimental approaches from whole animal models, cell cultures to isolated cells, and different bacteriological, histopathological, immunological and molecular techniques. Using a mouse model of pregnancy-associated listeriosis we have done a careful analysis of the host immune response to L. monocytogenes infection. Mice infected intravenously with listeria at day 15 of pregnancy showed a significantly impaired bacterial elimination, which resulted in a severe necrotizing hemorrhagic hepatitis. The impaired maternal immune response that has been found systematically as well as locally, faciliated bacterial multiplication in the placenta and, ultimately in the fetal tissues. Upon infection, TNF and occasionally IFN-gamma were transcribed in the placenta of pregnant animals. These proinflammatory cytokines were apparently not sufficient to mediate bacterial control, but may well contribute to the significantlly increased abortion rate. TNF-alpha exerts its biologic activity through two distinct receptors, TNF receptor type 1 (TNFR1, p55) and TNF receptor type 2 (TNFR2, p75). Using TNFR1 knock out (TNFR1KO) mice, we explored the role played by TNFR1 in immune regulation during neonatal listeriosis. Induction of protective immune response in wild type newborns resulted in the prompt control of infection with attenuated strain ∆actA-L. monocytogenes, accompanied by enhanced hepatic expression of mRNA for TNF-alpha, IFN-gamma, and IL-10. In contrast, TNFR1KO neonatal mice succumbed to infection due to an insufficient control of listeriosis. In addition to the exaggerated production of inflammatory mediators, mice lacking TNFR1 were unable to clear neutrophils and switch from the innate immune response to a specific reaction mediated by T-cells. Our findings illustrate a crucial role of TNFR1 signalling in antilisterial protection during the neonatal period. The results and further research may be useful for development of novel vaccines, diagnostics, and therapeutics that can be used in controlling infections caused by Listeria. Information from our studies may also be relevant to other microorganisms, especially bacteria with intracellular lifestyle.

Listeria monocytogenes; mouse model; pregnancy; TNF-alpha; neonatal period

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