Infection, Genetics and Evolution xxx (2015) xxxxxx

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Infection, Genetics and Evolution

journal homepage: www.elsevier.com/locate/meegid

Review

Recent advances and perspectives in molecular epidemiology of Taenia

solium cysticercosis
Akira Ito a,, Tetsuya Yanagida a,b, Minoru Nakao a
a
b

Department of Parasitology, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa 078-8510, Japan
Laboratory of Parasitology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan

a r t i c l e

i n f o

Article history:
Received 2 May 2015
Received in revised form 19 June 2015
Accepted 20 June 2015
Available online xxxx
Keywords:
Taenia solium
Asian vs Afro/American genotypes
Mitochondrial DNA
Nuclear DNA
Hermaphrodite
Outcrossing
Selng
Neglected tropical disease
Neglected zoonotic disease
Madagascar

a b s t r a c t
Cysticercosis caused by accidental ingestion of eggs of Taenia solium is spreading all over the world
through globalization and is one of the most neglected, neglected tropical diseases (NTDs) or neglected
zoonotic diseases (NZDs). In the present study, the reason why T. solium cysticercosis has been neglected
is discussed at rst, and followed with an overview on the most recent advances and perspectives in
molecular approaches for epidemiology of T. solium taeniasis/cysticercosis, since although taeniasis does
not constitute recognized zoonoses, transmission and complete development are dependent on human
denitive hosts. Main topics are discussions on (1) the two, Asian and Afro/American, genotypes of T.
solium, (2) comparative analysis of mitochondrial (haploid) and nuclear (diploid) genes, and (3) the
presence of hybrids of these two genotypes which indicates out-crossing of two genotypes in hermaphrodite tapeworms in Madagascar. Additional topics are on (4) the usefulness of phylogeographic analyses
to discuss where the infection was acquired from, and (5) miscellaneous unsolved topics around these
genetic diversity of T. solium.
2015 Elsevier B.V. All rights reserved.

Contents
1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.
Why is Taenia solium infection neglected? The present situation of cysticercosis in the world . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.
Why is T. solium infection neglected? The present situation in Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3.
Chaotic situation of cryptic NCC. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.4.
Burst from local into global NTD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.
Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Origin of T. solium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Outcrossing of closely related two species, T. saginata and T. asiatica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.
Comparative studies of mitochondrial DNA (haploid) and nuclear DNA (diploid) of T. solium in Madagascar . . . . . . . . . . . . . . . . . . . . . . .
2.4.
Perspectives from mitochondrial DNA and nuclear DNA analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Corresponding author.
E-mail addresses: akiraito@asahikawa-med.ac.jp (A. Ito), yanagi-t@yamaguchi-u.
ac.jp (T. Yanagida), nakao@asahikawa-med.ac.jp (M. Nakao).
http://dx.doi.org/10.1016/j.meegid.2015.06.022
1567-1348/ 2015 Elsevier B.V. All rights reserved.

Please cite this article in press as: Ito, A., et al. Recent advances and perspectives in molecular epidemiology of Taenia solium cysticercosis. Infect. Genet.
Evol. (2015), http://dx.doi.org/10.1016/j.meegid.2015.06.022

A. Ito et al. / Infection, Genetics and Evolution xxx (2015) xxxxxx

1. Introduction
1.1. Why is Taenia solium infection neglected? The present situation of
cysticercosis in the world
Cysticercosis (CC) including the most potentially lethal neurocysticercosis (NCC), ocular cysticercosis (OCC), subcutaneous cysticercosis (SCC) etc. is caused by the presence of larval stage,
cysticercus or cysticerci of the pork tapeworm, Taenia solium after
accidental ingestion of eggs released from adult tapeworm carriers
or autoinfection with eggs in the tapeworm carriers themselves
(Figs. 1 and 2). Disseminated cysticercosis cases are caused mainly
in tapeworm carriers themselves by autoinfection even if detection
of tapeworm(s) is not always easy (Schantz et al., 1983, 1998;
Margono et al., 2002; Kobayashi et al., 2013; Ito et al., 2014). The
only denitive host of T. solium is human, Homo sapiens (de
Queiroz and Alkire, 1998; Hoberg et al., 1999, 2001; Hoberg,
2002, 2006; Michelet and Dauga, 2012; Zarlenga et al., 2014a,b).
Adult tapeworm matures in the human intestine after eating
uncooked pork contaminated with cysticercus or cysticerci. The life
span of T. solium tapeworm is difcult to observe, but is probably
within a few years (Yoshino, 1934; Lightowlers, 2013) and critically differs from that of Taenia saginata for over 30 years
(Pawlowski and Schultz, 1972; Pawlowski, 1982). The size and
thickness of the gravid proglottid as well as the whole worm critically differ between T. saginata or Taenia asiatica and T. solium. T.
solium is much smaller and thinner than T. saginata or T. asiatica
(Fig. 3).
Although the eggs are infective not only to swine and humans
but also dogs, and the range of potential intermediate hosts is
broader than swine and dogs (Hoberg et al., 2001; Ito et al.,
2002a), the life cycle of this parasite is usually completed between
humans (tapeworm carriers, denitive host) and pigs (intermediate host). Therefore, T. solium is now considered to be the most
important foodborne parasite globally (Robertson et al., 2013,
2014) and so, rationally eradicable disease (Schantz et al., 1983;

Pawlowski et al., 2005; Flisser et al., 2006; Pawlowski, 2006,

2008; Schantz, 2006; Garca et al., 2007; WHO, 2010) but difcult
due to poverty, lack of education, traditional culture, etc.
In cysticercosis endemic areas in Asia or perhaps in Africa and
Americas, pigs and dogs are living together and free roaming.
Although our caution towards the control of cysticercosis has been
focused on humans and pigs, dogs should be included as risk factor
for both humans and pigs which may cause additional life cycle
between dogs and humans, and confusion in pigs contaminated
not with T. solium but with Taenia hydatigena (Ito and Budke,
2014; Ito et al., 2014; Ito, 2015; Wandra et al., 2015).
Dogs are the denitive host of T. hydatigena and several other
Taenia species (Table 1) (Nakao et al., 2013). Among these Taenia
species, T. hydatigena is the commonest species in livestock.
Therefore, pigs are commonly infected with cysticercus/cysticerci
of T. hydatigena. It might be more common than cysticercus/
cysticerci of T. solium in free roaming pigs where dogs and pigs
are living together (Ito et al., 2014; Wandra et al., 2015). This has
often been ignored, but many epidemiological survey of pigs where
dogs are living together should remind this fact in order to obtain
sound direct evidence of infection. Recent waves to use
antigen-ELISA without necropsy of pigs are difcult to evaluate if
antigen-ELISA positive pigs really include pigs infected with
T. solium, since pigs infected with T. hydatigena become strongly
positive (Fleury et al., 2003; Dorny et al., 2004). Without necropsy
of pigs to conrm infection with T. solium, it is not clear whether
the antigen-ELISA positive results are from contamination with
T. hydatigena, since the monoclonal antibody was prepared against
metacestodes of T. saginata and is highly possibly cross-reactive to
other Taenia species (Brandt et al., 1992; Fleury et al., 2003;
Dorny et al., 2004; Ito, 2013, 2015; Ito et al., 2014). Furthermore,
local people in many Asian countries love to eat dog meat
(Hoberg et al., 2001; Ito et al., 2002a, 2005, 2014; Ito and Budke,
2014). Therefore, there may be additional alternative but
minor transmission of T. solium between dogs and humans (Ito
et al., 2002a).

Fig. 1. Life cycles of human Taenia species (modied from CDC, and Ito and Budke, 2014; Ito et al., 2014).

Please cite this article in press as: Ito, A., et al. Recent advances and perspectives in molecular epidemiology of Taenia solium cysticercosis. Infect. Genet.
Evol. (2015), http://dx.doi.org/10.1016/j.meegid.2015.06.022

A. Ito et al. / Infection, Genetics and Evolution xxx (2015) xxxxxx

Fig. 2. Historical and present situation of taeniasis and/or cysticercosis due to T. solium in the world. Human population eating pork (orange circle) vs not eating pork (blue
circle) is roughly estimated as 4 vs 1, although the population is becoming bigger in 21st century than 20th century. Red circle is population at risk in rural and remote areas
in developing countries where pork is eaten and new endemicity in societies where pork is not consumed but contaminated by globalization (modied from Ito et al., 2014).
Cysticercosis without taeniasis is increasing in societies where pork is not eaten. In contrast, population in societies where pork is eaten is divided into two groups. One is
taeniasis after eating contaminated pork. This group is at high risk of disseminated cysticercosis due to autoinfection (Margono et al., 2002; Kobayashi et al., 2013). The other
is cysticercosis accidentally caused by contamination with eggs released from tapeworm carriers everywhere either pork is eaten or not (Schantz et al., 1992; Ikejima et al.,
2005). (For interpretation of the references to colour in this gure legend, the reader is referred to the web version of this article.)

Fig. 3. Morphology of gravid proglottids of T. solium (a) and T. saginata (b). The size (approximately 1 cm long) is smaller than half of T. saginata and much thinner.

Table 1
Major zoonotic Taenia species based on literatures (Pawlowski and Schultz, 1972;
Euzeby, 1974; Kamegai and Ishikara, 1983; Hailemaniam et al., 2014; Ito and Budke,
2014).

a
b
c
d
e

Species

Intermediate host

Denitive host

Taenia
Taenia
Taenia
Taenia
Taenia
Taenia
Taenia
Taenia
Taenia
Taenia

Pigs, dogs, humans

Cattle, (humansa)
Pigs, cattle, (humansb)
Rodents, humansc
Sheep, humansc
Pigs, sheep, goats, humansc
Rabbits, humansc
Rodents, humansc
Sheep, rabbits, humansc
Rabbits, rodents, humansc

Humans
Humans
Humans
Dogs, foxes
Dogs
Dogs
Dogs, foxes
Cats
Dogs, cats, wolves
Dogs, wolves, foxes

solium
saginata
asiatica
crassiceps
ovis
hydatigena
pisiformis
taeniaeformisd
coenuruse
serialis

Human infections are doubtful.

No report.
Human infections are very rare.
This species is now treated as Hydatigera taeniaeformis (Nakao et al., 2013).
This species is a synonym of Taenia multiceps (Loos-Frank, 2000).

Pigs are scavengers and get infection with eggs of T. solium from
human feces and those of T. hydatigena from dog feces, whereas
dogs are scavengers and get infection with eggs of T. solium from
human feces (Ito et al., 2002a). So far we know, there is no report
stressing the importance of dogs in cysticercosis endemic areas
which interferes the sound prevalence of T. solium in pigs. The
importance of dogs which contributes the endemicity of taeniasis/
cysticercosis is, therefore, stressed in order to grasp the risk factors
in humans and pigs (Ito et al., 2014).
The risk factors in pigs crucially differ in pigs reared under different conditions. (1) Pigs reared in indoor in endemic areas or in
door farming in developed countries are basically free of cysticercosis except the environment is accidentally contaminated with
eggs of T. solium. Laborers harboring T. solium tapeworm(s) from
endemic areas or countries are high risk of accidental contamination of pigs (Yanagida et al., 2012). Monitoring of antibody
responses or circulating antigens is highly useful, since T. solium
is only species which contaminates pigs. In contrast, (2) pigs have
high risk of infection with eggs of T. solium and T. hydatigena from
human and dog feces, respectively, where pigs are reared out door

Please cite this article in press as: Ito, A., et al. Recent advances and perspectives in molecular epidemiology of Taenia solium cysticercosis. Infect. Genet.
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A. Ito et al. / Infection, Genetics and Evolution xxx (2015) xxxxxx

with dogs. In this situation, more specic serology should be

introduced to differentiate pig contaminated with T. solium from
T. hydatigena. The latter is very common in endemic, remote areas
in developing countries all over the world (Ito et al., 2014).
In this review article, main topics are molecular approaches for
detection and identication of the pathogens in human, pigs and
dogs for epidemiological studies.
1.2. Why is T. solium infection neglected? The present situation in Asia
T. solium was considered to be distributed mostly in rural and
remote areas coincidental with regions where people under economic poverty consumed pork without meat inspections (Fig. 2)
(Robertson et al., 2013, 2014; Ito and Budke, 2014; Ito et al.,
2014). However, T. solium tapeworms have rarely been conrmed
even through microscopic examination of feces for the soil transmitted helminthiases (STHs) (Carney et al., 1980; Saksirisampant
et al., 2002; Belizario et al., 2004; Kepha et al., 2015; Greenland
et al., 2015; Ngui et al., 2015). In most of STH surveys, there is
no record of Taenia eggs. It is mainly because Taenia eggs are not
constantly distributed in stool samples, but they are abundant only
when gravid proglottids(s) were discharged in tapeworm carriers
intestine. The mechanism of discharging of gravid proglottid(s)
remains unsolved, although apoptosis may be involved in. Most
recent study of STHs with molecular tools is interesting (Gordon
et al., 2015). Although three human Taenia species have been
reported in the Philippines (de Leon, 2005; Yamane et al., 2013),
Gordon et al. (2015) detected T. saginata only. It might include both
T. saginata and T. asiatica or all might be T. asiatica. Distribution of
human Taenia in the Philippines may be highly variable among the
islands, since people living on each island have their unique culture
and different religion, etc. Further studies are necessary to get better understanding of the transmission of human Taenia in this
country.
In the mass drug administration (MDA), the priority of mass
treatment for deworming is directed against STHs, food-borne
trematodiases (FBT) and schistosomiasis. Besides, it is impossible
to morphologically identify the species for Taenia eggs under
microscope. Therefore, almost all eld works on helminthiases by
microscopy tend to describe just Taenia eggs without any identication of the species. Molecular identication is essential for Taenia
egg(s) (Nkouawa et al., 2009, 2010) but is thus far mostly impossible in rural or remote areas where epidemiology of STH, FBT and
schistosomiasis is carried out (Nkouawa et al., 2012).
Furthermore, deworming of Taenia spp. in MDA has some
problems. If praziquantel (PZQ) > 10 mg/kg B.W. is administered
to tapeworm carriers and if the species is T. solium, PZQ may cause
sudden seizure attack, acute symptomatic neurocysticercosis
(NCC) within a half day, since higher dose of PZQ has metacestocidal effect and the damage of living cysticerci may result in acute
allergic responses (Flisser et al., 1993; Sarti et al., 1994, 2000;
Willingham et al., 2008; Ito et al., 2013). Therefore, treatment with
corticosteroid is essential to avoid accidental seizure attacks after
high dose of PZQ treatment (Garca et al., 2004, 2014, 2015;
Willingham et al., 2008; Del Brutto and Garca, 2013; Del Brutto,
2013, 2014a,b; Nash et al., 2015). However, such complicated
treatment is not suitable for MDA (Ito et al., 2013). Alternatively,
PZQ < 10 mg/kg has been recommended for tapeworm carriers in
T. solium endemic areas which usually does not damage larval
stage of T. solium.
However, it is difcult or impossible to obtain such information
where T. solium is endemic until unexpected NCC cases are
reported. In contrast, among the three human Taenia species,
T. saginata, the beef tapeworm, is more common and much easier
to be detected by tapeworm carriers themselves, since a single
gravid proglottid separated from whole worm actively escapes

from anus to the outside any time of almost every day. In one volunteers case, he experienced more than 30 proglottids coming out
from his anus within one day (Itos own observation).
T. saginata is well known to be common in local people in Bali,
Indonesia (Suweta, 1991; Depary and Kosman, 1991; Theis et al.,
1994; Simanjuntak et al., 1997; Margono et al., 2002, 2005;
Wandra et al., 2006, 2015). Throughout our eld work in Bali from
2002 until 2010, all tapeworms discharged from more than 100
tapeworm carriers were denitively identied as T. saginata
(Wandra et al., 2015). Wandra and his colleagues treated
T. saginata taeniasis patients using PZQ, 15 mg/kg B.W., with no
expectation of asymptomatic NCC. However, after discharge of
T. saginata by PZQ treatment, unexpected sudden seizure attacks
were observed in several tapeworm carriers. From such work,
double infections with T. saginata adult tapeworm(s) in the intestine and T. solium cysticerci in the brain have been conrmed
(Sudewi et al., 2008; Wandra et al., 2013, 2015). Such situations
may be common in almost all countries in Southeast Asia, and if
low dose of PZQ would be administered for such tapeworm
carriers, one could overlook the veiled asymptomatic NCC cases
(Flisser et al., 1993; Sarti et al., 1994, 2000).
In many areas where taeniasis has been reported, we are therefore facing a problem how to identify the species and how to treat
taeniasis patients. In remote areas, low dose of PZQ is recommended for treatment of tapeworm carriers with no expected accidental epileptic attacks (Flisser et al., 1993; Sarti et al., 1994, 2000;
Wandra et al., 2013). However, it is impossible to obtain any information on the endemicity of hidden NCC without any accidental
seizure attacks. In rural areas on Bali where access to the capital
city is not difcult through semi-urbanization other than the endemic rural areas, high dose of PZQ may be recommended, because
the on time treatment of seizure attacked patients is possible. Or
alternatively, we recommend introduction of serology for cysticercosis in screening of taeniasis carriers and STHs in order to detect
asymptomatic NCC based on the recognition that cryptic infections
are endemic and potentially most lethal parasitic disease on Bali
(Margono et al., 2002; Sudewi et al., 2008; Wandra et al., 2015).
When some people are conrmed antibody positive to diagnostic
antigens for cysticercosis (Ito et al., 1998, 2014; Sako et al., 2013;
Ito and Budke, 2014), they are recommended to admit big city hospital(s) for further treatment. However, there is a nancial problem
how to cover the admission fees!
In conclusion, there is almost no data showing the real distribution of T. solium and epidemics of NCC without any accidental
detection of symptomatic NCC cases in the world including developed countries (Margono et al., 2000, 2005; Yamasaki et al., 2005;
Yanagida et al., 2012; Kobayashi et al., 2013).
1.3. Chaotic situation of cryptic NCC
Even if there are no such NCC cases and taeniasis cases are due
to T. saginata or T. asiatica, we have to note that asymptomatic NCC
could remain endemic, cryptic and neglected. This is the real present situation of cysticercosis in humans in Asia at least (Ito
et al., 2014; Wandra et al., 2015) and may be the same in other
areas. Endemicity of NCC or distribution of T. solium is exclusively
and accidentally recognized by detection of cysticercosis, mainly
symptomatic NCC cases. Furthermore, through globalization and
advances in diagnostics, symptomatic cysticercosis in humans
may become more common not only in developing countries
where people eat pork but also in developed countries where people do or do not eat pork (Fig. 2) (Schantz et al., 1998; Al Shahrani
et al., 2003; Hira et al., 2004; Sorvillo et al., 2007, 2011; Leshem
et al., 2011; ONeal et al., 2012; Fabiani and Bruschi, 2013;
Robertson et al., 2014; Ito and Budke, 2014; Ito et al., 2014; Ito,
2015; Wandra et al., 2015; OKeefe et al., 2015). People in capital

Please cite this article in press as: Ito, A., et al. Recent advances and perspectives in molecular epidemiology of Taenia solium cysticercosis. Infect. Genet.
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A. Ito et al. / Infection, Genetics and Evolution xxx (2015) xxxxxx

Fig. 4. A single immature cysticercus of T. solium shown by arrow was conrmed through careful meat inspection of a whole body of a one-year-old pig (a). A total of 30
immature cysticerci were counted from (a). Another pig (b) was full of fully developed cysticerci. These pigs were sero-positive to diagnostic antigens puried by cationexchange chromatography established by Sako et al. (2013). It is very easy for people in endemic areas to recognize (b), but how to conrm such a small number of immature
cysticerci (a) which may easily be evaluated to be free of cysticerci by a routine meat inspection (modied from Wandra et al., 2015).

cities in high-income countries are not free of risk of NCC any more
(Fig. 2) (Schantz et al., 1992; Hira et al., 2004; Leshem et al., 2011;
Khan et al., 2011; Yanagida et al., 2012; Del Brutto, 2013). An
increasing risk factor for transmission and infection relates to globalization of an immigrant work-force originating in countries
where T. solium is endemic.

1.4. Burst from local into global NTD

It is well known that cysticercosis is focal and local disease
where people kill pigs in the backyard of owners home, and pork
with or without contamination of cysticerci is only meat for the
family members, relatives and neighbours for special ceremonies.
Under very poor conditions, they cannot stop eating pork, since it
is only special meat available for the family members with no
money to buy pork (Ikejima et al., 2005; Li et al., 2006). Pigs, either
contaminated with T. solium or not, reared by the poor families are
the only meat source for the family members.
Much wider situation of populations at risk is by consuming
pork through rough meat inspection in endemic areas where economy of the populations is a little bit or much better than the poorest populations. If owners were heavily penalized when their pigs
were identied to be contaminated with T. solium, they used to sell
their pigs under dark or bush without meat inspection, and recommend preparation of delicious sausage, etc. Or they asked the
ofcials not to declare contaminated pigs under the table.
Corruption is another human attitude, and may be common not
only in Asia but also in other areas. More important is that it is difcult to check whole meat at all (Suweta, 1991) (Fig. 4). Pork with a
very small number of cysticerci of T. solium may easily be judged
safe without additional serological tests.
Travelers who are interested in visiting remote areas, and people visiting family members and relatives in the remote areas in
their home countries in Latin America and Southeast Asia, etc.
may get infection with tapeworms of T. solium as well after eating
local dish (Yanagida et al., 2010; Jongwutises et al., 2011). These
are populations with risk of taeniasis. Then, such taeniasis carriers
themselves become autoinfected with eggs (Schantz et al., 1983,
1998; Margono et al., 2002; Kobayashi et al., 2013) and simultaneously contaminate others who have intimate contact with the carriers themselves etc. (Schantz et al., 1992; Allan et al., 1996;
Ikejima et al., 2005). Thus far, cysticercosis as cryptic NTD is common in developing countries where pork is consumed.
Cysticercosis in general including different types of cysticercosis
may be more cryptic. Therefore, we better stress NCC but not cysticercosis as higher impact from public health. Pawlowski pointed

out that Control of T. solium infection is justied exclusively by

severe pathology caused by neurocysticercosis in humans.
Therefore, from medical point of view, it would be more appropriate to use the term control of taeniasis/neurocysticercosis (T/NCC)
rather than the traditional one control of taeniasis/cysticercosis
(T/CC). The formal change of the term would strengthen the clinical
justication of the control and also turn an attention to the
fecal-oral way of transmission of NCC in or around a T. solium carrier (Pawlowski, 2008). In contrast, taeniasis due to T. solium is not
present in populations with no pork-eating. The crucial barrier is
the religion Prohibit pork-eating! (Fig. 2).
Therefore, it is still sound that T/NCC due to T. solium may be
common but cryptic NTDs in rural and remote areas where people
eat pork under economic poor conditions. In contrast, people in
developed countries with high income are basically safe for T.
solium taeniasis, since they eat safe pork after meat inspection,
and produced in safe farms. The most serious or cryptic NCC populations at risk are people in the border of the two societies where
pork is or is not eaten, and people who are not infected with T.
solium tapeworm(s). The main risk of NCC is through globalization
with business, tourism and laborers from endemic areas. The border does not need to be geographic neighboring countries. T. solium
tapeworm carriers contaminate other people in any societies by
human to human infection with eggs through globalization (Fig. 2).
Cysticercosis is a highly disabilitating and even a mortal helminthic disease spreading worldwide, and causes similar
disability-adjusted life years as dengue fever or African trypanosomiasis (Mathers et al., 2007; Fbre et al., 2008; Zammarchi et al.,
2013; Bobes et al., 2014). In conclusion, cysticercosis is one of
the most neglected, neglected tropical diseases (NTDs) or
neglected zoonotic diseases (NZDs) spreading all over the world
(Budke et al., 2009).

2. Review
2.1. Origin of T. solium
In Table 1 there needs to be a distinction between those species
that occur as strobilated adults in humans as opposed to those species known only from metacestodes infection in humans. Of course
T. solium is unique in this respect. It is clear that the life cycles of
these all are maintained through the preypredator interactions
(Fig. 1). Although there are some reports of human cysticercosis
cases due to T. saginata, they may be misdiagnosed cases because
of the hookless cysticerci of T. solium (Pawlowski and Schultz,
1972; Ito, 2015). There are no known cases of human cysticercosis

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A. Ito et al. / Infection, Genetics and Evolution xxx (2015) xxxxxx

due to T. saginata or T. asiatica that have been conrmed by molecular genetic protocols (Ito, 2015). Among zoonotic Taenia infections (Table 1), thus far, only three species, T. solium, T. saginata
and T. asiatica are obligatory human parasite.
Zarlenga et al. (2014a,b) recently have reviewed what is currently known about the Out of Africa Hypothesis which was originally based on insights from comparative morphology. As this
review noted, current molecular phylogenies (Terefe et al., 2014)
provide what may be new and important insights about the timing
and mechanisms of independent events of host switching from carnivores to hominins that are associated with the origins of T. solium
and for T. saginata + T. asiatica. Insights derived from Terefe et al.
(2014) in general support the mechanisms of host switching proposed originally in Out of Africa by Hoberg et al. (2001), Hoberg
(2006) and Nakao et al. (2002) but provided a considerably more
complex or intricate historical picture which may involve Africa
and Eurasia. And technically if we consider T. solium-colonization
of hominins (modern humans were not present yet) occurred for
the common ancestor of Taenia arctos and T. solium, probably not
by T. solium (unless T. solium originated in a hominin lineage that
was a precursor for modern humans, followed by host colonization) (Zarlenga et al., 2014b).
When mitochondrial DNA of T. solium isolates from the world
was analyzed, they were divided into two clades, Asian and
Afro/American genotypes (Fig. 5) (Okamoto et al., 2001; Nakao
et al., 2002). It has been pointed out that there are several critical

differences in pathogenicity and antigenicity between the two

genotypes (Ito et al., 2003a). One is that NCC cases in Asia caused
by Asian genotype often show subcutaneous cysticercosis
(Margono et al., 2000; Wandra et al., 2000, 2015), whereas NCC
cases in America do not show subcutaneous cysticercosis (SCC).
In Africa, both types of NCC with or without SCC are reported from
different areas (Dumas et al., 1990; Cruz et al., 1994; Boa et al.,
1995; Vilhena et al., 1999; Nguekam et al., 2003; Phiri et al.,
2003; Zoli et al., 2003; Geerts, 2003; Ito et al., 2003a; Praet et al.,
2009; Winkler, 2012; Elliott et al., 2013; Rottbeck et al., 2013).
Another is that molecular sizes of diagnostic antigens of T.
solium cysticerci prepared using two different genotypes critically
differ each other (Fig. 6). However, it is due to post-translation
modication, especially glycosylation. There is no difference in
antigenicity of cyst uid of T. solium cysticerci or recombinant antigens to detect cysticercosis cases all over the world (Ito et al.,
2002b, 2003a; Sato et al., 2006; Sako et al., 2006).
As there are such genetic populations and the parasite was
traded by humans traveling histories (Hoberg et al., 2001;
Hoberg, 2006, 2010; Zarlenga et al., 2014a,b), one interesting country where inuence from both Africa and Asia is expected is
Madagascar. Michelet et al. (2010) analyzed 12 specimens from
11 different areas and found two specimens from one western
costal area were African genotype, but all others from 11 different
areas were Asian genotypes. It is easy for us to expect that such
chances of pigs and humans traveling were not rare but common
from the 15th century onwards at least. Both Afro/American and
Asian genotypes may be sympatrically distributed in many other
countries including not only the eastern cost countries but also
in Sub-Saharan Western countries in Africa (Geerts, 2003;
Nguekam et al., 2003; Eom et al., 2011), the Philippines
(Hinojosa-Juarez et al., 2008), Mexico (Hinojosa-Juarez et al.,
2008; Maravilla et al., 2008; Palafox-Fonseca et al., 2013) or Latin
Americas (Bruno et al., 2013) as speculated by Ito (2015), and consistent with historical assembly of a mosaic fauna through introductions representing disparate populations from different
geographic sources over time (Hoberg, 2010). Although there is
no data so far, NCC with SCC in Africa may be caused by the
Asian genotypes, whereas NCC without SCC may be by
Afro/American genotypes. Asian genotype has invaded into Africa
as it is predominant in Madagascar (Michelet et al., 2010;
Yanagida et al., 2014). Therefore, all SCC cases in Africa are strongly
recommended being checked for the genotyping in order to evaluate the conceived concept itself.
2.2. Outcrossing of closely related two species, T. saginata and T.
asiatica

Fig. 5. Neighbor-joining phylogenetic tree of 2 genotypes of T. solium inferred from

cob gene sequences. The bar represents the estimated number of nucleotide
substitutions per nucleotide site. Numbers at individual nodes are the bootstrap
condence values obtained after 1000 replicates (modied from Nakao et al., 2002).

It is stressed that the majority of platyhelminths including cestodes and trematodes except Schistosoma spp. are hermaphrodite.
Therefore, fertilization by autogamy (=selng) is expected to be
the main strategy in reproduction biology of cestodes, etc. especially when a single parasite is established.
In Asia, there are two other human Taenia species, T. saginata
and T. asiatica (Ito et al., 2003b). There was a mystery or a
long-standing puzzle that many researchers including Taiwanese,
Indonesian, Korean, Japanese and American researchers recognized
as strange phenomenon (Oi, 1915; Yokogawa et al., 1928;
Yokogawa, 1935; Huang et al., 1966; Kosin et al., 1972; Cross
et al., 1976; Soh et al., 1988; Depary and Kosman, 1991). It was
Adult tapeworms expelled from people in Asian countries
appeared to be T. saginata, although these people ate pork rather
than beef (Fan, 1988; Simanjuntak et al., 1997; Ito et al., 2003b).
This mystery was well studied by Taiwan group and the unique
T. saginata in Taiwan or in Asia was called as Taiwan Taenia or
Asian Taenia temporarily (Fan, 1988; Fan et al., 1988, 1990; Ito

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A. Ito et al. / Infection, Genetics and Evolution xxx (2015) xxxxxx

Fig. 6. Antibody responses to glycoproteins (GPs) puried by afnity chromatography using monoclonal antibody (4F10) of T. solium from Asia vs Africa/America illustrated
by immunoblots. Panel A: native GPs against polyclonal rabbit serum, Panel B: native GPs against moAb (4F10), Panel C: native GPs against serum from a neurocysticercosis
patient, Panel D: native GPs against a healthy person, Panel E: native GPs after treatment with N-glycosidase against moAb (4F10). Lane 1: Tanzania, Lane 2: Brazil, Lane 3:
China, Lane 4: Indonesia (modied from Sato et al., 2006).

et al., 2003). Fan and his colleagues including Soh from Korea and
Kosin from Indonesia expected it to be an undescribed species
(Kosin et al., 1972; Soh et al., 1988; Fan et al., 1990). However, as
the genetic differences between the two, classical and the new
T. saginata were very small, experts from USA and Australia recommended Fan not describing it as a new species (Zarlenga et al.,
1991; Bowles and McManus, 1994; McManus and Bowles, 1994;
Simanjuntak et al., 1997; Ito et al., 2003, 2004, 2005, 2014).
Finally, it was described as T. asiatica by other Korean group
(Eom and Rim, 1993; Eom, 2006). Hoberg (2006) provided the
initial phylogenetically based arguments for the independence of
T. saginata and T. asiatica as discrete species. Further, observations
from the estimates for divergence time for these two species proposed in Hoberg et al. (2000) had already provided some indication
of independent historical trajectories for these species.
Nonetheless, there is a debate if these two species are completely
independent each other (Okamoto et al., 2001, 2007, 2010;
Yamane et al., 2012, 2013).
Recent molecular studies including nuclear DNA gene markers
made possible to nd cases of nuclear-mitochondrial discordance.
Recent eld studies on Asian Taenia in Thailand (Anantaphruti
et al., 2007) and China (Li et al., 2006) have revealed that there
are many different types of hybrids or hybrid derived Taenia
between T. saginata and T. asiatica (Okamoto et al., 2010; Yamane
et al., 2012, 2013). It is clear that outcrossing occurs between the
two species, T. saginata and T. asiatica. Based on Biological
Species Concept (Mayr, 1996), these two species might be a single
species (Okamoto et al., 2010; Yamane et al., 2012, 2013), since
reproduction isolation is still incomplete. However, species delimitation and recognition is not limited to static concepts such as the
Biological Species Concept, and indeed this idea has been supplanted to a great degree by phylogenetic and historical
approaches that emphasize independence in space and time
(Brooks and McLennan, 2002; Hoberg, 2006). Additionally,
Hoberg (2006) proposed applying these criteria to exploring the
relationship and independence of T. saginata and T. asiatica which
are consistently in morphological and molecular based phylogenies considered to represent sister species.
2.3. Comparative studies of mitochondrial DNA (haploid) and nuclear
DNA (diploid) of T. solium in Madagascar
As cestodes are hermaphrodites, selng is expected to be the
main strategy in reproduction biology. There are many human cases

conrmed to be infected with a single tapeworm of T. solium. Even

selng is only way for fertilization in a single tapeworm infection,
it is not clear if fertilization occurs within a single gravid proglottid
or between different proglottids or both. As the two genotypes of T.
solium were conrmed in Madagascar (Michelet et al., 2010;
Michelet and Dauga, 2012), T. solium samples in Madagascar are
expected to be ideal for analyzing if there are any out-crossings or
not. For such studies, both mitochondrial and nuclear genes have
to be compared as it has been done for T. saginata and T. asiatica
(Okamoto et al., 2010; Yamane et al., 2012, 2013).
Yanagida et al. (2014) demonstrated candidate nuclear genes
(Ag2, rpb2 and pold) useful for differentiation of the two genotypes.
The results summarized in Fig. 7 and Table 2 strongly suggest that
outcrossing between the two genotypes of T. solium has happened
in the denitive host, humans, several time in Madagascar, since
two major haplotypes and 6 satellite haplotypes were identied.
It strongly suggests that introduction of Asian genotypes happened
at least once but widely distributed as a predominant genotype in
Madagascar. Interestingly, Asian haplotypes are closely related to
Indian and Nepal haplotypes but distantly related to the haplotype
in Indonesia (Fig. 7). It strongly suggests that introduction of Asian
genotypes were from Indian subcontinent but not from Indonesia.
Inconsistency between mitochondrial DNA and nuclear DNA
genotypes and different patterns of heterozygotes in 3 nuclear
DNA markers were conrmed (Table 2). These results indicate
cross-fertilization or out-crossing occurring between Asian and
Afro/American genotypes of T. solium in Madagascar (Yanagida
et al., 2014). Therefore, out-crossing may not be rare even in hermaphrodite, Taenia cestodes if two or more tapeworms are established at once. Exactly, 19 and 20 T. solium tapeworms were
conrmed from Thailand and China, respectively (Ito et al., 2013,
2014). Furthermore double infections with 23 T. solium plus 1
T. saginata (Li, personal communication), and 1 T. solium plus 2
T. asiatica have been conrmed in China (Li et al., 2006). Such
sympatric distribution and double infections with two or more
Taenia species may not be rare but cryptic without molecular
identication (Conlan et al., 2008; Jeon et al., 2013; Eom et al.,
2014; Okello et al., 2014). Thus far, it is impossible to prove
interspecic competition (Conlan et al., 2009).
On outcrossing in taeniid cestode infections, there are additional reports stressing outcrossing in Echinococcus infection
(Nakao et al., 2003; Haag et al., 2011). Therefore, outcrossing
may be common strategy for reproduction biology in multiple cestode infections.

Please cite this article in press as: Ito, A., et al. Recent advances and perspectives in molecular epidemiology of Taenia solium cysticercosis. Infect. Genet.
Evol. (2015), http://dx.doi.org/10.1016/j.meegid.2015.06.022

A. Ito et al. / Infection, Genetics and Evolution xxx (2015) xxxxxx

Table 2
Genotypes of T. solium cysticerci showing nuclear-mitochondrial discordance in
Madagascar (from Yanagida et al., 2014).

a
b

ID of samples

MtDNA haplotypea

Ag2

rpb2

pold

TsolMDG21b
TsolMDG29a
TsolMDG62a
TsolMDG62b

MDG1
MDG1
MDG1
MDG1

B/B
B/B
A/A
A/A

B/B
A/A
A/A
A/A

A/A
A/A
C/C
A/C

Toliara
Toamasina
Antananarivo
Antananarivo

TsolMDG67a

MDG1

B/B

B/B

TsolMDG68b
TsolMDG04a

MDG1
MDG7

B/B
B/B

B/B

A/C
C/C
A/A

Toliara
Antananarivo

TsolMDG04b
TsolMDG12b

MDG7
MDG7

B/B
A/A

TsolMDG13a

MDG7

A/A

TsolMDG13b
TsolMDG25a

MDG7
MDG7

A/B
B/B

A/C
A/A

A/A

A/A

TsolMDG28a
TsolMDG37a
TsolMDG50a

MDG7
MDG7
MDG7

A/B
A/A
A/A
A/A

A/B
B/B
A/A

A/C
C/C
A/A
A/A

TsolMDG50b

MDG7

A/A

TsolMDG69a

MDG7

TsolMDG69b

MDG7

A/B
B/B

Genotype at each
locusa,b

A/B
A/A
A/A

A/B
A/A

A/A

Localities

Toliara

Antananarivo
Antananarivo
Antananarivo
Antananarivo
Toliara
Toliara
Toamasina
Mahajanga
Mahajanga

B/B

A/C
C/C

Toliara

B/B

A/C

Toliara

Haplotypes and alleles in bold are AfroAmerican ones.

Genotypes with underline indicate those at heterozygous loci.

3. Conclusion
T. solium is traveling the world mainly with humans.
Throughout globalization, cysticercosis cases are more common
in everywhere including countries where pork is not eaten. As
there are two genotypes, it is important for us to study human
cases with genotypes and haplotype network and trace back
where, how and with whom T. solium travel the world.
Conict of interest
The authors conrm that they have no conicts of interest
regarding the content of this article.
Fig. 7. Haplotype network of T. solium based on the concatenated mtDNA DNA gene
sequences (cox1 and cob). The size of the ellipses is roughly proportional to the
haplotype frequency, and the actual numbers of haplotypes (>1) are enclosed in
parentheses. CHN, China; ID-PA, Indonesia (Papua); IND, India; NPL, Nepal; THA,
Thailand; BRA, Brazil; CMR, Cameroon; ECU, Ecuador; MEX, Mexico; TZA, Tanzania;
MDG, Madagascar (modied from Yanagida et al., 2014).

2.4. Perspectives from mitochondrial DNA and nuclear DNA analysis

As haplotypes of mitochondrial DNA of T. solium are unique to
the locality, areas or countries, it is highly useful for identication
or speculating where the infection was acquired from (Yanagida
et al., 2010; Jongwutises et al., 2011; Kobayashi et al., 2013).
Thus far, hybrids of the two genotypes of T. solium have been conrmed exclusively in Madagascar (Yanagida et al., 2014).
Additional cases of the co-distribution of two genotypes and
hybrids may be found from other countries as mentioned above
(Ito, 2015).
As shown in Fig. 6, there is a critical difference in the molecular
weight of diagnostic antigens between the two genotypes (Ito
et al., 2002b, 2003a; Sato et al., 2006). These differences in the size
of GPs were caused by different post-translational modications,
especially glycosylation (Fig. 6, panel E) (Sato et al., 2006).
Therefore, it is interesting to analyze which sizes of GPs are the
diagnostic antigens in hybrid cysticerci to understand the mechanism of glycosylation (Ito et al., 2014).

Acknowledgements
We sincerely thank anonymous reviewers for their great advice
in improving this article. The studies on cestode infections have
been supported by Grants-in-Aid for international collaboration
research funds from the Japan Society for the Promotion of
Science (JSPS) to A.I. (21256003, 24256002), M.N. (2722590376)
and T.Y. (15H05261) and by JSPS-Asia/Africa Scientic Platform
Fund (20062011), the Special Coordination Fund for Promoting
Science and Technology from the Ministry of Education, Culture,
Sports, Science & Technology, Japan (MEXT) (20032005, 2010
2012), and the Translational Research Fund from MEXT (2007
2011) to A.I.
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Please cite this article in press as: Ito, A., et al. Recent advances and perspectives in molecular epidemiology of Taenia solium cysticercosis. Infect. Genet.
Evol. (2015), http://dx.doi.org/10.1016/j.meegid.2015.06.022