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