A transient resistance to blood-stage malaria in interferon-γ-deficient mice through impaired production of the host cells preferred by malaria parasites.

Hiroko Okada,Tomoyo Taniguchi,Hajime Hisaeda,Kazutomo Suzue,Risa Onishi,Jun Hirata,Takashi Imai,Chikako Shimokawa

doi:10.3389/fmicb.2015.00600

Abstract

IFN-γ plays both pathological and protective roles during blood-stage malaria. One of its pathological roles is its contribution to anemia by suppressing erythropoiesis. Here, to evaluate the effects of IFN-γ-mediated alterations in erythropoiesis on the course of malaria infection, mice deficient in IFN-γ (GKO) were infected with two strains of the rodent malaria parasite Plasmodium yoelii, 17XL (PyL) and 17XNL (PyNL), whose host cell ranges differ. Regardless of genotype, all mice infected with PyL, which can invade any erythrocyte, developed high parasitemia and died quickly. Although PyNL caused a transient non-lethal infection in wild-type (WT) mice, some GKO mice were unable to control the infection and died. However, GKO mice were resistant to the early phase of infection, showing an impaired increase in parasitemia compared with WT mice. This resistance in the GKO mice was associated with having significantly fewer reticulocytes, which are the preferred host cells for PyNL parasites, than the WT mice. Compared with the amount of reticulocytes in GKO mice during the early stages of infection, there was a significant increase in the amount of these cells at later stages, which coincided with the inability of these mice to control the infection. We found that the growth of PyNL parasites correlated with the amount of reticulocytes. Thus, the reduced number of reticulocytes in mice lacking IFN-γ appears to be responsible for the limited parasite growth. Notably, these differences in GKO mice were at least partially reversed when the mice were injected with exogenous IFN-γ. Additionally, an artificial induction of hemolytic anemia and an increase in reticulocytes by phenylhydrazine treatment in GKO mice completely abolished the lower parasitemia and resistance during early phase infection. These results suggest that IFN-γ may contribute to the early growth of PyNL parasites by increasing the amount of reticulocytes, presumably by enhancing erythropoiesis.

Highlights

Malaria, caused by infection with genus Plasmodium protozoan parasites, produces over 200 million infections and approximately 600 thousand deaths every year (WHO, 2014)
Kinetics of Infection with P. yoelii in IFN-γ knock out mice (GKO) Mice Given the hematopoietic roles of IFN-γ, we aimed to reevaluate the contributions of IFN-γ to the host-parasite relationship during malaria by infecting GKO mice with two strains of the rodent malaria parasite, P. yoelii
We demonstrated here that mice deficient in IFN-γ were more resistant to the early phase of infection with Plasmodium yoelii 17XNL (PyNL) than WT mice, they eventually developed higher parasitemia and some of them succumbed to an infection that is nonlethal in WT mice

Summary

Introduction

Malaria, caused by infection with genus Plasmodium protozoan parasites, produces over 200 million infections and approximately 600 thousand deaths every year (WHO, 2014). The major reasons that malaria remains life-threatening are the absence of effective vaccines and the spread of chloroquineresistant parasites. Developing an effective vaccine for malaria is challenging because malaria infection induces complicated pathological consequences that are formed by both parasite factors and host immune responses. All malaria symptoms, including fever, anemia, and splenomegaly, appear while the malaria parasites undergo erythrocytic cycles. All species of malaria go through these cycles, the host cell specificities of the malaria parasites vary among species. The host cell preference of rodent malaria parasites influences their virulence. The P. yoelii 17XNL parasite infects only reticulocytes and causes a transient infection in wild-type (WT) mice (Jayawardena et al, 1983). The P. yoelii 17XL strain, a variant derived from P. yoelii 17XNL, invades a wide range of erythrocytes, resulting in a lethal infection with high parasitemia (Jayawardena et al, 1983; Otsuki et al, 2009)

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