The role of Toxoplasma gondii as a possible inflammatory ...

Family Medicine and Community Health

SYSTEMATIC REVIEW

Family Medicine and Community Health 2016;4(4):44–62 44www.fmch-journal.org DOI 10.15212/FMCH.2016.0128© 2016 Family Medicine and Community Health

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The role of Toxoplasma gondii as a possible inflammatory agent in the pathogenesis of type 2 diabetes mellitus in humans

Aus Molan1, Kazunori Nosaka1, Michael Hunter2,3, Wei Wang1

Abstract

Type 2 diabetes mellitus (T2DM) continues to be a major challenge for public health authorities

worldwide. While potential causes such as obesity, physical inactivity, and dietary patterns have

been proposed to explain the growing epidemic, there may also be unidentified environmental

determinants. An emerging field of research is starting to examine the association of infectious and

environmental pathogens with diabetes. In particular, the potential of these pathogens to cause low-

grade inflammation that facilitates the risk and development of T2DM. An understudied pathogen

of potential interest is the protozoan parasite Toxoplasma gondii (T. gondii). There is limited clinical

evidence supporting the association between chronic T. gondii infection and the development of

many disorders, including T2DM, in both animals and humans. This review (1) addresses the exist-

ing knowledge of the role of T. gondii in the inflammation process leading to T2DM, (2) examines

the current studies describing the relationship between T. gondii and T2DM, and (3) makes recom-

mendations for future studies to determine the role of T. gondii in the pathogenesis of T2DM. We

believe that T. gondii may be an important target for T2DM intervention, and propose a new field

of study, “toxoplasmic type 2 diabetes.”

Keywords: Etiology; inflammation; Toxoplasma gondii infection; toxoplasmosis; diabetes mel-

litus, type 2

1. School of Medical and Health

Sciences, Edith Cowan Univer-

sity, Joondalup, WA, Australia

2. Busselton Population and Med-

ical Research Institute, Busselton,

WA, Australia

3. School of Population Health,

University of Western Australia,

Nedlands, WA, Australia

CORRESPONDING AUTHOR:

Wei Wang, MD, PhD, FFPH

School of Medical and Health

Sciences, Edith Cowan Uni-

versity, 270 Joondalup Drive,

Joondalup WA 6027, Australia

Tel.: +61-8-63043717

E-mail: [email protected]

Received 24 August 2016;

Accepted 18 September 2016

Introduction

Diabetes mellitus is one of the most challeng-

ing public health burdens of the 21st century

[1]. It is a chronic disorder characterized by

persistent hyperglycemia with disturbances

in fat, carbohydrate, and protein metabo-

lism resulting from abnormalities in insulin

secretion, insulin action, or both [1, 2]. Type

2 diabetes mellitus (T2DM; International

Classification of Diseases, Tenth Revision,

Clinical Modification diagnosis code E11.9) is

characterized by reduced insulin production

and an inability of body tissues to fully respond

to insulin (insulin resistance) [1–3], account-

ing for approximately 90% of all diagnosed

diabetes cases [2, 3]. The pathogenesis of

T2DM has been recognized as an ongoing

deterioration of the insulin secretory capacity

of pancreatic β cells that does not allow com-

pensation for an increased peripheral insulin

demand [4, 5]. The prevalence of diabetes is

reaching epidemic levels, with an estimated

global prevalence of 9% among adults aged

18 years or older [6–12]. Additionally, dia-

betes places excessively high human, social,

and economic costs on all countries. In 2013,

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Molan et al.

45 Family Medicine and Community Health 2016;4(4):44–62

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5.1 million deaths were caused by diabetes worldwide (one

person every 6 s) [6, 12]. Looking ahead, it is estimated that

642 million people will be living with diabetes by 2040, which

is a more than 50% increase from 415 million in 2015 [7]. This

is mainly due to the increase in the numbers of people with

T2DM as a result of the increase in life expectancy, genetic

predisposition, physical inactivity, dietary changes, the obe-

sity epidemic, and the decreased mortality rates in diabetic

individuals [1, 3, 6–11]. However, there may also be additional

unidentified novel risk factors, such as subclinical inflamma-

tion caused by infectious agents, that contribute to this rising

prevalence of T2DM [13].

There are epidemiological data that link inflammatory bio-

markers as important risk indicators for future development of

diabetes [14]. In this regard, an emerging field of research is

beginning to investigate the potential of infectious and envi-

ronmental pathogens to cause low-grade inflammation that

may facilitate the risk and development of various metabolic

conditions, including diabetes and obesity. An understud-

ied pathogen of potential interest is the protozoan parasite

Toxoplasma gondii (T. gondii) (International Classification

of Diseases, Tenth Revision, Clinical Modification diagnosis

code B58.9). First described in 1908 by Nicolle and Manceaux

[15], T. gondii infects approximately one third of the world’s

population and is considered one of the most successful human

parasites [16–19]. Humans acquire T. gondii by the ingestion

of food, water, or soil contaminated by oocysts from the defin-

itive hosts, cats (Fig. 1). T. gondii is also transmitted in people

vertically via the maternal placenta and horizontally via blood

transfusion [18, 21–23]. T. gondii is capable of infecting all

warm-blooded animals [24], and toxoplasmosis is a disease

of considerable public health impact – the global prevalence

rates of infection by this parasite are phenomenal, with figures

ranging from 15% to 85% depending on dietary habits, cli-

mate conditions, hygiene standards, and geographical regions

[21, 23, 25–27]. Although T. gondii has a worldwide distribu-

tion and possibly the widest host range of any parasite, there

is only one species (T. gondii) in the genus Toxoplasma [28],

and cats are the only definitive host in which T. gondii sexual

development is known to occur [25, 20].

Toxoplasmosis can present with various nonspecific signs

and symptoms, but most are similar to general flulike indicators

[22, 23, 27]. In immunocompetent individuals, it is thought

that the disease is asymptomatic and that the individual recov-

ers without treatment because of an efficient immune system

which limits the spread of the rapidly multiplying tachyzoites

[22]. Therefore people are not routinely screened for T. gondii

infection unless they are immunocompromised or pregnant

[4, 23–25]. In all cases the parasite remains detectable in the

serum throughout the life of the host, with dormant cysts being

formed in various anatomical sites, including the central nerv-

ous system, often establishing latent toxoplasmosis [18, 22].

T. gondii can infect and replicate in any nucleated host cells,

leading to the production of various inflammatory markers

via the innate acute inflammatory responses and antigen-spe-

cific adaptive immunity [4]. This facilitates a state of chronic

inflammation at various anatomical sites in the host [4].

Chronic T. gondii infection has been linked to several auto-

immune disorders, including thyroid disease, systemic sclero-

sis, rheumatoid arthritis, and inflammatory bowel syndrome

[29]. In addition, several reports have demonstrated a positive

correlation between T. gondii infection and numerous neu-

rological disorders and cancers [4, 22, 23, 28, 30]. However,

T. gondii infection in individuals with T2DM has received

little recognition, and human studies investigating T. gondii

infection and inflammatory biomarkers in T2DM subjects are

not available. This review (1) addresses the existing knowl-

edge of the role of T. gondii in the inflammation process lead-

ing to T2DM, (2) examines the current studies describing

the relationship between T. gondii and T2DM, and (3) makes

recommendations for further studies to determine the role of

T. gondii in the pathogenesis of T2DM using inflammation

as the main outcome. The association between T2DM and

T. gondii, if proven, will have important and significant public

health outcomes. Routine screening for T. gondii infection in

individuals with T2DM would add to the risk prediction for

diabetes to target individuals for early aggressive interven-

tion. Targeting T. gondii and reducing its risk factors could be

used as an Achilles heel to reduce inflammation, leading to

improved glucose tolerance and reduced insulin resistance in

diabetic individuals. We believe that T. gondii latent infection

may have excellent potential as a novel target for T2DM inter-

vention and may pave a path for a new field of study, “toxoplas-

mic type 2 diabetes.”

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Host inflammatory responses to T. gondii infection

The founding study by Frenkel [31] demonstrated that the

transfer of serum from infected to uninfected animals failed

to protect the latter against parasite infection. This knowl-

edge assisted in pointing toward T cells rather than antibod-

ies as the major effectors of resistance to T. gondii infection.

Direct

Indirect

Fig. 1. The complete life cycle of Toxoplasma gondii. Infection consists of an acute phase followed by a chronic phase. The life cycle is divided

into the sexual and asexual stages, where the former occurs in the intestine of the definitive host, while the latter occurs in the intermediate hosts.

After completion of the sexual phase, oocysts released in the feces undergo sporulation to form sporocysts that become a source of infection

for intermediate hosts. When the oocysts are ingested, the internal sporocysts pass through the stomach and excyst in the intestine to release

sporozoites. These sporozoites invade epithelial cells and differentiate into tachyzoites, an actively replicating form of T. gondii. Because of their

active multiplication, tachyzoites cause extensive tissue damage and may disseminate to different tissues of the host. T. gondii infects circulating

cells and can use them as a Trojan horse to gain access to protective tissues such as the brain, where entry of immune cells is restricted. The

tachyzoites eventually undergo stage conversion and become slowly multiplying bradyzoites within tissue cysts. If for some reason the tissue

cyst becomes activated, the bradyzoites can undergo stage conversion and become tachyzoites. The bradyzoite form is the only stage that can

infect feline enterocytes and lead to oocyst production, restarting the life cycle. (Adapted from Hunter and Sibley [20] with permission).

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More recently, it has become clear that T. gondii manipulates

and modulates host resistance mechanisms at multiple points

along the proinflammatory pathway which in turn dictate

parasite burden and disease (Fig. 2) [32]. During the acute

phase of this infection, which lasts for less than 10 days, T.

gondii elicits a very strong T-helper type 1 (Th1) cell medi-

ated inflammatory response (Table 1) [41]. The ability of the

host to control T. gondii depends on the subsequent produc-

tion of interleukin (IL)-12 by macrophages and dendritic

cells, resulting from the differentiation and clonal expansion

of host Th1 cells in response to the recognition of conserved

T. gondii microbe molecular structures (glycosylphosphati-

dylinositol anchors and profilin) by Toll-like receptors [32,

92]. In turn, IL-12 stimulates natural killer cells and CD4+

and CD8+ T cells to release interferon gamma (IFN-γ), which

is also central in host resistance to T. gondii infection [32].

The Th1 response, defined by the production of IL-12 and

IFN-γ, is a characteristic of infection with intracellular patho-

gens, including T. gondii [93]. In fact, a significant discovery

that allowed progress toward the identification of essential

recognition and effector mechanisms involved in host resist-

ance to T. gondii infection was the identification of IFN-γ

as the major regulator of cell-mediated immunity to T. gon-

dii in both mouse and human cells [94–97]. Studies show-

ing the importance of T cells in resisting T. gondii infection

are unequivocal. For example, mice which lack functional T

cells are extremely susceptible to T. gondii infection [94, 95].

Likewise, IL-12- or IFN-γ-deficient mice are extremely sus-

ceptible to infection by T. gondii and demonstrate an inabil-

ity to control parasite burden [96, 97]. Furthermore, several

murine models have demonstrated the protection of naïve

mice against T. gondii infection as a result of adoptive trans-

fer of immune T cells [31, 98–100]. With regard to T. gondii

infection in humans, the importance of the adaptive immune

response has been demonstrated by the increase of suscep-

tibility to T. gondii infection in individuals with primary or

acquired T-cell function defects [96].

In addition to the systemic effects, T. gondii also induces

the production of a number of proinflammatory cytokines

(tumor necrosis factor alpha, TNF-α; IL-1; IL-1β; IL-6;

IL-18; IL-12p40; IL-8; IL-17; IL-22; IL-15), anti-inflam-

matory cytokines (transforming growth factor beta, TGF-β;

IL-4; IL-10; IL-27), nitric oxide synthase, and reactive oxy-

gen species that are associated with inflammatory responses

in various sites and cells, including the brain, microglial

cells, astrocytes, and infiltrating CD4+ and CD8+ T cells

[30, 32, 41, 50, 61–67, 92, 101–108]. It is important to note

that excess production of proinflammatory cytokines ends

up causing damage to the host; therefore a delicate balance

between the above mentioned proinflammatory and anti-

inflammatory signals is necessary for the survival of the host

[32]. Maintaining this immune homeostasis during T. gon-

dii infection requires both the capacity to control the host

immune response and the capacity to limit the replication of

the pathogen [93]. To this extent, IL-10, TGF-β, and IL-27

are key downregulators that prevent the overproduction of

Th1-type cytokines, thereby regulating inflammation [32,

92, 103, 104]. More specifically, during T. gondii infection,

the in vivo synthesis of both IL-12 and IFN-γ is modulated

by IL-10 to avoid an excessive immune response that could

cause host tissue damage and widespread inflammation [45,

109]. Paradoxically, while the host immune response lim-

its the tissue spread of the parasite to ensure the survival of

the host, it is also assisting in the survival of the parasite

by converting it into a bradyzoite, an intracellular dormant

resistant form persisting in the muscles, central nervous sys-

tem, and brain tissues [106]. Given that a strong Th1 immune

response is elicited to maintain the dormant bradyzoite stage

[110] and that a Th1 immune response is also maintained to

promote long-lasting immunity [111], hosts infected with T.

gondii remain in an “asymptomatic” state of constant low-

grade inflammation.

T2DM as an inflammatory disease

Inflammation not only participates in host defenses against

environmental and infectious agents such as T. gondii but also

contributes to the pathophysiology of many chronic diseases

[112]. Increased circulatory acute-phase response markers

and proinflammatory cytokines in individuals with T2DM

were first reported in 1997 [113]. Since then, the ideas that

inflammation participates in the pathogenesis of T2DM and

that T2DM is a chronic inflammatory disease have gained

undeniable attention, with many reports describing changes

to immune cell function [4, 43, 53, 55, 114–117]. In addition,

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Fig. 2. Important inflammatory regulators and antiparasitic effector mechanisms during acute infection with Toxoplasma gondii. Early in

T. gondii infection, dendritic cells, monocytes, and macrophages are the first cells to respond. T. gondii profilin interacts with Toll-like

receptor (TLR) 11 and TLR12 on dendritic cells. This is important for the host production of interleukin (IL)-12. In addition, macrophages

also induce tumor necrosis factor alpha (TNF-α) in response to TLR2- and TLR4-mediated detection of glycosylphosphatidylinositol (GPI)-

anchored parasite proteins. The innate immune response results in the production of interferon gamma (IFN-γ) from natural killer (NK) cells.

Eventually, this induces inflammatory mediators that control T. gondii multiplication and direct the developing adaptive immune system,

resulting in the expansion of T-helper type 1 (Th1) cells and cytolytic CD8+ T cells that secrete IFN- γ. Th1 cell differentiation is induced by

the release of IL-12 and IL-18, while T-helper type 17 (Th17) cell differentiation and expansion is promoted by transforming growth factor

beta (TGF-β), IL-6, and IL-23. This is counterregulated by T-helper type 2 (Th2) cells and regulatory T (Treg) cells mainly through the

production of IL-4 and IL-10. IL-10 and IL-27 are key to modulating these pathways and prevent the overproduction of Th1-type cytokines.

The production of IFN-γ during the innate and adaptive phases is responsible for activating cells to control parasite infection. IFN-γ

signaling promotes the development of signal transducer and activator of transcription 1 (STAT1; a nuclear transcription factor that controls

the expression of many genes) dependent antiparasitic effector mechanisms, including reactive oxygen intermediates and p47 GTPase

upregulation. The cell-mediated immune response that results limits parasite replication. IFNγR, Interferon gamma receptor; MC, mast cells;

MP, macrophages; ROS, reactive oxygen species.

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Tabl

e 1.

Im

mun

e re

spon

se to

Tox

opla

sma

gond

ii a

nd ty

pe 2

dia

bete

s m

ellit

us in

hum

an a

nd a

nim

al m

odel

s

Ana

lyze

d

biom

arke

r

B

iolo

gica

l act

ivity

Sel

ecte

d re

fere

nces

Type

2 d

iabe

tes

mel

litus

res

pons

e

Toxo

plas

ma

gond

ii re

spon

se

IL-1

β

PI. M

edia

tor

of in

flam

mat

ory

resp

onse

. Inv

olve

d in

a v

arie

ty o

f

cellu

lar

activ

ities

(ce

ll pr

olif

erat

ion,

diff

eren

tiatio

n, a

nd a

popt

osis

)

Secr

eted

fro

m m

onoc

ytes

: Mos

ser

and

Edw

ards

[33

], G

iulie

tti e

t al.

[34]

, Hat

anak

a

et a

l. [3

5], P

icku

p [3

6], P

icku

p an

d C

rook

[37

]

Ars

enije

vic

et a

l. [3

8], F

abia

ni e

t al.

[39]

, Tom

asik

et a

l. [4

0]

IL-6

PI

cyt

okin

e an

d A

I m

yoki

ne

(inc

reas

ed d

urin

g ex

erci

se).

Stim

ulat

es im

mun

e re

spon

se

Secr

eted

fro

m m

onoc

ytes

: Mos

ser

and

Edw

ards

[33

], G

iulie

tti e

t al.

[34]

, Hat

anak

a

et a

l. [3

5], P

icku

p [3

6], P

icku

p an

d C

rook

[37

]

Ars

enije

vic

et a

l. [3

8], F

ilise

tti a

nd C

ando

lfi [

41],

Prad

a an

d N

go-T

u [4

2], P

arlo

g et

al.

[21]

, Fab

iani

et a

l. [3

9]

IL-8

PI

. CX

CL

8. I

nduc

es c

hem

otax

is a

nd

phag

ocyt

osis

Secr

eted

fro

m m

onoc

ytes

: Mos

ser

and

Edw

ards

[33

], G

iulie

tti e

t al.

[34]

, Hat

anak

a

et a

l. [3

5], P

icku

p [3

6], P

icku

p an

d C

rook

[37

].

Secr

eted

fro

m β

cel

ls: J

agan

nath

an e

t al.

[43]

Parl

og e

t al.

[21]

IL-1

0

AI.

Dow

nreg

ulat

es e

xpre

ssio

n of

Th1

cyto

kine

s. I

nvol

ved

in r

egul

atio

n of

the

JAK

–STA

T s

igna

ling

path

way

Secr

eted

fro

m β

cel

ls: J

agan

nath

an e

t al.

[43]

.

Not

wel

l stu

died

Ars

enije

vic

et a

l. [3

8, 4

4], F

ilise

tti a

nd C

ando

lfi

[41]

, Gaz

zine

lli e

t al.

[45]

, Fab

iani

et a

l. [3

9]

IL-1

2

PI. I

nvol

ved

in d

iffe

rent

iatio

n of

nai

ve

T c

ells

into

Th1

cel

ls. S

timul

ated

prod

uctio

n of

IFN

-γ a

nd T

NF-

α

Weg

ner

et a

l. [4

6], T

siav

ou e

t al.

[47]

, Win

er

et a

l. [4

8]

Blis

s et

al.

[49]

, Fili

setti

and

Can

dolfi

[41

], G

azzi

nelli

et a

l. [5

0, 4

5], N

guye

n et

al.

[51]

, Par

log

et a

l. [2

1],

Fabi

ani e

t al.

[39]

, Lie

berm

an e

t al.

[60]

IL-1

7

PI. I

nduc

ed a

nd m

edia

tes

PI r

espo

nses

(pro

duct

ion

of I

L-6

, G-C

SF, G

M-C

SF,

IL-1

β, T

GF-

β, T

NF-

α)

Jaga

nnat

han

et a

l. [5

3], W

iner

et a

l. [5

4],

Her

der

et a

l. [5

5], A

ndri

anka

ja e

t al.

[56]

,

Osb

orn

et a

l. [5

7], Y

ang

et a

l. [5

8], A

cost

a-

Rod

rigu

ez e

t al.

[59]

Fabi

ani e

t al.

[39]

, Kel

ly e

t al.

[55]

TG

F-β

A

I. C

ontr

ols

prol

ifer

atio

n, c

ellu

lar

dif f

eren

tiatio

n

Lev

el in

crea

ses

in th

e pr

edia

betic

sta

ge

Fi

liset

ti an

d C

ando

lfi [

41],

Fis

cher

et a

l. [6

1],

Gaz

zine

lli e

t al.

[50]

, Nag

inen

i et a

l. [6

2]

IFN

-γ

PI. A

ctiv

ator

of

mac

roph

ages

and

indu

cer

of M

HC

cla

ss I

I m

olec

ule

expr

essi

on. A

berr

ant I

FN-γ

exp

ress

ion

is a

ssoc

iate

d w

ith a

num

ber

of

auto

infla

mm

ator

y an

d au

toim

mun

e

dise

ases

Jaga

nnat

han

et a

l. [5

3], F

euer

er e

t al.

[63]

,

Win

er e

t al.

[48]

Ara

ujo

and

Slif

er [

64],

Ars

enije

vic

et a

l. [6

5],

Filis

etti

and

Can

dolfi

[41

], G

avri

lesc

u an

d D

enke

rs

[66]

, Gaz

zine

lli e

t al.

[45]

, Her

mes

et a

l. [6

7], K

han

et a

l. [6

8], M

ordu

e et

al.

[69]

, Ngu

yen

et a

l. [5

1],

Peng

et a

l. [1

6], P

arlo

g et

al.

[21]

, Fab

iani

et a

l.

[39]

, Tom

asik

et a

l. [4

0]

TN

F-α

PI

. Inv

olve

d in

sys

tem

ic in

flam

mat

ion

Secr

eted

fro

m m

onoc

ytes

: Mos

ser

and

Edw

ards

[33

], G

iulie

tti e

t al.

[34]

, Hat

anak

a

et a

l. [3

5], P

icku

p [3

6], P

icku

p an

d C

rook

[37

]

Ars

enije

vic

et a

l. [4

4], B

liss

et a

l. [6

1], F

ilise

tti a

nd

Can

dolfi

[41

], G

azzi

nelli

et a

l. [5

0, 4

5], K

han

et a

l.

[68]

, Pra

da a

nd N

go-T

u [4

2], P

arlo

g et

al.

[21]

,

Fabi

ani e

t al.

[39]

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Ana

lyze

d

biom

arke

r

B

iolo

gica

l act

ivity

Sel

ecte

d re

fere

nces

Type

2 d

iabe

tes

mel

litus

res

pons

e

Toxo

plas

ma

gond

ii re

spon

se

IL-1

RA

A

I. M

embe

r of

the

IL-1

fam

ily.

Secr

eted

by

vari

ous

type

s of

cel

ls,

incl

udin

g im

mun

e ce

lls, e

pith

elia

l

cells

, and

adi

pocy

tes,

and

is a

nat

ural

inhi

bito

r of

the

PI e

ffec

t of

IL-1

β

Lev

el in

crea

ses

in th

e pr

edia

betic

sta

ge

IL-2

7

Bel

ongs

to th

e IL

-12

fam

ily.

Reg

ulat

es th

e ac

tivity

of

B a

nd T

lym

phoc

ytes

Lev

el in

crea

ses

in th

e pr

edia

betic

sta

ge

H

all e

t al.

[70]

IL-4

AI.

Ind

uces

dif

fere

ntia

tion

of n

aive

help

er T

cel

ls to

Th2

cel

ls

Ars

enije

vic

et a

l. [3

8], F

ilise

tti a

nd C

ando

lfi [

41],

Parl

og e

t al.

[21]

, Fab

iani

et a

l. [3

9]

Lep

tin

“S

atie

ty h

orm

one.

” M

ade

by a

dipo

se

cells

and

hel

ps to

reg

ulat

e en

ergy

bala

nce

by in

hibi

ting

hung

er

Ver

y hi

gh le

vel i

n pe

ople

with

type

2 d

iabe

tes

mel

litus

and

obe

sity

(hi

gh, >

15 n

g/m

L):

Mitt

endo

rfer

et a

l. [7

2], M

oon

et a

l. [7

3]

Bal

taci

and

Mog

ulko

c [7

1]

Adi

pone

ctin

M

odul

atio

n of

glu

cose

and

lipi

d

met

abol

ism

in in

sulin

-sen

sitiv

e tis

sues

Lev

el d

ecre

ases

in th

e pr

edia

betic

sta

ge

M

ilova

ncov

ic e

t al.

[74]

(un

affe

cted

)

PAI-

1

Key

reg

ulat

or o

f fib

rino

lysi

s,

thus

atte

nuat

es th

e ac

tivity

of

the

fibri

noly

tic s

yste

m

Auw

erx

et a

l. [7

5], V

ague

et a

l. [7

6], J

anss

on

et a

l. [7

7], S

amps

on e

t al.

[78]

, Juh

an-V

ague

et a

l. [7

9], P

ando

lfi e

t al.

[80]

, Gra

nt e

t al.

[81]

,

Nor

dt e

t al.

[82]

, Sch

neid

er a

nd S

obel

[83

],

Sobe

l et a

l. [8

4], A

less

i et a

l. [8

5], C

arm

assi

et a

l. [8

6], C

alle

s-E

scan

don

et a

l. [8

7], M

eigs

et a

l. [8

8]

Tom

asik

et a

l. [4

0]

IL-2

3

Secr

eted

by

activ

ated

den

driti

c ce

lls

and

activ

ated

mac

roph

ages

. IL

-23

func

tions

in in

nate

and

ada

ptiv

e

imm

unity

to r

egul

ate

Th1

7 fu

nctio

n

and

prol

ifer

atio

n

Men

sah-

Bro

wn

et a

l. [8

9], L

ukic

et a

l. [9

0]

(IL

-23

lead

s to

dia

bete

s in

duct

ion)

Muñ

oz e

t al.

[91]

, Lie

berm

an e

t al.

[52]

AI,

Ant

i-in

flam

mat

ory;

G-C

SF, g

ranu

locy

te c

olon

y st

imul

atin

g fa

ctor

; GM

-CSF

, gra

nulo

cyte

–mac

roph

age

colo

ny s

timul

atin

g fa

ctor

; IL

, int

erle

ukin

; IL

-1R

A, i

nter

leuk

in-1

rece

ptor

ant

agon

ist;

IFN

-γ, i

nter

fero

n ga

mm

a; J

AK

, Jan

us k

inas

e; P

AI-

1, p

lasm

inog

en a

ctiv

ator

inhi

bito

r 1;

PI,

pro

infla

mm

ator

y; S

TAT,

sig

nal t

rans

duce

r an

d ac

tivat

or o

f

tran

scri

ptio

n; T

GF-

β tr

ansf

orm

ing

grow

th f

acto

r be

ta; T

h1, T

hel

per

type

1; T

h2, T

hel

per

type

2; T

h17,

T h

elpe

r ty

pe 1

; TN

F-α,

tum

or n

ecro

sis

fact

or a

lpha

.

Tabl

e 1

(con

tinue

d)

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there are also experimental data that provide evidence for a

direct link between inflammation and T2DM, which supports

the notion that this disease is, at least in part, an inflammatory

condition [13, 112].

Serum-based inflammatory biomarkers as a measure-

ment of subclinical inflammation have been implicated in

the development of T2DM, with several cross-sectional and

prospective studies describing elevated circulating levels of

acute-phase proteins as well as chemokines and cytokines

(Table 1). For example, elevated levels of IL-6 (a cytokine

that induces differentiation of Th17 cells), IL-8, IL-17, TNF-

α, TGF-β, and IL-1β secreted from monocytes in T2DM

patients have been reported [33–35, 43, 53–59]. Elevated lev-

els of IL-1β, IL-6, and C-reactive protein are predictive of

T2DM [115, 117, 118], while elevated levels of IL-1 recep-

tor antagonist are observed during obesity and prediabetes

[117]. Moreover, patients with T2DM also have elevated

serum levels of IL-12, a cytokine that promotes Th1 cell dif-

ferentiation and increased INF-γ production [47, 48, 59, 63].

In addition, proinflammatory cytokines are increasingly

thought to contribute to the dysfunction and death of β cells

during the progression of T2DM [119]. More specifically, it

has been established that pancreatic β cells, as well as neural

cells, can be destroyed by several toxic agents and noxious

stimuli, such as reactive oxygen species, NO, and cytokines

(TNF-α, IL-1β, and IFN-γ) [4]. The subsequent proinflam-

matory cytokine balance has been directly linked to T2DM

by several in vivo studies showing that the inhibition of key

inflammatory cytokines protects rats from insulin resistance

[120–124]. These reports suggest that increased cytokine pro-

duction not only precedes but also maintains insulin resist-

ance in animals, hence adding detail to the current model of

T2DM being an inflammatory disease.

Spranger et al. [115] prospectively examined the effects

of IL-1β, IL-6, and TNF-α on the development of T2DM in

more than 27,000 individuals. In addition to observing ele-

vated levels of IL-6 and TNF-α in individuals with T2DM,

they also found that IL-6 was an independent predictor of

T2DM. Their data also showed that patterns of these cytokines

could modify the risk of T2DM by elevating the levels of both

IL-1β and IL-6, rather than elevating the level of IL-6 alone,

which increases the risk of T2DM. This strongly supports the

hypothesis that a subclinical inflammatory reaction has a role

in the pathogenesis of T2DM.

Possible association between obesity, T2DM, and

T. gondii infection

In addition to T2DM, obesity is also thought to be associ-

ated with a chronic systemic inflammatory response that

is characterized by altered cytokine production and activa-

tion of inflammatory signaling pathways [125]. Obesity has

previously been referred to as “a state of chronic inflamma-

tion” [26]. The increase in the production of inflammatory

cytokines, such TNF-α and IL-6, and certain adipokines

during the inflammatory process in obesity has been linked

to the development of insulin resistance by several reports

[126–128]. It is well established that insulin resistance pre-

cedes the onset of T2DM, at which point impaired glucose

tolerance occurs because of insulin deficiency as a result of

β-cell decomposition [129]. While there are several factors

such as genetics, environmental influences, and obesity that

link the development of insulin resistance with T2DM [129],

the possibility that obesity may enhance the release of inflam-

matory markers that trigger the development of insulin resist-

ance has generated interest in the field of diabetes for a number

of reasons. Predominantly, most individuals with T2DM are

overweight or obese, at least in the early phase, and obesity

is an established risk factor for the development of T2DM [2,

130, 131]. The significant increase in the incidence and preva-

lence of diabetes in the last 2 decades can be largely explained

by the global epidemic of obesity [131]. Furthermore, chronic

inflammation is associated with obesity, insulin resistance,

and T2DM, all of which belong to the metabolic diseases

known as “metabolic syndrome” [132].

The first molecular study to establish the link between

obesity, inflammation, and insulin resistance was published

in 1993 by Hotamisligil et al. [133]. They demonstrated that

the inflammatory cytokine TNF-α is constitutively expressed

in adipose tissue and overexpressed in obese rodents [133].

Furthermore, the inhibition of TNF-α in these obese rodents

significantly increased insulin sensitivity by increasing the

peripheral uptake of glucose in response to insulin. Two years

later, Hotamisligil et al. [134] examined the expression patterns

of TNF-α messenger RNA (mRNA) in the adipose tissues of

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19 obese and 18 control premenopausal women using Northern

blot analysis and found that the obese group expressed sig-

nificantly greater (2.5-fold, P<0.001) TNF-α mRNA in their

adipose tissue than the lean, control group. In addition, the

expression levels of TNF-α mRNA in adipose tissue showed

a strong correlation with the level of hyperinsulinemia, which

is an indirect measure of insulin resistance [134]. Lastly, they

also observed an increase in insulin sensitivity and a 45%

decrease in TNF-α mRNA expression (P<0.001) in adipose

tissue when the obese individuals reduced their body weight.

In support of a direct role for inflammation in the develop-

ment of obesity, the above-mentioned results were validated

by a human study that found a significant increase in adipose

TNF-α mRNA levels with increasing adiposity and that a sig-

nificant correlation exists between TNF-α mRNA levels and

percent body fat (P<0.05) [135]. It was also found that TNF-α

levels markedly decreased with weight loss and in some indi-

viduals the decreases were up to 46% of initial levels (P<0.02).

Further studies established TNF-α as a potent insulin receptor

inhibitor, hence further implicating this cytokine in the insulin

resistance of T2DM and obesity [136].

With use of animal models it has also been shown that

diet-induced obese mice have more T cells in adipose tissue

than lean, control mice [137], and diet-controlled weight loss

is associated with reduced adipose tissue inflammation [137].

In addition, the development of insulin resistance and other

metabolic abnormalities, including reduced metabolic rates,

has also been associated with chronic inflammation [138,

139]. Accordingly, it is possible that the chronic proinflamma-

tory state induced by latent T. gondii infection precipitates (in

nonobese individuals), perpetuates, or exacerbates (in obese

individuals) the inflammation-related weight gain. Reeves

et al. [130] reported a positive association between T. gondii

seropositivity and obesity from a sample of 999 human adults.

Their results showed that individuals with positive T. gon-

dii serological findings had twice the odds of being obese

(BMI >30 kg/m2) than seronegative individuals (P=0.01).

Furthermore, it has been proposed that infection with

T. gondii may be associated with obesity because of the abil-

ity of the organism to alter inflammatory fat distribution as

it adjusts and resides in fatty tissues [29]. Certainly, exces-

sive gestational weight gain has been previously reported

from a study comparing pregnant woman infected with T.

gondii with uninfected pregnant woman [120]. In that study,

979 mothers (mean age 30 years, range 19–44 years) were

examined, and 194 (19.2%) tested positive for T. gondii infec-

tion and 758 (80.2%) tested negative for T. gondii infection

during the 16th week of pregnancy. The study authors col-

lected data on maternal weight and other parameters before

pregnancy and at the 16th, 20th, 30th, and 36th weeks of

pregnancy. One of the main findings of the study was that

the mean maternal weight of the T. gondii-infected mothers

before pregnancy was much higher (63.6 kg) than that of the

uninfected mothers (61.5 kg). In addition, the effect of T. gon-

dii infection on weight gain was significant in the 16th week

(P=0.006) and the 20th week (P=0.049) of pregnancy and

nearly significant in the 30th week (P=0.073). Moreover, the

extra weight remained until the end of the pregnancies. In

another study, a murine pregnancy model was used to mimic

toxoplasmosis complications in humans and it was found that

dams infected with high doses of T. gondii tachyzoites had

significant excess body weight gain that led to fetal abortion

or mummified embryos [121]. Consistent with the conclusions

of the study authors, excessive weight gain during pregnancy,

especially in the first trimester, usually indicates a negative

effect of some internal (genetic or epigenetic) or external

(environmental) factor(s) [120].

Since obesity in humans is characterized by hyperleptine-

mia and a body-weight-suppressing response to exogenous

leptin [122], it is very interesting to note that the hormone

leptin has also been implicated in the T. gondii host inflamma-

tory response [29]. Using a rat model, Baltaci and Mogulkoc

[71] found that infection with T. gondii caused a significant

increase of plasma leptin concentrations (P<0.01), with no

change in body weight of the animals. They concluded that

this biomarker, similar in structure to IL-2, exerts a proinflam-

matory action in obese and diabetic individuals.

T. gondii may also influence motivation- and reward-driven

behaviors (e.g., overeating) via altered dopamine pathways.

Animal models have shown that T. gondii influences both

dopamine release and availability of the rate-limiting enzyme

in dopamine synthesis [121]. Dopamine antagonists can block

behavioral changes in T. gondii infected rats, and thus para-

site-induced host behavioral changes that may be driven by

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survival needs may have inadvertent effects on eating patterns

that promote obesity [130].

Accordingly, it can be concluded that the association

between T. gondii infection and obesity is very significant and

could alter the current views on obesity management and other

important public health issues related to obesity, especially

diabetes.

Studies describing the association between

diabetes and T. gondii infection

Only a handful of case–control epidemiological studies that

demonstrate the possible association between T. gondii infec-

tion and T2DM have been published [123, 124, 140, 141].

Most of these studies were conducted in less developed coun-

tries such as Iran, and showed an overall positive association

between T. gondii infection and T2DM (P≤0.001) (Table 2).

Gokce et al. [123] investigated the seropositivity rates

of anti-T. gondii antibodies in 807 individuals with T2DM

(351 men, 456 woman, age range 15–88 years, mean age and

standard deviation 52.8±14.01 years) in comparison with 250

healthy sex- and aged-matched controls (110 men, 140 woman,

age range 18–75 years, mean age and standard deviation

51.9±13.4 years). Using commercial IgG and IgM ELISA kits,

they found IgG antibodies more frequently in the T2DM group

(n=457, 56.6%) than in healthy, control group (n=56, 22.4%,

P<0.001). IgM antibodies were also found in 19 of the patients

with T2DM (2.4%) and only in four controls (1.6%, P=0.3).

Furthermore, a striking correlation was observed between the

duration of diabetes and T. gondii IgG seropositivity (Table 3).

In another serological study, anti-T. gondii IgG antibod-

ies were detected in 60.4% of diabetic patients (n=91) com-

pared with 37.7% of individuals in the healthy, control group

(n=93) [124]. In the same study, the risk of T. gondii infection

in diabetic patients was two-fold higher in comparison with

the healthy controls (odds ratio 2.21, 95% confidence interval

1.6–3.7, P=0.001). However, a similar study also conducted in

2013, by Siyadatpanah et al. [140], did not find a statistically

significant difference in the prevalence of T. gondii in diabetic

(52.6%) and nondiabetic (50.6%) individuals when they meas-

ured the IgG and IgM levels in a cohort of 300 individuals.

Most recently, Saki et al. [141] investigated the prevalence

of anti-T. gondii IgG and IgM antibodies in a cohort of 110 Tabl

e 2.

Des

crip

tion

of d

ata

extr

acte

d fr

om th

e ca

se–c

ontr

ol s

tudi

es d

escr

ibin

g as

soci

atio

n be

twee

n To

xopl

asm

a go

ndii

infe

ctio

n an

d ty

pe 2

dia

bete

s m

ellit

us

Ref

eren

ce

N

Age

M

atch

inga

D

efini

tion

M

easu

re o

f Tox

opla

sma

gond

ii ex

posu

re

Ser

opre

vale

nce

P

T2D

M

posi

tive

(n)

T2D

M

nega

tive

(n)

T2D

M p

ositi

ve

and

Toxo

plas

ma

gond

ii po

sitiv

e (n

) T

2DM

neg

ativ

e

and

Toxo

plas

ma

gond

ii po

sitiv

e (n

)

Saki

et a

l. [1

41]

(201

6, I

ran)

22

0

Adu

lts

No

U

nspe

cifie

d Ig

G/I

gM E

LIS

A (T

rini

ty B

iote

ch,

USA

) and

IFA

kit

(Eur

oim

mun

,

Uni

ted

Kin

gdom

)

11

0 11

0 50

(45

.4%

) 24

(21

.8%

) <0

.001

Siya

datp

anah

et a

l.

[140

] (20

13, I

ran)

30

0

Adu

lts

Uns

peci

fied

Uns

peci

fied

IgG

/IgM

EL

ISA

(V

IRO

,

Ger

man

y)

15

0 15

0 79

(52

.7%

) 76

(50

.6%

) 0.

729

Shir

bazo

u et

al.

[124

] (2

013,

Ira

n)

184

A

dults

Y

es

Uns

peci

fied

IgG

EL

ISA

(Pi

shta

z Te

b Z

aman

Dia

gnos

tics,

Ira

n)

91

93

55

(60

.4%

) 36

(38

.7%

) 0.

003

Gok

ce e

t al.

[123

]

(200

8, T

urke

y)

10

57

15–8

8 ye

ars

Yes

A

DA

Ig

G/I

gM E

LIS

A a

nd I

FAT,

imm

unofl

uore

scen

ce a

ntib

ody

test

(E

uroi

mm

un)

80

7 25

0 45

7 (5

6.6%

) 56

(22

.4%

) <0

.001

Tota

l

1761

–

–

–

–

11

58

603

641

(55.

4%)

192

(31.

8%)

<0.0

01

AD

A, A

mer

ican

Dia

bete

s A

ssoc

iatio

n; I

FA, i

mm

unofl

uore

scen

ce; I

FAT,

; T

2DM

, typ

e 2

diab

etes

mel

litus

.a M

atch

ing

is b

y ag

e an

d se

x al

one.

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diabetic pregnant woman and 110 nondiabetic controls and

found that the prevalence rate of both IgG antibody and IgM

antibody in the former group (42.7% and 2.7% respectively)

was significantly higher than in the latter group (21.8% and

0% respectively). They also examined the prevalence rate of

IgG antibody with the duration of diabetes and reported find-

ings similar to those of Gokce et al. [123] in that the preva-

lence rate of IgG antibody was directly associated with the

duration of diabetes.

An animal study has also shown a positive correlation

between both the T. gondii parasite load and the IgM antibody

titer and blood glucose levels in diabetic rats infected with

T. gondii and monitored at 15-day intervals for 60 days after

induction of diabetes and 105 days after T. gondii infection

[142]. During this period, Hassanain et al. [142] observed a sig-

nificant increase in the number of T. gondii cysts (in the brain)

and blood glucose levels in the infected diabetic group when

compared with the uninfected diabetic group. In addition, the

elevated brain parasite load and the IgM titer corresponded

to the elevated glucose levels in the infected diabetic group,

which led to the view that T. gondii infection can increase the

risk of developing diabetes [142].

Modrek et al. [143] reported a significantly high T. gondii

seroprevalence rate of 70.7% among diabetic patients in Iran

(n=205; age range 13–60 years). In addition, the difference

between the presence of toxoplasma antibodies and fasting

blood glucose levels was statistically significant (P<0.05).

While this study lacked a control group, a meta-analysis of

35 reports to determine the seroprevalence rate of T. gondii

infection in the Iranian general population reported an over-

all seroprevalence rate of 39.3% (95% confidence interval

33.0%–45.7%) [144]. This supports the suggestion of an asso-

ciation between T. gondii infection and diabetes in humans.

In addition, there is also evidence of possible indirect

associations between T. gondii infection and certain forms of

diabetes. For example, in 2015, researchers from the Czech

Republic reported significant findings from a cross-sectional

study looking at latent toxoplasma infection and the levels of

blood glucose in pregnant woman [27]. Serum samples for the

determination of T. gondii seropositivity were collected during

the 9th–12th gestational weeks from two subsets of woman

who were later screened for gestational diabetes mellitus in

the 24th–28th gestational weeks at the General University

Hospital in Prague in 2008. Pregnant women with latent toxo-

plasmosis had significantly higher (P=0.010) blood glucose

levels and a higher prevalence (19.5%) of gestational diabetes

mellitus (n=532, P=0.033) in the 24th–28th gestational weeks

than pregnant women without toxoplasmosis (healthy controls,

12%) (Table 4).

The role of T. gondii in the pathogenesis of T2DM remains

an enigma. One possible explanation could be the inflamma-

tory-mediated destruction of pancreatic β cells which leads to

the reduction in β-cell mass that ultimately contributes to the

failure of the β cell to produce enough insulin. This in turn

would increase the risk of developing acute and chronic pancre-

atitis as well as diabetes [5, 145–147]. Additionally, it is known

that T2DM is associated with an increased risk of developing

acute pancreatitis [148] and that T. gondii infection can cause

pancreatic tissue necrosis [149]. IL-18 and IL-1β are partly

responsible for the development of pancreatic inflammation,

and the neutralization of either of these cytokines decreases

inflammation [93]. Accordingly, individuals infected with T.

gondii may be at greater risk of developing diabetes than unin-

fected individuals. Certainly, insulin has been shown to have a

stimulatory effect on the in vitro replication of T. gondii [131].

Insulin and d-glucose have been shown to have a synergistic

Table 3. Relationship between the seropositivity rates of anti-Toxoplasma gondii antibodies analyzed in 807 individuals with type 2 diabetes

mellitus and duration of the disease (according to Gokce et al. [123])

Duration of T2DM (years) IgG-positive individuals (n) IgG-negative individuals (n)

0–5 39 (16.0%) 193 (83.2%)

6–10 149 (51.6%) 140 (48.4%)

>11 269 (94.1%) 17 (5.9%)

T2DM, type 2 diabetes mellitus.

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dose-responsive stimulating effect on the replication of T. gon-

dii tachyzoites in vitro [150].

Lastly, it has been argued that the simple explanation for

the relationship between T. gondii and T2DM may be that

diabetic patients are more susceptible to parasitic infections

because of the possibility of a suppressed immune system,

decreased arterial perfusion, and neuropathy [151–153].

However, there is evidence to suggest otherwise. A study

looking at parasitic infections in 200 diabetic individuals (16

with type 1 diabetes mellitus and 184 with T2DM) and 1024

nondiabetic individuals found no significant differences with

regard to the incidences of the presence of intestinal parasites

between the T2DM group and the control group (47% and

56% respectively) [154]. In light of above-mentioned reports,

there is a strong clinical and laboratory evidence to support

the notion of a genuine association between chronic latent T.

gondii infection and development of T2DM.

Desirable criteria for good-quality studies

on this topic

If the serological and inflammatory associations between T.

gondii and T2DM are further replicated, this will warrant the

need for further research to clarify whether T. gondii increases

the risk of developing T2DM, and the mechanisms that drive

this relationship, if any. Current reports are limited to associa-

tion studies, meaning that the authors are not able to determine

if there is a causal relationship between T. gondii and T2DM

or obesity, including possible reverse causality (i.e., T2DM

increasing the risk of T. gondii infection) or shared causal-

ity (i.e., common factor causing both T2DM and T. gondii

infection). In addition, studies measuring only T. gondii IgG

and IgM seropositivity cannot shed any light on the possible

inflammatory association between T2DM and T. gondii infec-

tion. Therefore future studies specifically designed to investi-

gate the role of T. gondii in T2DM using inflammation as the

main outcome are urgently needed so as to provide a more

robust link between T. gondii infection and T2DM. To this

extent, studies examining selected inflammatory biomark-

ers that are altered in the serum during and in the absence of

chronic T. gondii infection in individuals with T2DM versus

healthy controls without T2DM will be highly valuable.

Good-quality epidemiological research is warranted to

further help draw conclusions on this important subject. The

design should be a population-based case–control study with

samples representative of all age-groups matched for all pos-

sible confounding parameters. These studies should also use

standard criteria to define various parameters, especially

the diagnosis of T2DM, in addition to setting inclusion and

Table 4. Description of data highlighting the possible indirect association between latent Toxoplasma gondii infection with blood glucose levels

and gestational diabetes mellitus (according to Kankova et al. [27])

Subset 1 (n=191 pregnant women)

OGTT in the 24th–28th GW With Toxoplasma gondii Without Toxoplasma gondii P

Mean baseline BGL (mmol/L) after 8-h fast 5.04 (95% CI 4.92–5.17) 4.88 (95% CI 4.82–4.95) 0.026

Mean BGL (mmol/L) 60 min after administration of

glucose solution

7.73 (95% CI 7.09–8.37) 6.89 (95% CI 6.61–7.16) 0.007

Mean BGL (mmol/L) 120 min after administration of

glucose solution

6.43 (95% CI 6.03–6.83) 5.74 (95% CI 5.55–5.93) 0.001

0.010

Subset 2 (n=532 pregnant women)

GDM in the 24th–28th GW With Toxoplasma gondii (n) Without Toxoplasma gondii (n) P

24/123 (19.5%) 49/409 (12%) 0.033

Blood samples for Toxoplasma gondii analysis were collected in the 9th–12th gestational weeks.

BGL, Blood glucose level; CI, confidence interval; GDM, gestational diabetes mellitus; GW, gestational weeks; OGTT, oral glucose

tolerance test.

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exclusion criteria according to latest definitions of diabetes by

the World Health Organization. Lastly, individuals with psy-

chiatric conditions, including personality disorders, should

be excluded from these studies because of the association

between positive T. gondii serological findings and various

forms of serious mental illness, as previously reported [18,

21, 115].

Concluding remarks

T2DM is characterized by impaired pancreatic β-cell

function resulting in insulin resistance with an underlying

subclinical inflammation. Many reports suggest that obe-

sity and insulin resistance are associated with elevated

circulating levels of inflammatory cytokines such as IL-2,

IL-6, IL-12, IFN-γ, and TNF-α, raising the possibility that

metabolic abnormalities in diabetes may originate from or

be exacerbated by cytokine overproduction. A possible con-

tributor to this prolonged low-grade inflammation that sub-

sequently leads to the clinical expression of T2DM is the

protozoan parasite T. gondii. Cellular immunity has been

established as the key component of the host’s immune

response to infection by T. gondii. A wealth of data points

to the major role of T lymphocytes and type 1 cytokines

during murine T. gondii infection. In the clinical setting,

this has been confirmed by the emergence of T. gondii as

a major opportunistic infectious pathogen during the pro-

gression of many disorders and diseases. Thus T. gondii is

rapidly emerging as a pathogen of potential interest in obe-

sity and diabetes research. Much progress has been made

in recent years in determining how early innate responses,

namely, production of cytokines such as IL-12 and TNF-α,

drive the development of the strong Th1 response to T. gon-

dii. While this response is crucial to the control of infection,

it is becoming increasingly appreciated that an excessively

vigorous response induced by the parasite can lead to patho-

logical changes in the host. Therefore it is important for the

host and parasite to maintain tight control of the inflamma-

tory response, thereby prolonging it to the detriment of the

host. Human studies investigating inflammatory biomarkers

specifically in T2DM individuals with T. gondii infection

are urgently needed to provide a more robust link between

T. gondii infection and T2DM.

Conflict of interest

The authors declare no conflict of interest.

Funding

This work was partly supported by an Australia–China

international joint research grant (NHMRC-APP1112767-

NSFC-81561128020).

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