Targeting the master regulator mTOR: a new approach to prevent the neurological of consequences of parasitic infections?
Donnelly et al. Parasites & Vectors
Targeting the master regulator mTOR: a new approach to prevent the neurological of consequences of parasitic infections?
Sheila Donnelly 0
Wilhelmina M. Huston 0
Michael Johnson 0
Natalia Tiberti 0
Bernadette Saunders 0
Bronwyn O'Brien 0
Catherine Burke 0
Maurizio Labbate 0
Valery Combes 0
0 School of Life Sciences, Faculty of Science, University of Technology Sydney , Ultimo, NSW 2007 , Australia
A systematic analysis of 240 causes of death in 2013 revealed that parasitic diseases were responsible for more than one million deaths. The vast majority of these fatalities resulted from protozoan infections presenting with neurological sequelae. In the absence of a vaccine, development of effective therapies is essential to improving global public health. In 2015, an intriguing strategy to prevent cerebral malaria was proposed by Gordon et al. 2015 mBio, 6:e00625. Their study suggested that inhibition of the mammalian target of rapamycin prevented experimental cerebral malaria by blocking the damage to the blood brain barrier and stopping the accumulation of parasitized red blood cells and T cells in the brain. Here, we hypothesize that the same therapeutic strategy could be adopted for other protozoan infections with a brain tropism, to prevent cerebral parasitosis by limiting pathogen replication and preventing immune mediated destruction of brain tissue.
mTOR; Rapamycin; Neuropathology; Malaria; Protozoa; Adjunctive therapy; Cerebral Parasitosis
Protozoan parasites represent a significant threat to human
]. Three of the most important diseases caused by
protozoan parasites (malaria, trypanosomiasis and
toxoplasmosis) are associated with cerebral parasitosis which results
in fatalities or leaves survivors with debilitating neurological
defects (Table 1) [
]. These diseases contribute to
approximately 84 million disability adjusted life years globally, a
significant burden which is exacerbated by the lack of
licensed vaccines, making safe and effective drugs vital to
their prevention and treatment.
This review examines the potential use of inhibitors of
the mammalian target of rapamycin (mTOR) as
adjunctive therapy in the treatment of protozoan cerebral
parasitosis and explores the limitations of such approaches
by considering the function of mTOR in both the
parasite and the host.
Targeting mTOR: A new strategy to prevent cerebral malaria?
The most severe outcome from infection with the
protozoan Plasmodium falciparum is human cerebral malaria.
This condition is associated with pronounced
accumulation of multiple immune cells into the brain [
these, it is the CD8+ T cells that recognise parasite
antigens presented, in the context of MHC class1, by
parasitised red blood cells (PRBC), and subsequently produce
granzyme B and perforin to breakdown tight junctions
of the blood brain barrier (BBB) [
]. The increased
permeability permits trafficking of inflammatory leukocytes
into the brain. It is also these parasite-specific CD8+ T
cells that modulate the phenotype and function of
macrophages, which subsequently secrete damaging
The murine model of cerebral malaria (experimental
cerebral malaria, ECM) has been used for several decades
to improve understanding of the disease pathogenesis,
and to test new therapies, as it recapitulates most of the
features of the paediatric disease, including ataxia,
paralysis, coma and death [
]. These common features extend
also to post-recovery observations, such as long-term
cognitive impairment . However this model has been
the subject of many discussions, mainly because
pathogenesis of human CM is said to be driven by sequestration
of PRBC [
] while ECM is driven by immunological cells
such as CD8 T cells and macrophages [
]. It is, however,
accepted that PRBC sequestration alone is not sufficient
to explain the neuropathology observed during HCM [
In fact, recent advances in parasite labelling have
demonstrated that PRBC do sequester in microvessels in mice
] and that PRBC sequestration is indeed a canonical
feature of ECM [
]. The recent study by Strangward
et al.  also showed that ECM recapitulated neuronal
damage observed in humans. CD8 T cells are a major
mediator of ECM; however, these cells were also identified
in post-mortem samples from children who died from
CM albeit in small numbers [
]. In a recent review
Howland et al. [
] suggested that rather than the presence in
mice and absence in human, it was the level of
sequestration of immune cells such as CD8 T cells that differed
between HCM and ECM with the phenomenon always
present and likely relevant. In addition, it is important to
note that for understandable reasons, post-mortems
studies are only allowing end-point observations, and it is
therefore difficult to evaluate the relevance of findings
such as the presence of CD8 T cells within the samples.
Nonetheless, findings that levels of CXCL-10, a major
mediator of CD8 and CD4 T cells migration, allow to
differentiate patients with CM from those with severe
anaemia and is associated with higher mortality risk,
suggests that a non-negligible role can be given to CD8 T
cells in the pathogenesis of HCM [
]. Using this model,
Gordon et al. [
] identified a potential new adjunctive
therapy by targeting the mammalian target of rapamycin
(mTOR), a kinase with a central role in maintaining
Under steady-state conditions, multiple mechanisms
operate in concert to inhibit mTOR expression and/or
activity and maintain/restore T cell homeostasis [
After the recognition of antigen by naïve T cells, mTOR
becomes activated and plays an integral role in the
differentiation of CD4+ T cells into distinct effector
subsets (Th1, Th2, Th17, Tregs and follicular Th cells), and
the activation and clonal expansion of CD8+ T cells.
Thus, mTOR determines T cell fate [
]. In addition,
mTOR regulates the function of most other immune
cells, including B cells, neutrophils,
monocytes/macrophages, dendritic cells, mast cells, and NK cells, making
mTOR a central regulator of both innate and adaptive
immune responses [
]. Given this breadth of activities,
the modulation of mTOR functions was recognised as
an attractive therapeutic target, notably in T cell driven
Gordon et al. [
] observed an increased survival rate in
mice infected with the murine parasite Plasmodium berghei
ANKA and treated with rapamycin. This was associated
with reduced breakdown of the BBB, less haemorrhaging in
the brain parenchyma and reduced accumulation of PRBC
and leukocytes (notably CD4+ and CD8+ T cells) within the
brain microvasculature. In agreement with these
observations, a genome-wide DNA analysis showed that the most
affected pathways, both in the brain and the spleen, were
associated with immune functions such as chemotaxis,
cellular invasion or lymphocyte proliferation. Somewhat
paradoxically, modulation of mTOR activity, via rapamycin
treatment, significantly increased the magnitude of the
proinflammatory response, both in the target organ and
peripherally, notably the spleen.
mTOR plays a pivotal role in determining the outcome
of parasite antigen recognition by CD8+ T cells, because it
functions as a principal sensor and integrator of the
nutrient and energy status. In the same murine model of ECM,
Mejia et al. [
] reported that dietary restriction during
infection was associated with reduced mTORC1
(mechanistic Target of Rapamycin Complex 1) activity in T cells
and resulted in protection against the onset of disease.
Rapamycin treatment also inhibited mTORC1 and
prevented ECM pathology. Together these studies support
the mTOR pathway as a potential target for adjunctive
therapeutic strategies in cerebral malaria treatment.
mTOR: A therapeutic target for cerebral
Disruption of the BBB combined with neuro-inflammation
is a hallmark of infection with human protozoan parasites
clinically presenting with cerebral pathology [
Therefore, we are suggesting that targeting the mTOR pathway
would represent a novel approach for the treatment of
cerebral parasitosis. In addition, rapamycin is approved for use
in humans (currently prescribed for some cancer patients
and organ transplant patients), making it an appealing
choice of therapeutic strategy [
]. Although not widely
investigated in the context of protozoan infection, we
propose that there are sufficient indications in the literature
to warrant an investigation into the potential use of
rapamycin as a treatment for cerebral parasitosis.
A primary candidate for consideration must be human
African trypanosomiasis (HAT), caused by the protozoa
Trypanosoma brucei gambiense and T. b. rhodesiense.
After infection through the bite of the tsetse fly,
parasites initially disseminate in the blood and lymphatic
systems. As infection progresses, parasites penetrate into
the central nervous system (CNS) initiating the
meningoencephalitic stage of infection, a critical step in the
progression of disease [
]. Invasion of the CNS by
trypanosomes is not related to the level of parasitemia but
is dependent on the host immune response and
facilitated by T cells. In particular, a Th1 immune response
increases trypanosome neuroinvasion; in the absence of
interferon IFN-γ and T cells, parasite entry into the
brain parenchyma is greatly reduced [
]. CD4+ T cells
have been proposed to be the principal source of IFN-γ
in T. brucei-infected mice, while CD8+ T cells have been
associated with mortality, with CD8−/− mice showing
prolonged survival following infection compared to wild
type mice [
]. Such a central role for T cells in the
mediation of trypanosome neuroinvasion would support a
possible therapeutic application for rapamycin. Of
interest, daily administration of minocycline, a tetracycline
antibiotic, to T. brucei infected mice reduced
trypanosome CNS invasion [
]. This antibiotic displays a direct
effect on T cells, preventing activation and
transmigration, an outcome that was proposed as the mechanism
impeding the movement of trypanosomes into the brain
parenchyma. The impact of minocycline treatment was
specific to the CNS, as the growth of T. brucei and the
levels of cytokines in the spleen were unaffected. This
study strongly supports the possibility that the use of
rapamycin to target T cell activation would prevent the
cerebral parasitosis associated with T. brucei infection.
Acanthamoeba are the causative agents of
granulomatous amoebic encephalitis, a fatal disease of the CNS that,
primarily presents in immune compromised patients [
The mechanisms by which Acanthamoeba breaches the
BBB are complex but appear to involve both parasite
proteases and host proinflammatory immune responses.
Combined, these mediate increased permeability and
apoptosis of brain endothelial cells, which disrupts the
BBB and permits CNS invasion by the parasite [
relevance to our hypothesis is the observation that
programmed cell death of brain endothelial cells mediated
by Acanthamoeba is dependent on the activation of
phosphatidylinositol 3-kinase (PI3K; [
]). Considering that
mTOR is activated by p-Akt downstream of PI3K, it is
likely that the administration of rapamycin would control
the protozoan induced apoptosis of endothelial cells and
thus block the movement of parasites into the brain.
Indeed, rapamycin has been shown to inhibit programmed
cell death induced by HIV infection, paclitaxel, UV
irradiation and TNF [
It is estimated that up to 50% of the world’s population
is infected with Toxoplasma gondii and that even though
many people harbour dormant brain cysts which contain
the slowly dividing bradyzoite stage of the parasite, most
immune competent people are asymptomatic [
However, when an individual’s immune system is compromised
the encysted bradyzoites covert to the tachyzoite stage,
which in the brain results in a recrudescence of acute
infection leading to toxoplasmic encephalitis (TE), a
debilitating manifestation of the infection that can lead to
severe and often life threatening meningitis [
important step leading to TE is during the acute stage of
infection, when the tachyzoite breaches the BBB, allowing
dissemination to the brain parenchyma. Unlike ECM or
HAT, there appears to be no role for T cells in the
movement of T. gondii into the CNS. Instead, the most recent
study suggests that this parasite compromises the blood
brain barrier by invading, replicating in and then lysing
brain endothelial cells. [
]. Importantly, activation of the
mTOR pathway within cells was shown to be critical to
support parasite expansion [
]. The correlation between
increased mTOR activity and increased
rapamycinsensitivity of cell cycle progression in T. gondii infected
cells therefore supports the application of rapamycin as a
therapeutic approach to prevent parasite replication
within brain endothelial cells and thus subsequent lysis
and movement of the parasite into the CNS.
Numerous other neuropathogenic protozoa interact
with the blood-brain barrier for the establishment of
CNS infections [
]. The elucidation of a role for mTOR
in the core processes of blood-brain barrier destruction
for these additional pathogens could establish rapamycin
as a novel therapeutic strategy to combat cerebral
pathology caused by these protozoa.
Targeting mTOR: A double pronged approach to regulate host and parasite metabolism
Given the critical role for mTOR signaling in cell
metabolism it is perhaps unsurprising that Tor signaling is
emerging as a functional pathway in the regulation of
protozoan growth and proliferation. This implies that in
addition to inhibiting the degradation of the BBB,
targeting the parasite’s TOR pathway might directly impact
the development of protozoan parasites and thus
attenuate the pathogenesis during infection.
Initial support for this notion came from the observation
that the liver-stage, asexual and sexual
intraerythrocyticstage of P. falciparum was inhibited by Torin2, the mTOR
ATP-competitive kinase inhibitor [
identification of putative Plasmodium binding partners suggested
that the inhibitory effect of Torin2 was not due to a
targeted effect on the TOR pathway [
]. Instead, Torin2
was shown to interact with a number of proteins involved
in the parasite’s metabolic pathways, including a putative
nutrient transporter, a phosphoribosyl pyrophosphatase
synthetase and an aspartate carbamoyltransferase [
More recently, mass spectrometry analysis of Torin-treated
parasites identified a rapid and selective reduction in
hemoglobin derived peptides, which indicated that Torin2
may be mediating its inhibitory effect by inhibiting essential
hemoglobin catabolism [
]. Moreover, to date, no mTOR
homologs have been identified in the genomes of
Plasmodium parasites, which further negates the possibility that
rapamycin could have a direct effect on the growth and
proliferation of the parasite. Indeed, rapamycin treatment
of mice infected with Plasmodium berghei resulted in
elevated peripheral parasitemia [
Although also classified as protozoan, the
trypanosomatids are phylogenetically quite distinct from the
apicomplexan plasmodium parasites [
]. Indeed, analysis of the
genomes of the trypanosomatid parasites Leishmania
major and T. brucei has revealed the presence of two
conserved signalling complexes, TOR1 and TOR2 [
whose functions appear analogous to that described for
mammalian TORs that mediate essential functions for cell
growth. Accordingly, either depletion T. brucei mTOR2 or
rapamycin exposure (which prevents tbTOR2 formation)
resulted in aberrant cell morphology, impaired
endocytosis, and blocked cytokinesis . Similarly, the inability to
general homozygous knockouts of L. major TOR1 or
TOR2 supports essential roles in the survival of the
]. In contrast, L. major parasites deficient in a third
TOR (TOR3) showed normal morphology. They were
however, unable to survive or replicate in macrophages in
vitro, or to induce pathology or establish infections in
mice in vivo, which suggests an important role in the
virulence of the parasite. Of interest, virulence of Leishmania
parasites has been associated with the presence of
sequence polymorphisms in other components of the
mTOR pathway, with a mutation in a GTPase enzyme,
shown to contribute to the attenuation of the cutaneous
strain of L. donovani in visceral infection [
Thus, targeting the TOR pathway presents an
opportunity for the design of anti-parasite agents for some
protozoan parasites. As our knowledge and
understanding of the genomes and proteomes of protozoans are
expanded, it will be important to determine the level of
requirement for TOR and other elements of the TOR
pathway on parasite growth, as this will determine the
potential effectiveness of rapamycin to inhibit both
parasite proliferation and host immune responses.
The observations described support the possibility that
strategically targeting mTOR could influence the
immune-mediated clinical cerebral outcomes of
hostprotozoan interactions and additionally act to limit
protozoan replication. However, this may not always be
the case. For example, after internalization, the human
Leishmania protozoan secretes a protease (GP63) which
cleaves mTOR, thus removing regulation of the
translational repressor 4E-BP1, resulting in the promotion of
parasite proliferation within cells. Consistent with these
observations, rapamycin induced the activation of
4EBP1, which increased the level of parasitic replication
]. Despite preventing ECM when administered day 1
or day 4/5 post-infection, treatment with rapamycin at
day 1 was associated with earlier death of the animals
from hyperparasitaemia caused by an indirect effect on
the mechanisms that control the parasite growth via the
adaptive immune response [
]. Thus the differential
host, protozoan-specific and disease phase-specific
functions of mTOR must be more fully understood to
optimize timing and parasite targets to determine
whether it is realistic to target for therapeutic
intervention. While clearly much more investigative work is
required, we believe that the known mechanisms by
which protozoan parasites traverse the blood brain
] provide sufficient support to our hypothesis
that targeting mTOR represents a novel strategy in the
treatment of cerebral parasitosis.
BBB: Blood brain barrier; CNS: Central nervous system; ECM: Experimental
cerebral malaria; HAT: Human African trypanosomiasis; IFN: Interferon;
mTOR: Mammalian target of rapamycin; mTORC1: Mechanistic Target of
Rapamycin Complex 1; PRBC: Parasitised red blood cells; TE: Toxoplasmic
The authors acknowledge general discussion and literature searches conducted
by members of the Parasites, Microbes and Host Immunity Team that helped
formulate this hypothesis, namely Raquel Alvarado and Anthony George.
This hypothesis paper was written with funding support from the School of
Life Sciences and Faculty of Science, University of Technology Sydney. The
authors acknowledge that there were many other important primary
literature sources that could not be cited that helped form this hypothesis.
Availability of data and materials
All authors were involved in the formulation of the hypothesis, drafting and
editing of the manuscript. SD, WH and VC critically revised the manuscript
and MJ designed the table. All authors read and approved the final
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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