UPR in intracellular parasite-infected cells
Although a large number of studies have been done to characterize the UPR and its effects in metabolic syndromes and cells infected by bacteria, there is a shortage of investigations on its role in shaping the outcome of intracellular parasitic infections. Many pathogens induce ER stress and UPR via interacting with the ER functions[26], [27] yet several pathogens can subvert the UPR to promote their survival and replication[8]. Parasites-triggered ER stress response pathways have been investigated and reported to a certain extent in infections by Apicomplexan and Trypanosomatid protozoan parasites that are responsible for malaria, toxoplasmosis, cryptosporidiosis, and leishmaniasis[8].
Plasmodium species is the causative agent of malaria and are obligate intracellular parasites belonging to the phylumApicomplexa [28]. During the initial stages of infection,Plasmodium sporozoites migrate to the liver and infect hepatocytes[29]. Inácio et al. demonstrated that upon infecting mice with Plasmodium berghei the UPR pathways of host hepatocytes are activated. They showed that as a result of the UPR triggered by Plasmodium berghei infection, the expression of spliced XBP1, which is the downstream effector of the IRE1 branch and liver-specific branch of the UPR mediated by the cAMP-responsive element binding protein-hepatocyte (CREBH) are induced, favoring the liver stage infection of Plasmodium [30]. Experimental mouse models of cerebral malaria have demonstrated the presence of all three main sensor proteins of UPR, indicating the activation of three main arms of UPR[31].
Toxoplasma gondii is another obligate intracellular protozoan parasite that belongs to the phylum Apicomplexa. These parasites can invade any nucleated cell from a wide range of warm-blooded animals[32]. Upon invasion of the host cell, Toxoplasma gondii forms a unique parasitophorous vacuole (PV) that does not fuse with the endolysosomal system and acts as a protective niche.ROP18 kinase, a key virulence factor that is secreted into host cells during the invasion by T. gondii has been found to target ATF6β; a member of the ATF6 family which operates UPR. Experiments done by Yamamoto et al. demonstrated that ATF6β deficient mice were susceptible to infection, indicating that tATF6β has a role in resistance against Toxoplasma gondii infection[8], [33]. Studies done by two individual study groups; Wang et al. and Zhouet al. reported that Toxoplasma gondii induces apoptosis in neural stem cells (NCS) by up-regulation of CHOP, caspase-12, and JNK which are associated with ER stress signal pathways[32], [34]. A recent study done by Augusto et al. reported thatToxoplasma triggers the UPR in host cells through the release of calcium from ER. Furthermore, they have shown that IRE1 is activated in the host during the infection and involved in a non-canonical role in the cytoskeletal remodeling of infected cells, thus enhancing cell migration[35].
Cryptosporidium parvum yet another intracellular protozoan parasite belonging to phylum Apicomplexa, that is identified as using the host UPR for its survival Cryptosporidium parvum is partially dependent on the host for its polyamine requirement. It poses a retro-conventional pathway that can produce spermidine and spermine, utilizing spermidine/spermine N1-acetyltransferase (SSAT)[36], [37] and it has been demonstrated that upon the cell invasion, Cryptosporidium parvum triggers host UPR pathways that cause expression of SSAT in the human host which will then lead to overproduction and excretion of N1-acetylspermine and N1-acetylspermidine[37].
Leishmania species and the disease