IFNGR1 signaling is associated with adverse pregnancy outcomes during infection with malaria parasites

Abstract

Complicated/severe cases of placental pathology due to Plasmodium falciparum and P. vivax, especially adverse pregnancy outcomes during P. vivax infection, have been increasing in recent years. However, the pathogenesis of placental pathology during severe malaria is poorly understood, while responses against IFN-γ are thought to be associated with adverse pregnancy outcomes. In the present study, we explored the role of IFN-γ receptor 1 (IFNGR1) signaling in placental pathology during severe malaria using luciferase-expressing rodent malaria parasites, P. berghei NK65 (PbNK65L). We detected luciferase activities in the lung, spleen, adipose tissue, and placenta in pregnant mice, suggesting that infected erythrocytes could accumulate in various organs during infection. Importantly, we found that fetal mortality in IFNGR1-deficient mice infected with PbNK65L parasites was much less than in infected wild type (WT) mice. Placental pathology was also improved in IFNGR1-deficient mice. In contrast, bioluminescence imaging showed that parasite accumulation in the placentas of IFNGR1-deficient pregnant mice was comparable to that in WT mice infected with PbNK65L. These findings suggest that IFNGR1 signaling plays a pivotal role in placental pathology and subsequent adverse pregnancy outcomes during severe malaria. Our findings may increase our understanding of how disease aggravation occurs during malaria during pregnancy.

Interferons and Proinflammatory Cytokines in Pregnancy and Fetal Development

“…Other studies show a correlation between poor pregnancy outcomes and systemic concentrations of cytokines and chemokines including TNF-α, IFN-γ, IL-10, and CXCL9 in women infected with malaria (Fried et al, 2017). Consistent with these findings, mouse models show that TLR4 signaling and IFN-γ signaling are mediators of abnormal development of the placenta labyrinth vasculature and fetal growth restriction caused by malaria infection (Barboza et al, 2017; Niikura et al, 2017). Thus, the inflammatory response to malaria appears to be a key mediator of malaria-related pregnancy complications.…”

Innate Immune Mechanisms to Protect Against Infection at the Human Decidual-Placental Interface

“…Type II IFN, IFNγ, predominantly produced by NK and CD4+ T cells is crucial in controlling parasitic infection, such as T. gondii in mice (94,119). However, elevated levels of IFNγ in response to T. gondii infection can lead to pathological effects during pregnancy including fetal demise (119,120). Severe placental pathology and fetal death have also been associated with elevation of IFNγ during pregnancy in a murine model of malaria (121).…”

“…However, elevated levels of IFNγ in response to T. gondii infection can lead to pathological effects during pregnancy including fetal demise ( 119 , 120 ). Severe placental pathology and fetal death have also been associated with elevation of IFNγ during pregnancy in a murine model of malaria ( 121 ). Hence, proper regulation of type I and II IFN-mediated signaling at the uterine-placental interface is crucial in limiting pathogen replication, whilst preserving a balanced environment for normal placental development ( 122 ).…”

Malaria in the postpartum period causes damage to the mammary gland

“…In a study using a mouse model, dendritic cells activated via TLR signaling expand pathogenic CD4 + T cells and CD8 + T cells, as well as the production of proinflammatory cytokines (e.g., IFN-γ) [ 10 ]. In addition to pathogenic CD4 + T cells and CD8 + T cells, macrophages and neutrophils (via IFN-γ receptor 1 [IFNGR1]) cause development of cerebral and placental malaria [ 11 – 14 ].…”