Malaria is a devastating disease, causing approximately 700,000 deaths per year. This disease is caused by Plasmodium parasites. Plasmodium is transmitted to humans via the bite of an infected female anopheline mosquito. During a blood meal, the mosquito injects sporozoites, the form of Plasmodium that initiates the infection, into the skin of the human host. From the skin, the sporozoites migrate to the liver, where they traverse Kupffer cells and enter hepatocytes to begin growing and dividing. This stage of the infection is asymptomatic. From the liver, Plasmodium is released into the blood stream, where clinical disease begins. If the infection process can be inhibited in the liver stage the disease manifestation is prevented. However, the liver stage is not well understood. The goal of this project is to understand how Plasmodium sporozoites can traverse Kupffer cells, the macrophages of the liver, and prevent an immune response from occurring. Insight into the Plasmodium-Kupffer cell interaction can guide future interventions aimed at modulating this interaction to allow the Kupffer cell to stop the infection at this stage. We will determine how specific Kupffer cell and parasite proteins are involved in traversal and immune evasion by measuring the cellular response of Kupffer cells to sporozoite attachment/traversal. This project will focus on the host cell protein triggering receptor expressed on myeloid cells 2 (TREM2), a Kupffer cell protein recently implicated in sporozoite recognition. Transcriptomic and proteomic analyses of this protein will be performed to understand regulation pre- and post-exposure to sporozoites. Additionally, recombinant TREM2 will be expressed and used to identify its binding partners on the sporozoite. This project will also focus on the Kupffer cell immune response following exposure to a parasite secreted protein, the Plasmodium berghei homolog of the macrophage migration inhibitory factor (PbMIF). We will use cytokine detection arrays, qRT-PCR, and immunofluorescence microscopy to quantify the effect of PbMIF on Kupffer cell immune regulation. Finally, this project will examine the comparative Kupffer cell response to intact P. berghei sporozoites. Kupffer cells will be exposed to sporozoites for defined, relevant periods of time, and their cytokine secretion and immune activation will also be monitored. Overall, we anticipate that this project will shed new light on the Kupffer cell response to Plasmodium sporozoites and identify new potential targets for interventions to prevent this deadly disease.
Studying the immunobiology of the malaria parasite interaction with liver-resident macrophages will provide basic insight into the pathways subverted by the pathogen in promoting its transmission and establishment in the human host. Knowledge into this critical stage of the initial malaria infection process can help lead to new interventions to prevent disease.
