Early Transcriptional Responses of HepG2-A16 Liver Cells to Infection by Plasmodium falciparum Sporozoites

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.

CSP—A Model for In Vivo Presentation of Plasmodium berghei Sporozoite Antigens by Hepatocytes

“…In addition, these claims seem to be supported by the notion that hepatocytes act as tolerizing cells [27], [28]. On the other hand, given the large number of hepatocyte genes affected by sporozoites and salivary gland components, including some related to antigen processing and presentation and chemokine production it is not far fetched to hypothesize that infected hepatocytes become full-fledged antigen presenting cells upon infection [29], [30]. This would allow the activation of T-cells specific to sporozoite and late liver stage antigens (14).…”

Viral Vector Malaria Vaccines Induce High-Level T Cell and Antibody Responses in West African Children and Infants

“…Immunogenicity data from efficacy trials demonstrated that the levels of anti-CS antibodies induced in 6- to 12week-old infants were 3-fold lower than in 5- to 17-month-olds, suggesting that RTS,S/AS01 is less immunogenic in young infants 15, 23. This stage of the parasite life cycle is an attractive target for a humoral response as sporozoites can be eliminated before infecting host hepatocytes, however, this window may be as brief as 30 min 24 . The liver-stage of the P. falciparum life cycle is also a leading target for vaccination.…”

Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins

“…In this respect, the hepatocyte constitutes far superior "raw material" compared with the RBC; hepatocytes are not only metabolically active, but also highly versatile cells, which are capable of altering uptake, storage, production, and degradation of a wide array of macromolecules in response to cellular and organismal requirements. The presence of a growing Plasmodium parasite is sensed by the host hepatocyte, which responds with activation of cellular stress responses and altered metabolism (26,27). The mammalian target of rapamycin (mTOR) kinase integrates signals from amino acids, stress, oxygen, energy, and growth factors and responds by altering cellular protein and lipid synthesis, as well as autophagy (28).…”