Abstract
Although exo-erythrocytic forms (EEFs) of liver stage malaria parasite in the parasitophorous vacuole (PV) are encountered with robust host innate immunity, EEFs can still survive and successfully complete the infection of hepatocytes, and the underlying mechanism is largely unknown. Here, we showed that sporozoite circumsporozoite protein (CSP) translocated from the parasitophorous vacuole into the hepatocyte cytoplasm significantly mediated the resistance to the killing of EEFs by interferon-gamma (IFN-γ). Attenuation of IFN-γ-mediated killing of EEFs by CSP was dependent on its ability to reduce the levels of autophagy-related genes (ATGs) in hepatocytes. The ATGs downregulation occurred through its enhanced ubiquitination mediated by E3 ligase NEDD4, an enzyme that was upregulated by CSP when it translocated from the cytoplasm into the nucleus of hepatocytes via its nuclear localization signal (NLS) domain. Thus, we have revealed an unrecognized role of CSP in subverting host innate immunity and shed new light for a prophylaxis strategy against liver-stage infection.
Highlights
Malaria is still one of the most devastating diseases worldwide and is caused by infection with the genus Plasmodium that is initiated in the mammalian host by inoculation of sporozoites into the skin by Anopheles mosquitoes
Immunofluorescence assay with anti-upregulated in infective sporozoite gene 4 (UIS4), a parasitophorous vacuole membrane (PVM) specific marker and anti-circumsporozoite protein (CSP) demonstrated that the CSP of mutant sporozoites was significantly inhibited to translocate from the PV into the hepatocyte cytoplasm when infecting HepG2 cells (Figure 1A)
CSP is a multifunctional protein of the malaria parasite that is critical for the invasion of sporozoites into hepatocytes but is essential for sporozoite development in mosquitoes [32,33,34,35,36,37,38]
Summary
Malaria is still one of the most devastating diseases worldwide and is caused by infection with the genus Plasmodium that is initiated in the mammalian host by inoculation of sporozoites into the skin by Anopheles mosquitoes. Sporozoites travel to the liver via blood circulation, where they infect hepatocytes. Sporozoites bind to highly sulfated heparin sulfate proteoglycans (HSPGs) on the hepatocyte surface by circumsporozoite protein (CSP), which triggers their invasion into hepatocytes [1]. Sporozoites inside a parasitophorous vacuole (PV) and transform into exo-erythrocytic forms (EEFs). To avoid fusion of the PV with lysosomes and to shield itself from the cytosol of the host, the PV membrane is modified by parasite-derived proteins, such as upregulated in infective sporozoite gene 4 (UIS4) and exported protein 1 (EXP-1) [2, 3].
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