Protective Vaccination Reshapes Hepatic Response to Blood-Stage Malaria of Genes Preferentially Expressed by NK Cells.

Marcos J Araúzo-Bravo,Frank Wunderlich,Denis Delic,Daniela Gerovska

doi:10.3390/vaccines8040677

Abstract

The role of natural killer (NK) cells in the liver as first-line post infectionem (p.i.) effectors against blood-stage malaria and their responsiveness to protective vaccination is poorly understood. Here, we investigate the effect of vaccination on NK cell-associated genes induced in the liver by blood-stage malaria of Plasmodium chabaudi. Female Balb/c mice were vaccinated at weeks 3 and 1 before being infected with 106 P. chabaudi-parasitized erythrocytes. Genes preferentially expressed by NK cells were investigated in livers of vaccination-protected and non-protected mice on days 0, 1, 4, 8, and 11 p.i. using microarrays, qRT-PCR, and chromosome landscape analysis. Blood-stage malaria induces expression of specific genes in the liver at different phases of infection, i.e., Itga1 in expanding liver-resident NK (lrNK) cells, Itga2 in immigrating conventional NK (cNK) cells; Eomes and Tbx21 encoding transcription factors; Ncr1, Tnfsf10, Prf1, Gzma, Gzmb, Gzmc, Gzmm, and Gzmk encoding cytolytic effectors; natural killer gene complex (NKC)-localized genes encoding the NK cell receptors KLRG1, KLRK1, KLRAs1, 2, 5, 7, KLRD1, KLRC1, KLRC3, as well as the three receptors KLRB1A, KLRB1C, KLRB1F and their potential ligands CLEC2D and CLEC2I. Vaccination enhances this malaria-induced expression of genes, but impairs Gzmm expression, accelerates decline of Tnfsf10 and Clec2d expression, whereas it accelerates increased expression of Clec2i, taking a very similar time course as that of genes encoding plasma membrane proteins of erythroblasts, whose malaria-induced extramedullary generation in the liver is known to be accelerated by vaccination. Collectively, vaccination reshapes the response of the liver NK cell compartment to blood-stage malaria. Particularly, the malaria-induced expansion of lrNK cells peaking on day 4 p.i. is highly significantly (p < 0.0001) reduced by enhanced immigration of peripheral cNK cells, and KLRB1F:CLEC2I interactions between NK cells and erythroid cells facilitate extramedullary erythroblastosis in the liver, thus critically contributing to vaccination-induced survival of otherwise lethal blood-stage malaria of P. chabaudi.

Highlights

Malaria is still a major threat of human health in tropical countries, causing globally an estimated228 million cases and 405,000 deaths in 2018, in particular about 266,000 deaths in children aged under 5 years [1]
As a continuation of these previous studies, here we aim to study systematically the possible effects of vaccination on gene expression associated with the natural killer (NK) cell compartment of the liver of mice infected with blood-stage malaria of P. chabaudi
Vaccination reshapes the response of the NK cell compartment in the liver to primary blood-stage infections of P. chabaudi malaria, evidenced by relative impairment of the malaria-induced expansion of liver-resident NK (lrNK) cells peaking on day 4 p.i. due to enhanced immigration of conventional NK (cNK) cells into the liver

Summary

Introduction

Malaria is still a major threat of human health in tropical countries, causing globally an estimated228 million cases and 405,000 deaths in 2018, in particular about 266,000 deaths in children aged under 5 years [1]. The most prominent candidate, RTS,S, has been recently reported to induce partial protection, which, is obviously dependent on age of vaccines and wanes with time [2]. Malaria is caused by parasitic protozoans of the genus Plasmodium. Their blood-stages are responsible for morbidity and mortality, which develop and multiply within host red blood cells [3]. The main effector organ against blood-stage malaria is the spleen, which is able to eliminate senescent and other aberrant erythrocytes including Plasmodium-parasitized erythrocytes [4,5]. Kupffer cells with their erythrophagocytic capacity are currently regarded as mainly responsible for removal of Plasmodium-infected erythrocytes in the liver [7,8,9,10]. There is increasing information, though controversially debated, that natural killer (NK) cells in the liver may play a critical role in the elimination of Plasmodium-infected erythrocytes [11,12]

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