Innate immune response against Plasmodium liver-stage parasites is enhanced by targeted nutritional supplementation

Introduction: During the asymptomatic liver stage of malaria infection, Plasmodium parasites scavenge host nutrients to support their multiplication[1]. One of these nutrients is arginine (Arg), whose metabolism is crucial for the parasite’s intra- hepatic development[1]. Arg is the only amino acid-based supplementation evaluated in the context of malaria. However, although Arg supplementation can enhance nitric oxide (NO) production and improve survival in animal models of Plasmodium infection, results obtained in the clinic are unclear[2–4]. Aim: Preliminary results from the host laboratory have shown that supplementation of C57BI/6J mice with RKV, which combines Arg (R) with Lysine (K) and Valine (V), two amino acids described as inhibitors of the arginase enzymes[5], leads to a striking decrease of hepatic infection by the rodent malaria parasite P. berghei. Thus, our aim was to elucidate the mechanism of hepatic parasite elimination upon RKV supplementation. Methods: Plasmodium liver infection was characterized employing real-time PCR and immunofluorescence microscopy. The impact of RKV supplementation on the immune system was ascertained employing knockout mice and depleting specific immune cell populations. Results: The decrease in Plasmodium liver infection upon RKV supplementation results mostly from a reduction in the number of infected hepatocytes, supporting a role of the host’s immune system on parasite elimination. Parasite elimination does not rely on NO production nor on a boost of the Type-I IFN response, previously reported as crucial to control liver stage infection[6,7]. Natural Killer (NK) cells were identified as the effector cells involved in RKV-dependent parasite elimination. Signaling via Myd88, seems to also be essential for this elimination process, although the cells in which this signaling occurs remain unidentified. Conclusion: We found that NK cells, commonly used in immunotherapies against cancer and viral infections[8], can also be stimulated to act against Plasmodium liver stage infection, making these immune cells an appealing target for new antimalarial strategies.