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Is There a Cholinergic Survival Incentive for Neurotropic Parasites in the Brain? Abdul Mannan Baig* The Aga Khan University, Karachi 74800, Pakistan ABSTRACT: The reason why some parasites specifically target the brain remains a mystery. Often, it is seen that the primary site of infection is quite remote from the brain, but an eventual involvement of the cerebral tissue is seen to occur that becomes the cause of death of the majority of the patients. In the absence of a clear preferential reason for targeting the brain, chemicals produced by the nervous system, which have miniature concentrations in the blood, appear to set up a chemical attraction that eventually causes them to migrate to the neural tissue. We studied the possible chemicals of neural origin that can lure the parasite toward the brain, enabling them to cause meningoencephalitis. The identification of these chemicals could be of enormous prophylactic significance as blocking the chemotaxis of neurotropic parasite by antagonist drugs and chemicals can prevent cerebral infection and provide ample time to eradicate the parasites at the primary site of infection. KEYWORDS: Acanthamoeba, cerebral parasitic infections, brain-eating amoeba, chemotaxis of parasites
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that is mostly derived from circulating blood cells and is known to be a chemoattractant for mast cells. The reality that a widespread action of even slightly elevated ACh can endanger the life more than any of the abovementioned neurotransmitters can be gauged by the fact that human plasma contains acetylcholinesterase (AChE) to inactivate any circulating ACh that escapes the vicinity of CNS synapses or from the PNS effector organs like glands and muscles. ACh can induce chemotaxis in a parasite that is capable of binding ACh, which then moves toward the increasing concentration of ACh in CNS neurons. Chemotaxis via muscarinic receptor binding ACh has has been postulated for Naegleria fowleri and Acanthamoeba spp. Infection by rat lungworm Angiostrongylus cantonensis has recently caught attention as a total of nine confirmed cases of Angiostrongylus cantonensis infected patients were reported in the state of Hawaii alone and 100 local infection cases were documented on the islands as well, which accounts for around 90% of the cases in the United States.2 Like the brain-eating amoebae mentioned above, it was interesting to note that a motility promoting effect by an excitatory cholinergic mechanism in this rat lungworm Angiostrongylus cantonensis was found to be mediated through nicotinic receptors (nAChR) that were basically similar to that reported in Ascaris suum.3 In the CNS infection caused by another neurotropic parasite Toxoplasma gondii, the finding of an increased activity of plasma levels of AChE has been studied in rats.4 This enhanced activity of AChE was considered to be a type of immune response mounted by the circulating blood cells against this neurotropic parasite. In this case it is easy to compute why there was a need to decrease ACh levels in the blood by elevating the levels of AChE during maximum parasitaemia. A reduction in plasma ACh levels by elevating the AChE as described above could be an attempt of the body
reatment of cerebral infections caused by parasites remains a daunting task, as the diagnosis is often delayed. It is somewhat easy to implicate a particular parasite as a cause of meningoencephalitis if an extracerebral site of infection precedes the neurological signs and symptoms of meningoencephalitis. In most of the cases, neurotropic parasites cause subtle or no symptoms at their portal of entry into the host and it is only the eventual sign and symptoms of meningoencephalitis that requires a hospitalization of the affected patient. The exact cause why some of the parasites exhibit selectivity for the brain is not known. As the blood-brain barrier (BBB) protects the central nervous system (CNS) from free passage of microbes, parasites, and toxic chemicals into the CNS, there has to be an explanation of selectivity of some parasites for the neurological tissue. The finding of the reason for this neuroselectivity can have a translational value, as it not only can help in preventing the potential cerebral involvement, but also the possibility of targeting the parasite. There are numbers of metazoan parasites (helminths and arthropods) that are known to target the CNS. A search was made at the Centers for Disease Control (CDC) and other databases for neurotropic parasites (Table 1) that illustrated the record of names like Toxoplasma gondii, Angiostrongylus cantonensis, Trypanosoma brucei, and free-living amoeba, for example, Acanthamoeba, Balamuthia mandrillaris, and Naegleria fowleri. Human CNS and peripheral nervous system (PNS) neurons produce many chemicals that are known to function as a neurotransmitters. Though secreted in both CNS and periphery, these chemicals are normally either inactivated in the synaptic cleft or drained into the venous circulation to be degraded by organs like the liver, which is known for metabolizing chemicals like hormones and cytokines. Example of chemicals that get access into the circulation and where minute traces of them have been found in circulation include acetylcholine1 (ACh). Other neurotransmitters that are present in blood are adrenaline, noradrenaline, and dopamine, but they are mostly adrenal rather than cerebral in origin. Serotonin (5HT) is another candidate neurotransmitter © XXXX American Chemical Society
Received: September 25, 2017 Accepted: September 26, 2017
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DOI: 10.1021/acschemneuro.7b00370 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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oral cavity, GIT uncooked/undercooked meat, Toxoplasma bradyzoites; milk, Toxoplasma tachyzoites Tsetse fly of genus Glossina day-time biting
Toxoplasma gondii
brain, intestines, liver, lungs, eye brain, liver, eye
brain
brain, blood
eyes, brain, heart, liver
consumption of mollusks harboring infective third-stage larvae prawns, frogs, and lizards, as well brain, intestine as contaminated vegetables, could besources of infection
pica, unwashed food, contamined Toxocara eggs, undercooked livers of chicken
stool from raccoons
soil-contaminated wounds
nasopharynx or by hematogenous spread to the brain
Sappinia pedata
Trypanosoma brucei Halicephalobus gingivalis baylisascaris procyonis Toxocara canis, Toxocara cati Angiostrongylus cantonensis
upper nasal cavity nasopharynx, brain
brain, meninges
skin wound, nose, nasal sinus
Balamuthia mandrillaris Naegleria fowleri
organs and tissues involved brain, eye, skin, organs in transplant recipients brain, paranasal sinus, skin
portal of entry: source and transmission skin wound, eye, nose
Acanthamoeba spp.
nomenclature in latin
*Free-living amoeba; +non-amoeba parasites of diverse origin. Note that Angiostrongylus cantonensis and Sappinia pedata are added to the list.
angiostrongyliasis
+
toxocariasis
+
baylisascariasis
+
halicephalobiasis
+
sleeping sickness
+
*granulomatous amoebic encephalitis (GAE) *Balamuthia amoebic encephalitis (BAE) *primary amoebic meningoencephalitis (PAM) *nonlethal case of amoebic encephalitis + toxoplasmosis
diseases caused:
Table 1. List of Neurotropic Parasite. Common Names, Portal of Entry, Prevalence, and Tissues Involveda prevalence
Southeast Asia; new cases are now reported in the United States
worldwide
North America
worldwide, one of the most common human parasites 50 000−70 000 people; exclusively found in Africa
single human case
worldwide
worldwide
worldwide
ACS Chemical Neuroscience Viewpoint
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DOI: 10.1021/acschemneuro.7b00370 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
Figure 1. Results (24 h) of the proliferation of 1 × 106 Acanthamoeba trophozoites in growth medium PYG alone (A) and with 10 mM ACh (A1). Effects of 50 μg/mL pirenzipine (B) and 30 μg/mL dicyclomine (B1) on 1 × 106 Acanthamoeba trophozoites in growth medium PYG for 24 h. Note the proliferative influences of ACh (A1) and the amoebicidal effects of both pirenzipine and dicyclomine (mAChR antagonists) on Acanthamoeba spp. Dead cells were confirmed by Trypan blue staining (data not shown), confirming the cytotoxic effects of these drugs.
to other parasites (Table 1) which can facilitate the understanding of the role of ACh in these parasites that choose the CNS as a target.
immune system to inhibit parasite proliferation or the cerebral migration of Toxoplasma gondii. We further investigated this neuroselectivity by expanding the range to include other neurotropic parasites like Trypanosoma brucei that causes African sleeping sickness by targeting the brain. Similar to the finding noted above with Toxoplasma gondii, it has been found that AChE levels in infected brains of rabbits with Trypanosoma brucei were directly or indirectly related to cerebral symptoms in animals and possibly humans.5 It is noteworthy that associations of of ACh with motility of the neurotropic parasites via nAChR/mAChR, the attempts of the body to reduce serum and tissue levels of ACh during parasitaemia and the brain infections, cannot be just a coincidence of the relationship between ACh and CNS selectivity of neurotropic parasites. Additionally, the fact a sustained ACh induced cholinergic receptor stimulations by the use of organophosporus compounds that can cause the excitotoxicity, has been in use for decades now as an antiparasitic and insecticidal agent, reinforces the significance of ACh in the biology of parasites in general and neurotropic protozoa in particular. There is a need to further study the significance of ACh in the biology of these neurotropic parasites as it appears that the role of ACh is more complex and extends beyond the chemotaxis and motility it induces in neurotropic parasites.3 The quest to find answers to these questions has led to the recent discovery of a cell membrane expression of human-like mAChR6 the presence of a complete cascade of a cholinergic enzymatic system, the migration in response to ACh, and the presence of this chemical in a neurotropic free-living amoeba Acanthamoeba spp. (unpublished data). A similar approach could be extended
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CHALLENGING QUERIES AND FUTURE DIRECTIONS The chemotaxis of any cell has an ultimate rationale, as, for example, seen in the case of the white blood cells; they move to the epicenter of the chemotaxis inducing chemicals like leukotrienes and bacterial lipopolysaccharides and kill the target invader that in most cases are the bacteria. What is then the ultimate rationale of chemotaxis of a neurotropic parasite? Convincingly enough, here again the rationale could be the movement along a chemical gradient, followed by killing of the neurons in the CNS to use them as a food resource. For braineating amoeba, in depth studies have revealed that although they do the same as described above, but their intention appears to gain an additional proliferative drive by approaching the ACh secreting neurons in the CNS. The ACh induces a clear proliferative influence on amoeba by promoting their growth and cell division. The latter effect has been observed in Acanthamoeba (Figure 1A1), Balamuthia mandrillaris, and Naegleria fowleri in many studies that we have done in the past.6 Supporting evidence has come from the finding that mAChR antagonism terminates the proliferative effects resulting in an amoebicidal activity (Figure 1B, B1). Similarly, it is easy to comprehend that nAChR receptor antagonism could block the excitatory cholinergic mechanism in Angiostrongylus cantonensis that is known to involve the nicotinic receptors for its motility3 and therefore possibly the invasion of C
DOI: 10.1021/acschemneuro.7b00370 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
Viewpoint
ACS Chemical Neuroscience the CNS. The identification of the single most important kingpin chemical involved the pathogenesis of a cerebral parasitic infestation sounds optimistic, but there are instances where few chemicals with multifunctional potential can explain the complex events commencing from the portal of entry of the parasite up to its tissue tropism in the host. Future studies are needed in which experimental animal models infected with neurotropic parasites that are pretreated with anticholinergic are observed for parasite motility, level of parasitaemia, and their movement across the BBB to access the role of ACh and other neurochemicals in the pathogenesis of neurotropic meningoencephalitis.
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AUTHOR INFORMATION
Corresponding Author
*Mailing address: The Department of BBS, Aga Khan University, Medical College, Karachi 74800, Pakistan. E-mail:
[email protected]. ORCID
Abdul Mannan Baig: 0000-0003-0626-216X Notes
The author declares no competing financial interest.
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REFERENCES
(1) Watanabe, M., Kimura, A., Akasaka, K., and Hayashi, S. (1986) Determination of acetylcholine in human blood. Biochem. Med. Metab. Biol. 36 (3), 355−62. (2) Lv, S., Zhou, X. N., and Andrews, J. R. (2017) Eosinophilic Meningitis Caused by Angiostrongylus cantonensis. ACS Chem. Neurosci. 8 (9), 1815−1816. (3) Mentz, M. B., and Graeff-Teixeira, C. (2003) (2003). Drug trials for treatment of human angiostrongyliasis. Rev. Inst. Med. Trop. Sao Paulo 45 (4), 179−84. (4) Tonin, A. A., da Silva, A. S., Thorstenberg, M. L., et al. (2013) Influence of Toxoplasma gondii Acute Infection on Cholinesterase Activities of Wistar Rats. Korean Journal of Parasitology 51 (4), 421− 426. (5) Amole, B. O., Thomas, K. D., Jones, B. R., and Nelson, C. A. (1994) Acetylcholinesterase Levels in Brains of Rabbits Infected with Trypanosoma brucei: A Preliminary Study. In Mycotoxins, Wood Decay, Plant Stress, Biocorrosion, and General Biodeterioration. Biodeterioration Research (Llewellyn, G. C., Dashek, W. V., and O’Rear, C. E., Eds.), Vol 4, Springer, Boston, MA. (6) Baig, A. M., and Ahmad, H. R. (2017) Evidence of a M1Muscarinic GPCR homolog in a unicellular eukaryotes: featuring Acanthamoeba spp bioinformatics 3D-modelling and experimentations. J. Recept. Signal Transduction Res. 37, 267−75.
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DOI: 10.1021/acschemneuro.7b00370 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
