A Plasmodium Cross-Stage Antigen Contributes to the Development of Experimental Cerebral Malaria.

Priyanka Fernandes,Roland Frank,Maria A Hernández-Castañeda,Ann-Kristin Mueller,Laurent Rénia,Philipp Wiedemann,Angelika Hoffmann,Shanshan W Howland,Kirsten Heiss,Klára Obrová,Martin Bendzus

doi:10.3389/fimmu.2018.01875

Abstract

Cerebral malaria is a complex neurological syndrome caused by an infection with Plasmodium falciparum parasites and is exclusively attributed to a series of host–parasite interactions at the pathological blood-stage of infection. In contrast, the preceding intra-hepatic phase of replication is generally considered clinically silent and thereby excluded from playing any role in the development of neurological symptoms. In this study, however, we present an antigen PbmaLS_05 that is presented to the host immune system by both pre-erythrocytic and intra-erythrocytic stages and contributes to the development of cerebral malaria in mice. Although deletion of the endogenous PbmaLS_05 prevented the development of experimental cerebral malaria (ECM) in susceptible mice after both sporozoite and infected red blood cell (iRBC) infections, we observed significant differences in contribution of the host immune response between both modes of inoculation. Moreover, PbmaLS_05-specific CD8+ T cells contributed to the development of ECM after sporozoite but not iRBC-infection, suggesting that pre-erythrocytic antigens like PbmaLS_05 can also contribute to the development of cerebral symptoms. Our data thus highlight the importance of the natural route of infection in the study of ECM, with potential implications for vaccine and therapeutic strategies against malaria.

Highlights

Cerebral malaria is a severe manifestation of an infection with Plasmodium falciparum parasites and a major cause of morbidity and mortality in developing countries [1]
In contrast to observations made after sporozoite inoculation, we found a significant reduction in the number of infiltrated CD4+ and CD8+ T cells in the brains of KO-infected red blood cell (iRBC)-infected mice, along with reduced numbers of Pb1-specific IFN-γ+ CD8+ T cells when compared to mice infected with wildtype PbGFP Luccon (WT)-iRBC (Figure 7A)
While the abrogation of experimental cerebral malaria (ECM) was consistent after both sporozoite and iRBC infections, parasite sequestration and the host immune response differed significantly between the two modes of infection

Summary

Introduction

Cerebral malaria is a severe manifestation of an infection with Plasmodium falciparum parasites and a major cause of morbidity and mortality in developing countries [1]. Sequestered parasites obstruct blood vessels in the brain causing hypoxia and vasogenic edema [17], leading to activation of the endothelium [18, 19] and the recruitment of iRBCs, leukocytes, neutrophils, and macrophages [20, 21] which together contribute to local inflammation and breakdown of the blood–brain barrier [22,23,24,25,26,27,28,29,30] Both sequestration and inflammation independently or in combination contribute to vascular leakage and neurological damage [31]

Methods

Results

Conclusion