Research Article: Microvesicles from malaria-infected red blood cells activate natural killer cells via MDA5 pathway

Date Published: October 4, 2018

Publisher: Public Library of Science

Author(s): Weijian Ye, Marvin Chew, Jue Hou, Fritz Lai, Stije J. Leopold, Hooi Linn Loo, Aniruddha Ghose, Ashok K. Dutta, Qingfeng Chen, Eng Eong Ooi, Nicholas J. White, Arjen M. Dondorp, Peter Preiser, Jianzhu Chen, Martin Goodier.


Natural killer (NK) cells provide the first line of defense against malaria parasite infection. However, the molecular mechanisms through which NK cells are activated by parasites are largely unknown, so is the molecular basis underlying the variation in NK cell responses to malaria infection in the human population. Here, we compared transcriptional profiles of responding and non-responding NK cells following exposure to Plasmodium-infected red blood cells (iRBCs) and identified MDA5, a RIG-I-like receptor involved in sensing cytosolic RNAs, to be differentially expressed. Knockout of MDA5 in responding human NK cells by CRISPR/cas9 abolished NK cell activation, IFN-γ secretion, lysis of iRBCs. Similarly, inhibition of TBK1/IKKε, an effector molecule downstream of MDA5, also inhibited activation of responding NK cells. Conversely, activation of MDA5 by liposome-packaged poly I:C restored non-responding NK cells to lyse iRBCs. We further show that microvesicles containing large parasite RNAs from iRBCs activated NK cells by fusing with NK cells. These findings suggest that NK cells are activated through the MDA5 pathway by parasite RNAs that are delivered to the cytoplasm of NK cells by microvesicles from iRBCs. The difference in MDA5 expression between responding and non-responding NK cells following exposure to iRBCs likely contributes to the variation in NK cell responses to malaria infection in the human population.

Partial Text

Human malaria is caused by parasites of the genus Plasmodium, and of which, P. falciparum causes most cases of severe malaria. The host innate immune system is the first line of defense against Plasmodium infection, and the outcome of early host-parasite interaction is a strong determinant for later immunopathology and adaptive immune responses [1]. Natural killer (NK) cells, a key cell type of innate immunity, play a critical role in limiting acute malaria infection by both cell-mediated cytotoxicity and IFN-γ secretion [2]. In murine models, malaria infection leads to a rapid proliferation of NK cells [3], and depletion of NK cells results in higher parasitemia and accelerated disease progression [4–6]. In malaria-infected children, elevated NK cell counts and increased NK cell cytotoxicity are correlated with lower parasitemia [7]. Similarly, elevated NK cell counts are observed in adult malaria patients [8]. NK cells can directly lyse Plasmodium-infected red blood cells (iRBCs) [9, 10] and are also one of the earliest sources of IFN-γ and soluble granzyme following experimental infection of malaria-naïve volunteers with P. falciparum [11]. Furthermore, a single P. falciparum challenge is sufficient to induce lasting NK cell responses [12].

NK cells play a critical role in the immediate responses to malaria parasite infection through rapid activation of cytotoxic activities and secretion of cytokines. Poor NK cell cytotoxicity is often associated with acute malaria [7, 9] and the low NK cell cytotoxicity in pregnant women is associated with higher chance of a positive blood smear for malaria parasites [23]. Interestingly, NK cell responses to malaria infection vary significantly in the human population. NK cells from ~30% of malaria naïve individuals do not become activated nor produce much IFN-γ in response to iRBCs [20]. We also observed similar heterogeneity of NK cell responses to iRBCs among malaria naïve individuals. Besides deficiencies in NK cell activation and IFN-γ production, we further show that NK cells from non-responders are unable to control parasitemia in vitro. Analysis of NK cells from patients with uncomplicated or severe malaria also suggests an association of non-responding NK cells with severe malaria.