Plasmodium bergheihistamine-releasing factor favours liver-stage development via inhibition of IL-6 production and associates with a severe outcome of disease

Abstract

SummaryPlasmodium spp., which causes malaria, produces a histamine-releasing factor (HRF), an orthologue of mammalian HRF. Histamine-releasing factor produced by erythrocytic stages of the parasite is thought to play a role in the pathogenesis of severe malaria. Here, we show in a rodent model that HRF is not important during the erythrocytic but pre-erythrocytic phase of infection, which mainly consists in the transformation in the liver of the mosquito-injected parasite form into the erythrocyte-infecting form. Development of P. berghei ANKA cl15cy1 liver stages lacking HRF is impaired and associated with an early rise in systemic IL-6, a cytokine that strongly suppresses development of Plasmodium liver stages. The defect is rescued by injection of anti-IL-6 antibodies or infection in IL-6-deficient mice and parasite HRF is sufficient to decrease IL-6 synthesis, indicating a direct role of parasite HRF in reducing host IL-6. The target cells modulated by HRF for IL-6 production at early time points during liver infection are neutrophils. Parasite HRF is thus used to down-regulate a cytokine with anti-parasite activity. Our data also highlight the link between a prolonged transition from liver to blood-stage infection and reduced incidence of experimental cerebral malaria.

Immunological memory to blood-stage malaria infection is controlled by the histamine releasing factor (HRF) of the parasite

“…Therefore, RT-PCR analysis in the liver indicated a > 48 h delay in the completion of the pre-erythrocytic phase. This phenotype is similar to another hrf mutant made previously in a distinct Plasmodium berghei strain, Pb ANKA ( Pb ANKA- hrf Δ) 34 . One of the immunological features observed previously with the Pb ANKA- hrf Δ model, in contrast to the WT parasite, was an early rise of IL-6 in the liver 34 .…”

“…This phenotype is similar to another hrf mutant made previously in a distinct Plasmodium berghei strain, Pb ANKA ( Pb ANKA- hrf Δ) 34 . One of the immunological features observed previously with the Pb ANKA- hrf Δ model, in contrast to the WT parasite, was an early rise of IL-6 in the liver 34 . Here we assessed the levels of IL-6 expression and found that at 48 hpi, IL-6 transcripts were the sole among those tested that were differentially expressed between infections with WT and Pb NK65- hrf Δ parasites, being increased six-fold in Pb NK65- hrf Δ-infected liver samples (Fig.…”

“…Our work, the present data and our previous reports 25 , 34 , explored in detail all compartments of innate and adaptive immune responses associated with protection elicited by the Pb NK65 hrf Δ parasite. Since such detailed analysis of effector immune mechanisms are not available for blood-stage GAP reported by other groups, it cannot be conclusively established whether or not common protective mechanisms are induced by all self-resolving GAP infections.…”

“…Pb NK65 hrf Δ or Pb ANKA hrf Δ 25 , 26 . Indeed, similar to infection with Pb ANKA hrf Δ sporozoites 34 , a delayed development of Pb NK65 hrf Δ sporozoites in the liver was associated with a sharp peak of IL-6 up-regulation in this tissue at 48 h p.i (Fig. 1D ).…”

Protection against malaria in mice is induced by blood stage–arresting histamine-releasing factor (HRF)–deficient parasites

“…Recently, we described the crucial role of histamine-releasing factor (HRF), also known as translationally controlled tumor protein, during development of P. berghei ANKA ( Pb ANKA) in the host liver ( Mathieu et al, 2015 ). In vivo development of HRF -deficient Pb ANKA parasites is severely impaired in the liver, caused by elevated levels of IL-6 ( Pied et al, 1991 ).…”