Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality

Abstract

Malaria infection triggers vigorous host immune responses; however, the parasite ligands, host receptors, and the signaling pathways responsible for these reactions remain unknown or controversial. Malaria parasites primarily reside within RBCs, thereby hiding themselves from direct contact and recognition by host immune cells. Host responses to malaria infection are very different from those elicited by bacterial and viral infections and the host receptors recognizing parasite ligands have been elusive. Here we investigated mouse genome-wide transcriptional responses to infections with two strains of Plasmodium yoelii (N67 and N67C) and discovered differences in innate response pathways corresponding to strain-specific disease phenotypes. Using in vitro RNAi-based gene knockdown and KO mice, we demonstrated that a strong type I IFN (IFN-I) response triggered by RNA polymerase III and melanoma differentiation-associated protein 5, not Toll-like receptors (TLRs), binding of parasite DNA/RNA contributed to a decline of parasitemia in N67-infected mice. We showed that conventional dendritic cells were the major sources of early IFN-I, and that surface expression of phosphatidylserine on infected RBCs might promote their phagocytic uptake, leading to the release of parasite ligands and the IFN-I response in N67 infection. In contrast, an elevated inflammatory response mediated by CD14/TLR and p38 signaling played a role in disease severity and early host death in N67C-infected mice. In addition to identifying cytosolic DNA/RNA sensors and signaling pathways previously unrecognized in malaria infection, our study demonstrates the importance of parasite genetic backgrounds in malaria pathology and provides important information for studying human malaria pathogenesis.

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

“…During P. chabaudi infection, IFNAR -/-mice had elevated (72), unchanged (21), or reduced parasitemia (73,74). The role of type I IFN in the control of P. yoelii (another model of nonlethal blood-stage malaria) is also variable, as disruption of type I IFN signals has been demonstrated to either increase (75) or decrease parasite burden (28,33). Furthermore, increased type I IFN signals associated with knockout of the IRF3 repressor FOSL1 lead to reduced parasite burden (76).…”

“…To examine antigen-specific CD4 + T cells responding to infection, P. yoelii were generated that constitutively express the Lymphocytic choriomeningitis virus-derived (LCMV-derived) glycoprotein (GP) epitope (GP [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] ). This allows for the identification and analysis of antigen-specific CD4 + T cells using previously described GP66:I-A B tetramer enrichment strategies (16).…”

Phagosomal Acidification Prevents Macrophage Inflammatory Cytokine Production to Malaria, and Dendritic Cells Are the Major Source at the Early Stages of Infection

“…3) (41,48). In any case, type I IFN-and IL-12-producing CD8␣ Ϫ DCs promote Th1 development at the early stage of infection (19).…”

Genome-wide Analysis of Host-Plasmodium yoelii Interactions Reveals Regulators of the Type I Interferon Response

“…For example, an early increase (24 h) in type I interferon (IFN-I) has been shown to be associated with control of some rodent malaria infections (Liehl et al, 2014; Miller et al, 2014; Wu et al, 2014), but the level of IFN-I declines quickly(Wu et al, 2014), suggesting activation of negative regulators of IFN-I. Various IFN-I regulators have been identified (Pan et al, 2014; Peng et al, 2014), but many more are likely unknown, particularly those that are activated during infections involving complex eukaryotic organisms.…”