Sporozoite-mediated hepatocyte wounding limits Plasmodium parasite development via MyD88-mediated NF-kappa B activation and inducible NO synthase expression.

Abstract

Plasmodium sporozoites traverse several host cells before infecting hepatocytes. In the process, the plasma membranes of the cells are ruptured, resulting in the release of cytosolic factors into the microenvironment. This released endogenous material is highly stimulatory/immunogenic and can serve as a danger signal initiating distinct responses in various cells. Thus, our study aimed at characterizing the effect of cell material leakage during Plasmodium infection on cultured mouse primary hepatocytes and HepG2 cells. We observed that wounded cell-derived cytosolic factors activate NF-kappaB, a main regulator of host inflammatory responses, in cells bordering wounded cells, which are potential host cells for final parasite infection. This activation of NF-kappaB occurred shortly after infection and led to a reduction of infection load in a time-dependent manner in vitro and in vivo, an effect that could be reverted by addition of the specific NF-kappaB inhibitor BAY11-7082. Furthermore, no NF-kappaB activation was observed when Spect(-/-) parasites, which are devoid of hepatocyte traversing properties, were used. We provide further evidence that NF-kappaB activation causes the induction of inducible NO synthase expression in hepatocytes, and this is, in turn, responsible for a decrease in Plasmodium-infected hepatocytes. Furthermore, primary hepatocytes from MyD88(-/-) mice showed no NF-kappaB activation and inducible NO synthase expression upon infection, suggesting a role of the Toll/IL-1 receptor family members in sensing cytosolic factors. Indeed, lack of MyD88 significantly increased infection in vitro and in vivo. Thus, host cell wounding due to parasite migration induces inflammation which limits the extent of parasite infection.

• Authors: Ralph Torgler, Silayuv E Bongfen, Jackeline C Romero, Aubry Tardivel, Margot Thome, Giampietro Corradin
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 180 Issue 6 Pg. 3990-9 (Mar 15 2008) ISSN: 0022-1767 [Print] United States
• PMID: 18322208 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• NF-kappa B
• Nitric Oxide Synthase Type II

Topics

• Animals
• Cell Line, Tumor
• Cells, Cultured
• Cytosol (immunology, metabolism, parasitology)
• Gene Expression Regulation, Developmental (immunology)
• Hepatocytes (enzymology, metabolism, parasitology, pathology)
• Malaria (enzymology, metabolism, parasitology, prevention & control)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Differentiation Factor 88 (deficiency, genetics, physiology)
• NF-kappa B (metabolism, physiology)
• Nitric Oxide Synthase Type II (biosynthesis, deficiency, physiology)
• Plasmodium berghei (enzymology, growth & development, immunology, metabolism)
• Sporozoites (immunology)
• Wound Healing (immunology)