Sporozoite-Mediated Hepatocyte Wounding Limits Plasmodium Parasite Development via MyD88-Mediated NF-κB 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-κB, 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-κB 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-κB inhibitor BAY11-7082. Furthermore, no NF-κB activation was observed when Spect−/− parasites, which are devoid of hepatocyte traversing properties, were used. We provide further evidence that NF-κB 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-κB 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.

Caspase-1 Activation of Interleukin-1β (IL-1β) and IL-18 Is Dispensable for Induction of Experimental Cerebral Malaria

“…In line with this result, it has been demonstrated previously that MyD88-deficient C57BL/6 mice have a higher hepatic parasite load than WT animals (49). In contrast to the published data, we did not observe any difference in the development of liver-stage parasites between WT and MyD88 Ϫ/Ϫ (or TLR2/ 4 Ϫ/Ϫ ) mice.…”

Myeloid Differentiation Factor 88 Promotes Growth and Metastasis of Human Hepatocellular Carcinoma

“…LPS suppressed glucose production in hepatocytes through the TLR4/ MyD88/NF-kB pathway (38). In Plasmodium-infected hepatocytes, MyD88 was required for NF-kB activation and inducible nitric oxide synthase expression (39). Here, we showed that elevated hepatic MyD88 was involved in the growth and metastasis of HCC cells.…”

A TLR2 ligand suppresses inflammation by modulation of chemokine receptors and redirection of leukocyte migration

“…BAY-11 blocks NFB activity by suppressing the phosphorylation of IB-␣ and has been previously used in several studies to demonstrate NFB involvement in a range of inflammatory contexts. [18][19][20][21][22] When tested at 3 and 30 mol/ L, it was apparent that BAY-11 was an efficient blocker of NF-B signaling, at the higher concentration, as measured by its ability to inhibit BLP-induced CCL3 expression ( Figure 4A). In addition, 30 mol/L BAY-11 blocked the reduction in expression of CCR2 ( Figure 4B) as well as CCRs 1 and 5 (data not shown).…”