DR AMIT PRASAD (Orcid ID : 0000-0002-4235-9201)

Accepted Article
Article type : Review

Recent Advancements and New Perspectives in Animal Models for

Neurocysticercosis Immunopathogenesis

N. ARORA1, S. TRIPATHI1,2, P. KUMAR1, P. MONDAL1, A. MISHRA3& A. PRASAD1*

1
School of Basic Sciences, Indian Institute of Technology Mandi, Mandi, Himachal Pradesh,

India 175005

2
Boston University School of Medicine, Department of Medicine, Boston, MA, United States

of America

3
Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur,

Rajasthan, India 342011

*To whom correspondence should be addressed: Amit Prasad; E-mail:

amitprasad@iitmandi.ac.in
This article has been accepted for publication and undergone full peer review but has
not been through the copyediting, typesetting, pagination and proofreading process,
which may lead to differences between this version and the Version of Record. Please
cite this article as doi: 10.1111/pim.12439

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 Disclosure: None
Accepted Article
SUMMARY

Neurocysticercosis (NCC), one of the most common parasitic diseases of the central nervous

system, is caused by Taenia solium. This parasite involves two hosts, intermediate hosts (pig

and human) and a definitive host (human), and has various stages in its complex life cycle

(eggs, oncosphere, cysticerci and adult tapeworm). Hence, developing an animal model for T.

solium that mimics its natural course of infection is quite challenging. We have reviewed here

the animal models frequently used to study immunopathogenesis of cysticercosis and also

discussed their usefulness for NCC studies. We found that researchers have used mice, rats,

guinea pigs, dogs, cats and pigs as models for this disease with varying degrees of success.

Mice and rats models have been utilized extensively for immunopathogenesis studies due to

their relative ease of handling and abundance of commercially available reagents to study

these small animal models. These models have provided some very exciting results for in

depth understanding of the disease. Of late, the experimentally/naturally infected swine model

is turning out to be the best animal model as the disease progression closely resembles human

infection in pigs. However, handling large experimental animals has its own challenges and

limitations.

Key words: Neurocysticercosis, Taenia solium, Tapeworm, Immunopathogenesis and Animal

model

INTRODUCTION

Cysticercosis, is a major public health problem especially in the developing world. It is

caused by larval infection of cestode tapeworm Taenia solium. Neurocysticercosis (NCC) is

caused when cysticerci cross blood brain barrier and infect central nervous system (CNS) (1,

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 2). NCC is considered to be one of the most common parasitic infections of the CNS and is
Accepted Article the single most common cause of active epilepsy in the developing countries (2, 3). It is also a

major cause of acquired epilepsy worldwide (1, 3, 4). Many international organizations like

World Health Organization (WHO), the Food and Agriculture Organization (FAO) and the

UK Department for International Development (DFID) have listed it among the 17 neglected

zoonotic diseases that can be effectively controlled (5). While developing and tropical

countries are the main endemic areas of this parasite, it is increasingly regarded as a public

health concern also in the United States, especially in the immigrant population and among

persons who have traveled to endemic cysticercosis regions (6). The life cycle of T. solium

involves two hosts, human and pig, and both can act as intermediate hosts and harbor the

larvae in different organs (cysticercosis). However, human is the only definitive host that

harbors adult tapeworm in the intestine (taeniasis). Both of them get cysticercosis through

ingestion of ova excreted in faeces by a human carrier (3). The larvae infect tissues and

cavities, especially those with pulsatile or contractile property like diaphragm, heart tissue,

skeletal muscles, peritoneum, pleura and subcutaneous tissues etc. (7). In humans, the parasite

has developed an affinity for brain, eyes and spinal cord (8). The larvae develop into adult

tapeworm in human intestine when humans consume cysticercus-infected un/half cooked

meat. Besides swine, mammals like dogs and cats have also been reported to harbor cysticerci

of T. solium (9, 10, 11). Since T. solium was reported in animals other then swine or human,

more choices for animal models are available and several had been tried.

Animal models are critical towards understanding the immunopathology of disease,

host-parasite interactions, other factors involved with the disease acquisition/progression, and

for development of novel therapeutic agents and intervention strategies. The need for a

reliable animal model closely mimicking human pathology is highly desirable for studying

any disease. There is an increased necessity of a suitable animal model for NCC, as CNS

infection by cysts causes epilepsy only in humans and therefore understanding the biology of

the parasite is difficult. So far, several mammals have been evaluated as experimental models

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 of adult T. solium infection or for cysticercosis, but developing a reliable NCC model is still a
Accepted Article challenge. Although, the pig model most closely resembles the human pathology, but keeping

and handling of such a large animal in the confinements of laboratory for long periods of time

has its own challenges and ethical issues. Hence, researchers across the globe have tried mice,

rats, rabbits, guinea pigs, young dogs, rhesus monkeys, gibbons, hamsters and cats as animal

models for cysticercosis for NCC. We have summarized in Table 1 the list of major taeniid

species and their intermediate host animals that have been used in animal model studies. In

this review we have discussed various animal models along with recent developments in this

field due to use of these models.

ANIMAL MODELS FOR TAENIASIS

Several animal models for taeniasis have been evaluated like rhesus monkey, white rat, white

mouse, cat, gerbil, guinea pig, gibbon etc (10-13). In the young dog cysticerci survived only

for 8 days after infection, whereas in macaques, cats and rabbits, in spite of being made

immunodepressed, they did not develop adult T. solium tapeworms (10). However, in

chinchilla and hamster, researchers could get viable eggs after proglottids infection and these

eggs were capable of developing to cysticerci in another host (12). Hence, only these two

animal models are considered for further discussion here.

Chinchilas (Chinchilla lanigera)

Chinchilla is the only host species that has shown promise as an experimental definitive host

for T. solium other than primates. Maravilla et al. (2011) have reported recovery of gravid

tapeworms proglottids containing viable and infective eggs from immunodepressed

chinchillas (12). Chinchillas were made immunodepressed with 6 or 8 mg of methyl-

prednisolone acetate on the day of infection and every 14 days thereafter. A total of 55 female

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 chinchillas were made immunodepressed and orally infected with four cysticerci each, and
Accepted Article 8% of these infected chinchillas showed parasite gravidity after seven weeks of infection.

Viability of the collected eggs as determined with different stains varied between 7-62%

based on different methods applied. It was highest with propidium iodide (62%), followed by

trypan blue (54%), neutral red (34%), oncosphere activation (30%) and 7% with bromide 3-

(4,5-dimetil-tiazol-2-il)-2,5-difenil-tetrazolio (MTT) reduction. These eggs were further used

to infect pigs and after three months the percentage of infection was similar to T. solium eggs

recovered from humans. In the same study they obtained gravid parasites in 8% of infected

animals, thus this is the only experimental model other than Gibbon in which gravid T. solium

parasite develops. These results strongly suggest chinchilla as an alternative model for

taeniasis and the eggs obtained from this model can be used for animal infection studies.

However, authors have not commented about role of this model in cysticercosis or its

usefulness for immuno-pathogenesis studies.

Hamster (Mesocricetus auratus)

Several researchers have long used golden hamster across the globe as an animal model of

various diseases including NCC. Initially, Pathak and Gaur (1985) described the use of

hamster for studying taenia infection study (14) and later Avila et al., (2003) used this model

to study kinetics of T. solium antibodies and antigens (15). They infected hamsters with eggs

and obtained gravid parasites in up to 41% of hamsters immunosuppressed with 6 or 8 mg of

methyl-prednisolone acetate on the day of infection and every 14 days thereafter. When

infected with eggs, they also reported that copro-antigen ELISA was positive up to 18 weeks

post infection in infected animals. Recently, Mendlovic et al., (2015) used this model to study

the cytokines and proliferative cellular response after recombinant T. solium calreticulin

(rTsCRT) infection in hamsters having T. solium taeniosis (16). They found dominant Th2

immune response with significantly high IL-10 and IL-4 cytokines. However, they also

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 studied immune response to rTsCRT in taeniosis only and not in NCC. Toral-Bastida E et al.,
Accepted Article (2011 ) developed a taeniosis model by infecting hamster with T. pisiformis, which uses

canines as a definitive host and rabbit as an intermediate host (17). The eggs obtained from

infected hamsters successfully developed cysticerci in rabbits, and thereby confirming the

pathogenicity of these eggs.

ANIMAL MODELS FOR NEUROCYSTICERCOSIS

Several animal models like mice, rats, pigs, gerbils, rabbits, cats, monkeys and dogs have

been tried for cysticercosis, but cysticercosis or brain involvement (NCC) was absent in most

of these animal models except for mouse/rat, pig and monkey.

Mouse and Rat

Rodents are the most commonly used animals in laboratories. Using a mouse based animal

model has its own advantages, like it is closely related to human, its whole genome sequence

is known, it has a short life span and there is abundance of reagents available for its study and

analysis. Since mice are not susceptible to T. solium infection naturally, T. saginata, T.

crassiceps or other cestodes are usually used to infect mouse as their metacestodes are

infectious to mouse/rat. Ito et al., (1997) first used T. asiatica (Asian Taenia) to infect NOD-

scid mice by oral route, as this immunodeficient mice strain was found to be highly

susceptible to T. saginata oncosphere (18). They found fully developed metacestodes either in

peritoneal cavity or back of the skin only in female mice after four months of infection. T.

crassiceps and T. solium, both have been used to infect mice but these models need to be

experimentally infected and are not using the natural oral route for infection. They are directly

injected in the peritoneal or intracranial cavity, which is not their natural route of infection.

Moura et al., (2015), used the same model to study the cellular immune response. They

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 noticed mixed Th1/Th17 responses at acute phase of infection and a predominantly Th2
Accepted Article response at late stage (19).

Mesocestoides corti is another commonly used parasite. The life cycle of this cestode

is very much similar to T. solium as it also has an intermediate host (mouse or lizard) and

upon ingestion by definitive host (dog, cat or skunk) it matures into intestinal worms.

However, it does not involve CNS infection, and hence this model also requires intracranial

injection to develop CNS infection. This model was first used by Cardona et al., (1999). This

parasite can be maintained easily in laboratory by serial intra-peritoneal inoculation of 8-12

week old female BALB/c mice with 50-75 metacestodes in 500 micro liter of buffered saline

(20). They injected approximately 40 parasites in each mouse and the mice started showing

symptoms from 3-4 days post infection. Prominent cells identified in the infiltrate were

neutrophils, macrophages, NK cells and T cells. Alvarez et al., (2008) used this model to

determine the role of glyco-conjugates (GCs) present in the parasite tegument (21). They used

fluorochrome-labeled hydrazides and lectins with specificity to different carbohydrates. GCs

bound by wheat germ agglutinin and concavalin-A were continuously released throughout the

infectious process. They proposed that rapid and persistent release of tegumental GCs play a

key role in the immunomodulation, immune evasion and life-long inflammatory squeals seen

in many NCC patients (21). Intracranial route of infection has also been tried extensively to

develop NCC in mice by M. corti infection (22). However, in this case the growing parasites

displaced most of the nervous tissue making this model unsuitable for further

histopathological studies in CNS infection.

Recently, Verastegui et al., (2015) did not find any significant difference in number

of cysts developed in the brain in young rats (10-26 days) injected with variable numbers of

activated T. solium oncospheres by extraparenchymal or intraparenchymal routes (23). The

majority of cysts (80%) were viable with vesicular appearance. The rate of infection went

from 83% in 10-day old rats, to 66% in 18-day olds and only 25% in 26-day olds.

Serologically, 74% (20/27) rats were ELISA positive and 67% (18/27) were enzyme electro

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 immune transfer blot/western blot (EITB) positive. This rat model appears to have several
Accepted Article advantages over the previously used models. Authors were able to obtain CSF that can be

used to identify biomarkers for various stages of infection. The rate of cyst formation among

injected animals was much higher (up to 80%) and most of the cysts were at viable stage

making anthelminthic drug efficacy studies feasible with this model. A cheap and accurate

animal model of NCC using T. solium as the primary infecting agent would provide an

effective means for studying this disease. However, the results/data obtained from this model

will have the same limitation as of data coming from other small animals, so may not be so

important for translational point of view.

Pig/Swine

Swine cysticercosis closely resembles human cysticercosis and pigs are natural intermediate

hosts of this parasite, thus making it a good animal model. Most of our understanding about

immunopathogenesis of cysticercosis is based on the mice or rat models, which cannot be

extrapolated to human beings. A series of studies with T. solium have established that the

course of infection and its histopathology and the response shown against anti-parasitic

treatment in swine is similar to the one in humans (24-28). However, a major drawback of

this model is that being a large animal the handling of pig is costly and requires a dedicated

facility with skilled manpower.

Both experimentally infected and naturally infected swine have been used for various

studies. Interestingly, despite the presence of thousands of cysticerci throughout the body of

pigs, taenia infection was believed to be benign for them (29). However, clinical signs like

excessive salivation, excessive blinking and tearing and subconjunctival nodules have been

reported in swine with NCC, suggesting that the infected animals might have some infection

related stress (30). In earlier studies from India, Kaur et al., (1995) and Grewal et al., (2000)

experimentally infected immunosuppressed young piglets with 20,000-5,00,000 eggs to

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 develop cysticercosis, but none of the pigs developed cysticerci in brain (31, 32). A study
Accepted Article from Mexico showed that only 35.7% of the piglets (two month old) that received 1,000 or

more eggs of T. solium orally developed metacestodes in the brain (33).

Recently, Fleury et al., (2105) published a surgical method to directly infect the pig

brain to develop an NCC model (24). In this method, eggs collected from human T. solium

carriers were hatched in vitro using 0.75% sodium hypochlorite in water. These activated

oncospheres (500-1000 eggs/pig) were surgically implanted in the cerebral subarachnoid

space of twenty-four two-month old piglets. These piglets were sacrificed after four months

of infection to assess the efficacy of procedure. They found infection efficiency of 3.6-5.4%

only and the number of cysticerci developed varied from 2-11/pig only. Surprisingly most of

these cysticerci were in caseous or calcified (60.3%) stage and were surrounded by an

exacerbated inflammatory response with lymphocyte infiltration. The authors opine that this

model will be useful for cysticidal or anti-inflammatory approach. However, development of

very few cysticerci and establishment of calcified stage of cyst primarily in this model may

limit its use in future studies looking for anthelminthic drug efficacy or immunopathogenesis

at different stages of cyst development. Probably, as suggested by authors, reducing the time

between infection, treatment and necropsy will allow getting cysticerci of different stages in

order to be able to evaluate treatment/drug efficacy (24).

Naturally infected pig as a study model is gradually becoming more popular (24, 25,

27-30, 34, 35), as this model is easily available across all endemic areas and the infected pigs

can be identified easily based on clinical signs (30) together with either tongue or neck

muscle examinations (26). We have extensively used this model to study immuno-pathology

of disease and the effect of cysticidal drugs as this model provides good number of cysts of

different stages (27, 28). The major problem with this model, apart from animal handling

issues, are lack of information about date of infection of animal, number, location and stage

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 of parasites. These questions complicate the demonstration of clear differences between
Accepted Article groups for intervention studies. We extensively used MRI in our animal studies to ascertain

number, stages and locations of parasites in each animal enrolled for the studies. Practice of

MRI gave this model great strength. We studied the immune response of viable and

degenerating cysts and found increased expression of IL-10 cytokines near viable cysts. We

also observed that the degenerating cysts had increased levels of IFN-, TNF-, IL-1, IL-2,

IL-6 and IL-8 whereas calcified cysts had elevated levels of IL-4, IL-10, TNF- and IL-6

(28). We further used naturally infected swine to study the effect and efficacy of anti-

cysticidal therapy (albendazole with and without steroid) and pigs were followed for 12

weeks (27). We found Th1-response associated with cyst in case of albendazole only

treatment and mixed Th1 and Th2 response when treated with albendazole and steroid.

Researchers from The Cysticercosis Working Group in Peru and National Institutes of Health,

USA (NIH) have also used this model to study the effect of Praziquantel treatment-induced

pericystic inflammation and its association with blood brain barrier (BBB) (34). They noticed

disruption of BBB and enhanced inflammation after 120 hours of drug treatment. They also

observed that increased pericystic inflammation (IL-6, TNF-, IFN- ) is co-related with

increased damage to the cysticerci cell wall and disruption of BBB. Interestingly, they also

noticed diminished expression of IL-10, a regulatory cytokine, in Evans blue stained cyst

capsule or cyst undergoing degeneration. These observations were similar to our earlier

observation about degenerating cyst in natural condition without any treatment (28), thus

confirming Th1 and Th2 immune responses operate in the vicinity of metacestodes. The type

of immune response generated may be responsible for disease severity and BBB damage,

BBB damage further aggravates the immune response or CNS tissue damage and it correlates

with inflammation as detected on MRI (36). These results also validate that the naturally

infected swine model can be used to study host inflammatory mechanisms and anthelminthic

agents/drugs/therapy with increased reliability. The Cysticercosis Working Group in Peru

also used the naturally infected pig model to study immune response of cysts from different

brain locations after anticystic drug (Praziquantel) treatment. They found that the

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 inflammatory response to cysticerci located in the meninges was significantly decreased
Accepted Article compared to cyst located in brain parenchyma (35). Although they also cautioned about the

interpretation of results coming from this model as the parasite burden in naturally infected

swine is much higher and the longevity of infection is shorter in pigs (34). The heavy burden

of parasite antigens may also have a dampening effect on inflammatory responses as observed

in other helminthic infections.

Rhesus Monkey (Macaca mulatta)

Recently one group has used Rhesus monkey (Macaca mulatta) to develop an animal model

for NCC, by simply feeding two monkeys in with 12,000 and 6,000 eggs (37). All the four

infected monkeys developed CNS infection. The heavily infected monkeys (n = 2) developed

clinical signs like hyperexcitability (10 days post infection, DPI), anorexia (45 DPI), epileptic

seizures (50 DPI) progressively and finally died on 67 and 132 DPI. The lightly infected

monkeys (n = 2) also developed all these symptoms but survived and were finally sacrificed

on 144 and 147 DPI. On histopathological examination, brain of monkeys fed with 12,000

eggs mostly contained necrotizing lesions, while monkeys fed with 6,000 eggs had typical

foreign body granulomas with central liquefaction, surrounded by a rim of chronic

inflammatory cells comprising macrophages, plasma cells, lymphocytes, and eosinophils,

besides large number of foreign body giant cells and fibroblasts. These changes in the rhesus

monkeys closely resemble human pathology. This model could be very useful to study

epilepsy due to vast similarities of monkeys with humans in their cognitive responses.

However, the use of non-human primates for research requires strict monitoring and huge

infrastructure.

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 DISCUSSION
Accepted Article
Animal models contribute immensely in understanding parasites life cycle, host-pathogen

interaction and immunopathology of the disease, which is very important to develop any

effective therapeutic strategies. The list of animal models used for studying taeniasis and

NCC with their main advantages and disadvantages are summarized in Table 2. For NCC

studies, the use of small or large animals has made immense contribution towards

understanding the basic biology of T. solium parasite. However, still a large number of

questions exist without any conclusive findings, like the role of host/parasite genetic factors

responsible for outcome of infection, effect of host nutrition on disease outcome, contribution

of parasite strains to pathogenesis, effect of location of parasite in brain on occurrence of

epilepsy, role of different immune cells in clearance of parasite, resistance of some cysts in

brain to anti-helminthic drugs, role of excretory secretory proteins of parasite in immune

evasion etc. Although, mouse/rat models have provided us significant insights about immuno-

pathogenesis via use of closely resembling helminthic parasites, the swine model resembles

human infection most closely. Identification of clinical signs for the naturally infected swine

and more availability of commercial reagents specific to pig will help swine procurement and

make its use as a model for immuno-pathogenesis studies less cumbersome. However, swine

model will always need more resources for study as compared to mice/rat model.

ACKNOWLEDGMENT

NA is supported by PhD studentship from the Indian Institute of Technology Mandi. AP and

ST acknowledge financial support from Ramalingaswami Fellowship Department of

Biotechnology, Government of India, New Delhi, India. Science and Engineering Research

Board (SERB), Department of Science and Technology, Government of India support AM

and AP grant numbers EMR/2016/000716 and ECR/2016/000817/LS respectively.

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Accepted Article

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 Table 1. Some major taeniid species and their intermediate host animals that
Accepted Article have been used in animal model studies with their references

Species Intermediate host described/used (references)

Taenia solium Dog [9], Pig [24-36], Hamster [14, 15, 16, 38], Chinchilla [12],

Rat [23], Monkey [37]

T. saginata asiatica Pig [39, 40], Mouse [18]

(T. asiatica)

T. saginata Reindeer [46]

T. multiceps Goat [49]

T. crassiceps Gerbil [42, 48], Hamster [42, 47], Mouse [19, 42, 44]

M. corti Mouse [20, 21, 22, 45]

T. pisiformis Hamster [17]

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 Table 2. Animal models for taeniasis and neurocysticercosis (NCC) and their
Accepted Article main advantages and disadvantages

Animal model Cestode used Advantage Disadvantage

(scientific name)

Chincilla (Chinchilla Taenia solium Easy in handling No CNS

lanigera) and maintenance involvement only
taeniasis

Hamster Mesocestoides corti, Easy in handling No CNS

(Mesocricetus T. pisiformis, T. and maintenance involvement only
auratus) solium taeniasis

Mice (Mus T. crassiceps , M. Can be injected Does not follow

musculus) corti directly in brain, natural route of
Easy in handling, infection, infectious
Plenty of cestode is other
commercial than T. solium,
reagents available parasite is
proliferative in
nature

Rat (Rattus rattus) T. crassiceps Can be injected Does not follow

directly in brain, natural route of
Easy in handling, infection, infectious
Plenty of cestode is other
commercial than T. solium
reagents available

Rhesus monkeys T. solium Easy to develop Non-human primate

(Macaca mulatta) infection, cognitive research is strictly
behavior and regulated, need
pathology huge infra structure
resembles to human

Pig (Sus T. solium, T. saginata Pathology Large animals

domesticus/Sus asiatica resembles to human handling need
scrofa) NCC, naturally trained man power,
infected can be resource
used, useful for consuming, scarcity
clinical studies of commercially
available regents

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