Parasite‐induced ER stress response in hepatocytes facilitates Plasmodium liver stage infection

Abstract

Upon infection of a mammalian host, Plasmodium parasites first replicate inside hepatocytes, generating thousands of new parasites. Although Plasmodium intra-hepatic development represents a substantial metabolic challenge to the host hepatocyte, how infected cells respond to and integrate this stress remains poorly understood. Here, we present proteomic and transcriptomic analyses, revealing that the endoplasmic reticulum (ER)-resident unfolded protein response (UPR) is activated in host hepatocytes upon Plasmodium berghei infection. The expression of XBP1s--the active form of the UPR mediator XBP1--and the liver-specific UPR mediator CREBH is induced by P. berghei infection in vivo. Furthermore, this UPR induction increases parasite liver burden. Altogether, our data suggest that ER stress is a central feature of P. berghei intra-hepatic development, contributing to the success of infection.

NOD1 and NOD2: Beyond Peptidoglycan Sensing

“…Similarly, the role of NOD2 in sensing influenza virus infection (discussed above) could be related to activation of IRE1α-induced inflammatory responses [71], because influenza virus is known to trigger ER stress [73]. Further, in the case of malaria, the liver stage of P. berghei can elicit the unfolded protein response in hepatocytes to promote its intracellular replication [74]. While this latter study did not assess hepatic inflammation, it is tempting to speculate that the role of NOD1/NOD2 in malaria parasite-induced inflammation could be linked to induction of the IRE1 pathway.…”

Alterations in Phosphorylation of Hepatocyte Ribosomal Protein S6 Control Plasmodium Liver Stage Infection

“…Once a parasite is inside a hepatocyte, its survival is also influenced by host cell factors, including levels of the tumor suppressor p53 (Douglass et al, 2015; Kaushansky et al, 2013), the degree of endoplasmic reticulum (ER) stress (Inácio et al, 2015; Kaushansky and Kappe, 2015), and regulation of an extensive network of kinases (Arang et al, 2017; Prudêncio et al, 2008; Ruivo et al, 2016). Interestingly, a large portion of the hepatocyte kinome regulates LS infection (Arang et al, 2017), suggesting that phosphosignaling in the cell might be globally altered in the context of infection.…”

Leishmania infantum Induces Mild Unfolded Protein Response in Infected Macrophages

“…For example, the activation of UPR mediated by viruses can suppress innate antiviral immunity [12]. Moreover, Plasmodium infection of hepatocytes is associated with ER stress and UPR [14]; Mycobacterium tubercolosis infection leads to ER stress-induced apoptosis [15]; the intracellular parasite Toxoplasma gondii promotes the proteasome-mediated degradation of ATF6β in infected cells through the virulence factor ROP18 [16]; Pseudomonas aeruginosa induces UPR to facilitate survival of infected host cell [17]. …”