Abstract
Invasion of hepatocytes by Plasmodium sporozoites deposited by Anopheles mosquitoes, and their subsequent transformation into infective merozoites is an obligatory step in the initiation of malaria. Interactions between the sporozoites and hepatocytes lead to a distinct, complex and coordinated cellular and systemic host response. Little is known about host liver cell response to sporozoite invasion, or whether it is primarily adaptive for the parasite, for the host, or for both. Our present study used gene expression profiling of human HepG2-A16 liver cells infected with Plasmodium falciparum sporozoites to understand the host early cellular events and factors influencing parasite infectivity and sporozoite development. Our results show that as early as 30 min following wild-type, non-irradiated sporozoite exposure, the expressions of at least 742 genes was selectively altered. These genes regulate diverse biological functions, such as immune processes, cell adhesion and communications, metabolism pathways, cell cycle regulation, and signal transduction. These functions reflect cellular events consistent with initial host cell defense responses, as well as alterations in host cells to sustain sporozoites growth and survival. Irradiated sporozoites gave very similar gene expression pattern changes, but direct comparative analysis between liver gene expression profiles caused by irradiated and non-irradiated sporozoites identified 29 genes, including glypican-3, that were specifically up-regulated only in irradiated sporozoites. Elucidating the role of this subset of genes may help identify the molecular basis for the irradiated sporozoites inability to develop intrahepatically, and their usefulness as an immunogen for developing protective immunity against pre-erythrocytic stage malaria.
Highlights
Malaria transmission occurs when Plasmodium sporozoites from the salivary glands of female Anopheles mosquitoes are inoculated into vertebrate hosts during a blood meal
Little is known about host liver cell response to sporozoite invasion, considerable progress have been made in elucidating the parasite genes and proteins that are important for liver infection [5,6,7,8,9,10,11,12,13]
Hierarchical clustering analysis using these genes showed that study samples can be grouped into three broad aggregated clusters representative of treatment conditions: Control, salivary gland extract from uninfected mosquitoes (SalGld), and sporozoite-infected HepG2-A16 liver cells (Spor) with IrradSpor together, indicating that gene expression changes caused by Spor and IrradSpor exposure were very similar (Fig. 2A)
Summary
Malaria transmission occurs when Plasmodium sporozoites from the salivary glands of female Anopheles mosquitoes are inoculated into vertebrate hosts during a blood meal. Interactions between host and pathogens are diverse and are regulated in specific patterns by unique molecules and mechanisms involving activation of transcriptional events of innate and adaptive immunity [1,2,3,4] In malaria, this complex interaction between pathogen and host is a critical factor in determining the progression and outcome of the development in liver of the parasite. Genomewide microarray analyses have been used to study malaria sporozoite-hepatocyte interactions (18 –20), these studies are limited to either transcriptome profiling of the sporozoites or of non-human host cells/parasite combinations. Our present study was aimed at identifying changes in human hepatocyte transcripts differentially regulated following early P. falciparum sporozoites infection. Differential effects on liver gene expression profiles caused by wild-type and radiation-attenuated sporozoites were determined
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