Different TLR signaling pathways drive pathology in experimental cerebral malaria vs. malaria-driven liver and lung pathology

Abstract

Malaria infection causes multiple organ-specific lethal pathologies, including cerebral malaria, and severe liver and lung pathologies by inducing strong inflammatory responses. Gene polymorphism studies suggest that TLR4 and TLR2 contribute to severe malaria, but the roles of these signaling molecules in malaria pathogenesis remain incompletely understood. We hypothesize that danger-associated molecular patterns (DAMPs) produced in response to malaria activate TLR2 and TLR4 signaling and contribute to liver and lung pathologies. By using a mouse model of Plasmodium berghei NK65 infection, we show that the combined TLR2 and TLR4 signaling contributes to malaria liver and lung pathologies, and mortality. Macrophages, neutrophils, NK cells, and T cells infiltrate to the livers and lungs of infected wild type (WT) mice more than TLR2,4-/- mice. Additionally, endothelial barrier disruption, tissue necrosis, and hemorrhage were higher in the livers and lungs of infected WT mice than in those of TLR2,4-/- mice. Consistent with these results, the levels of chemokine production, chemokine receptor expression, and liver and lung pathological markers were higher in infected WT mice than in TLR2,4-/- mice. In addition, the levels of HMGB1, a potent TLR2- and TLR4-activating DAMP, were higher in livers and lungs of WT mice than TLR2,4-/- mice. Treatment with glycyrrhizin, an immunomodulatory agent known to inhibit HMGB1 activity, markedly reduced mortality in WT mice. These results suggest that TLR2 and TLR4 activation by HMGB1 and possibly other endogenously produced DAMPs contribute to malaria liver and lung injury via signaling mechanisms distinct from those involved in cerebral malaria pathogenesis.