Rev Bras Psiquiatr.

2013;35:81–87

Revista Brasileira de Psiquiatria

Psychiatry Official Journal of the Brazilian Psychiatric Association
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SPECIAL ARTICLE

Pathophysiology of bacterial infection of the

central nervous system and its putative role in
the pathogenesis of behavioral changes
Tatiana Barichello,1 Jaqueline S. Generoso,1 Graziele Milioli,1 Samuel G. Elias,1
Antônio Lúcio Teixeira2

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DESCRIPTORS: Abstract
%DFWHULDO,QIHFWLRQ Invasion of the central nervous system (CNS) by microorganisms is a severe and frequently fatal
%HKDYLRU event during the course of many infectious diseases. It may lead to deafness, blindness, cerebral
&HQWUDO1HUYRXV6\VWHP palsy, hydrocephalus, cognitive impairment or permanent neurological dysfunction in survivors.
,QÁDPPDWLRQ Pathogens can cross the blood-brain barrier by transcellular migration, paracellular migration
0HQLQJLWLV and in infected macrophages. Pathogens may breach the blood-brain barrier and be recognized
by antigen-presenting cells through the binding of Toll-like receptors. This induces the activation
of nuclear factor kappa B or mitogen-activated protein kinase pathways and subsequently induces
OHXNRF\WH LQÀOWUDWLRQ DQG SUROLIHUDWLRQ DQG WKH H[SUHVVLRQ RI QXPHURXV SURWHLQV LQYROYHG LQ
LQÁDPPDWLRQDQGWKHLPPXQHUHVSRQVH0DQ\EUDLQFHOOVFDQSURGXFHF\WRNLQHVFKHPRNLQHV
DQG RWKHU SURLQÁDPPDWRU\ PROHFXOHV LQ UHVSRQVH WR EDFWHULD VWLPXOL DV D FRQVHTXHQFH
SRO\PRUSKRQXFOHDUFHOOVDUHDWWUDFWHGDQGDFWLYDWHGDQGUHOHDVHODUJHDPRXQWVRIVXSHUR[LGH
DQLRQDQGQLWULFR[LGHOHDGLQJWRSHUR[\QLWULWHIRUPDWLRQDQGR[LGDWLYHVWUHVV7KLVFDVFDGHOHDGVWR
OLSLG SHUR[LGDWLRQ PLWRFKRQGULDO GDPDJH DQG EORRGEUDLQ EDUULHU EUHDNGRZQ FRQWULEXWLQJ
to cellular injury during neuronal infection. Current evidence suggests that bacterial CNS infections
FDQSOD\DUROHLQWKHHWLRSDWKRJHQHVLVRIEHKDYLRUDOGLVRUGHUVE\LQFUHDVLQJSURLQÁDPPDWRU\
cytokines and bacterial virulence factors. The aim of this review is to summarize the current
knowledge of the relevant pathophysiologic steps in CNS infections.
© 2013 Associação Brasileira de Psiquiatria. Published by Elsevier Editora Ltda. All rights reserved.

&RUUHVSRQGLQJDXWKRU3URI7DWLDQD%DULFKHOOR3K'/DERUDWyULRGH0LFURELRORJLD([SHULPHQWDO33*&6
8QLYHUVLGDGHGR([WUHPR6XO&DWDULQHQVH&ULFL~PD6&%UD]LO)D[(PDLOWED#XQHVFQHW
© 2013 Associação
1516-4446 Brasileira de
- © 2013 Associação Psiquiatria.
Brasileira PublishedPublished
de Psiquiatria. by Elsevier
by Editora
Elsevier Ltda. AllLtda.
Editora rights
Allreserved.
rights reserved.
doi: 10.1016/j.rbp.2012.11.003
82 T. Barichello et al.

Introduction
Bacterial infection of the central nervous system (CNS) is a
life-threatening condition with a high rate of mortality. Even
with protective barriers, pathogens can reach the CNS.1 The
replication of these microorganisms within the CNS occurs in
association with the release of compounds such as peptido-
JO\FDQVFHOOZDOOIUDJPHQWVOLSRWHLFKRLFDFLGVIURP*UDP
positive bacteria)2OLSRSRO\VDFFKDULGHVIURP*UDPQHJDWLYH
ZLWKLQWKH&16FEDFWHULDOLQGXFWLRQRI&16LQÁDPPDWLRQ
and (d) the role of bacterial infection in the development of
behavioral disorders.
Microbial traversal of the blood-brain barrier
The CNS is protected by a bony skull, the leptomeninges, the
blood-brain barrier (BBB) and the blood-cerebrospinal
ÁXLGEDUULHU1 The BBB is composed of brain microvascular
endothelial cells, astrocytes and pericytes. It maintains
EDFWHULDDQGH[RWR[LQVZKLFKDUHKLJKO\LPPXQRJHQLFDQG
PD\HOLFLWDQLQFUHDVHGLQÁDPPDWRU\UHVSRQVHLQWKHKRVW
7KHKRVW·VLQÁDPPDWRU\UHVSRQVHDJDLQVWWKHLQIHFWLRQKDV
been increasingly recognized as playing a central role in
neurological morbidity and mortality. CNS infections may
present clinically as meningitis, meningoencephalitis and,
more rarely, myelitis.
Cognitive outcomes after bacterial meningitis include
impairment of memory, decreased psychomotor performance
DQGLPSDLUPHQWRIDWWHQWLRQH[HFXWLYHIXQFWLRQV6 In neona-
tal meningitis, the main pathogens are Streptococcus agalac-
tiae and Escherichia coli K1, which together are responsible
for at least two thirds of all meningitis deaths in Europe.
Listeria monocytogenes, also causes meningitis, usually in
WKH QHXUDO PLFURHQYLURQPHQW E\ UHJXODWLQJ WKH IOX[ RI
molecules into and out of the brain, and protects the brain
IURPPLFURRUJDQLVPVDQGWR[LQVWKDWFRPHIURPWKHEORRG3
Pathogens can cross the BBB by transcellular migration, para-
cellular migration and by “hitch-hiking” inside infected
PDFURSKDJHV8VLQJWUDQVFHOOXODUPLJUDWLRQSDWKRJHQVFDQ
cross the BBB without any evidence of intercellular tight-
junction disruption or detection of microorganisms between
endothelial cells.16 S. agalactiae, S. pneumoniae, E. coli
and N. meningitidis reach the CNS through this mechanism3
()LJXUe 1a). The paracellular traversal mechanism involves
the penetration of the pathogen between barrier cells, with
or without evidence of tight-junction disruption. Borrelia sp
and Treponema pallidum cross the BBB through this mecha-
immunocompromised individuals and in pregnant women.10
E. coli. LQIHFWLRQ LQFOXGHV FRJQLWLYH LQYROYHPHQW LQ 
of patients.11 The main bacterial agents causing meningitis
in young children and adults are Streptococcus pneumoniae
and Neisseria meningitidis, with the former being responsible
IRUWZRWKLUGVRIFDVHVLQ(XURSHDQGWKH8QLWHG6WDWHV
QLVP)LJXUHE2WKHUSDWKRJHQVFDQFURVVWKH%%%LQVLGH
infected macrophages. L. monocytogenes enters host cells
during internalization of phagosomal vacuoles, and produces
phospholipase C and the pore-forming cytolysin listeriolysin O
to escape the phagosome and replicate within the host cyto-
sol. Mycobacterium tuberculosis also crosses the BBB while
Pneumococcal meningitis leads to cognitive impairment in
WRRIVXUYLYLQJSDWLHQWV2LQFOXGLQJOHDUQLQJGLIÀFXO-
WLHV FRJQLWLYH VORZQHVV VKRUWWHUP PHPRU\ GHÀFLWV DQG
poor academic performance. The aim of this review is to
summarize the current knowledge of the relevant pathophysi-
ologic steps of CNS infections: (a) bacterial crossing through
residing in the phagosomes of macrophages)LJXUHF
Mechanisms of innate immunity in the CNS
The innate immune response represents the first line
of defense against invading microorganisms. Bacterial
compounds such as peptidoglycans, cell wall fragments,
WKH EORRGEUDLQ EDUULHU E EDFWHULDO VXUYLYDO DQG JURZWK lipopolysaccharides and lipoteichoic acid, collectively known

Figure 10HFKDQLVPVRIPLFURELDOWUDYHUVDORIWKHEORRGEUDLQEDUULHUD7UDQVFHOOXODUWUDYHUVDOE3DUDFHOOXODUWUDYHUVDODQG
c. the “Trojan horse” mechanism.
Pathophysiology of bacterial infection 83

DVSDWKRJHQDVVRFLDWHGPROHFXODUSDWWHUQV3$03VDUHKLJKO\ second signal that is provided by intracellular protein com-
LPPXQRJHQLFDQGHOLFLWVWURQJLQÁDPPDWRU\UHVSRQVHVLQWKH SOH[HVNQRZQDVLQÁDPPDVRPHV7KH1/53FU\RS\ULQDQG
host. These compounds are recognized by antigen-presenting
cells through binding to pattern recognition receptors (PRRs),
including the Toll-like receptors (TLRs). Eleven members of
the TLR family have been described to date in humans. TLRs
DUH HLWKHU H[SUHVVHG DW WKH FHOO VXUIDFH IRU H[WUDFHOOXODU
ligand recognition or localized to endosomal compartments
for the recognition of pathogen-associated nucleic acids. 7KXVZKHQEDFWHULDUHDFKWKH&163$03VDUHUHFRJQL]HGE\
0LFURJOLDOFHOOVH[SUHVVDOO7/5VLGHQWLÀHGWRGDWHDVWURF\WHV
H[SUHVV7/5DQGQHXURQVH[SUHVV7/5DQGDQG
ROLJRGHQGURF\WHVH[SUHVV7/5DQG0RVW7/5VWUDQVGXFH
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in pneumococcal infection, respectively, mediate cleavage
RISUR,/şLQWRPDWXUH,/ş26 NLRP3 has been implicated
in responses to the following bacteria: Staphylococcus au-
reus, L. monocytogenes, Klebsiella pneumoniae and E. coli.
PRRs, initiating the activation of the host immune response,
ZKLFKWULJJHUVWKHSURGXFWLRQRISURLQÁDPPDWRU\F\WRNLQHV
DQGFKHPRNLQHVDQGWKHH[SUHVVLRQRIFRVWLPXODWRU\PRO-
their signal through a common intracellular adapter protein ecules1)LJXUH,QUHVSRQVHWRWKHVHVWLPXOLOHXNRF\WHV
NQRZQDVP\HORLGGLIIHUHQWLDWLRQIDFWRU0\'200\' DUHDWWUDFWHGIURPWKHEORRGDQGDFWLYDWHG)RULQVWDQFH
is associated with Interleukin-1 (IL-1) and receptor-associated polymorphonuclear leukocytes cross the BBB by binding to
NLQDVH ,5$. ZKLFK LVD VHULQHWKUHRQLQH NLQDVH WKDW VHOHFWLQV ( DQG 3 DORQJ ZLWK ,/ &;&/71)Ş LQGXFHV
plays an essential role in signal transduction by Toll/IL-1 SURGXFWLRQRIDGKHVLRQPROHFXOHV,&$0DQG,&$0ZKLFK
receptors (TIRs).21 Subsequently, IRAK interacts with the tu- DOORZH[WUDYDVDWLRQRIWKHOHXNRF\WHDORQJFKHPRDWWUDFWDQW
PRUQHFURVLVIDFWRU71)UHFHSWRUDVVRFLDWHGIDFWRU75$) concentration gradients. Leukocytes work to eliminate the
IDPLO\SURYLGLQJDOLQNWR1)ŧ%LQGXFLQJNLQDVHUHVXOWLQJ invading pathogen through a rapid and robust production
LQ WKH QXFOHDU WUDQVORFDWLRQ RI 1)ŧ%22 1)ŧ% FRPSULVHV RIUHDFWLYHR[\JHQVSHFLHV5267KH\UHOHDVHKLJKDPRXQWVRI
a closely associated family of transcription factors, which VXSHUR[LGH DQLRQ 22 DQG QLWULF R[LGH 12 JHQHUDWLQJ
SOD\DNH\UROHLQWKHH[SUHVVLRQRIJHQHVLPSOLFDWHGLQWKH
development of accessory cell and lymphocyte populations.23
1)ŧ% LV DOVR D WUDQVFULSWLRQDO DFWLYDWRU RI YDULRXV JHQHV
involved in neuronal pathogenesis and in the production of
cytokines and chemokines. ,/ş SURGXFWLRQ UHTXLUHV D
SHUR[\QLWULWH 2122 7KH UHVXOWLQJ R[LGDWLYH VWUHVV
leads to activation of cytokines, enhancing leukocyte activa-
WLRQOLSLGSHUR[LGDWLRQPLWRFKRQGULDOGDPDJHDQGPHWDO-
loproteinase activation. In humans with meningococcal
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Figure 2 Pathogenesis and pathophysiology of bacterial CNS infections. The majority of TLRs utilize a common intracellular adapter
SURWHLQNQRZQDVP\HORLGGLIIHUHQWLDWLRQIDFWRU0\'ZKLFKDFWLYDWHV,5$.6XEVHTXHQWO\1)ŧ%LVDFWLYDWHGDQGLQGXFHVWKHSUR-
GXFWLRQRIF\WRNLQHVDQGFKHPRNLQHV%DFWHULDOWR[LQVLQFUHDVHUHDFWLYHR[\JHQVSHFLHVUHVXOWLQJLQPLWRFKRQGULDOG\VIXQFWLRQWKDWOHDGV
WRWKHUHOHDVHRIDSRSWRVLVLQGXFLQJIDFWRUVLQWRWKHF\WRVRO7KHKRVWLPPXQHUHVSRQVHLQLWLDWHGE\ZKLWHEORRGFHOOVDFWLYDWHVSDQG
$70ZKLFKFRQYHUJHRQWKHPLWRFKRQGULDWRLQLWLDWHWKHUHOHDVHRIF\WRFKURPHF7KLVUHOHDVHDFWLYDWHVWKHDSRSWRVRPHFRPSRVHGRI
$SDIWKDWDFWLYHFDVSDVHÀQDOO\UHVXOWLQJLQWKHDFWLYDWLRQRIFDVSDVH$70DWD[LDWHODQJLHFWDVLDPXWDWHG7/5WROOOLNHUHFHS-
WRU,5$.UHFHSWRUDVVRFLDWHGNLQDVH
84
fatal outcomes.3171)ŞLVUHOHDVHGLQWRVHUXPEHIRUH,/
in meningococcal septic shock. High serum levels of
IL-6 are also associated with unfavorable outcomes. In ad-
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KDG KLJK VHUXP OHYHOV RI ,/ 71)Ş /36 DQG UDSLG IDWDO
outcomes.32+RZHYHULQWKH&6)RISDWLHQWVZLWKPHQLQJLWLV
KLJKHUFRQFHQWUDWLRQVRI71)ŞZHUHREVHUYHGWKDQSDWLHQWV
ZLWKVHSWLFVKRFNEDFWHUHPLDDQGWKH&6)EORRGJOXFRVHZDV
LQYHUVHO\FRUUHODWHGZLWK71)Ş,/DQG,/33 Patients with
SQHXPRFRFFDOPHQLQJLWLVDOVRH[KLELWDFHUHEUDOSURGXFWLRQ
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Neuronal damage in the context of bacterial
infection of the CNS
Brain injury and neuronal death are not mediated simply by
the presence of a viable pathogen, but they also occur as a
consequence of the host’s reaction to bacterial compounds.
Bacterial cell wall compounds, mainly polysaccharide cap-
sules, are most likely the most important virulence factor.
%DFWHULDOFHOOZDOOFRPSRXQGVWULJJHUDKRVWLQÁDPPDWRU\
response from leukocytes and activate the tumor suppressor
T. Barichello et al.
and TLR6.7KHSURWHLQÁDJHOOLQLVUHFRJQL]HGE\7/5
L. monocytogenesLVDFODVVLFH[DPSOHRIDF\WRVRODGDSWHG
pathogen. It can escape quickly from the phagosomes of
macrophages (or other cell types) and it reproduces rapidly
in the cytosol.7KLVPLFURRUJDQLVPDOVRH[SUHVVHVWKHWR[LQ
listeriolysin O, which is responsible for forming pores in the
cell and causing lymphocyte apoptosis. E. coli produces the
HQGRWR[LQOLSRSRO\VDFFKDULGHZKLFKLVUHFRJQL]HGE\7/5
)XUWKHUPRUHE. coli damages the microvascular endothelial
cells that constitute the BBB in the human brain. Another
important pathogen, S. pyogenes, produces bacterial viru-
OHQFHIDFWRUVVXFKDV0SURWHLQK\DOXURQLFDFLGFDSVXOH
ÀEURQHFWLQELQGLQJSURWHLQVVWUHSWRO\VLQ2DQGVWUHSWRO\VLQ
67KH0SURWHLQELQGVWRFRPSOHPHQWIDFWRUVDQGRWKHUKRVW
proteins, allowing the pathogen to avoid activation of the
alternate complement pathway evade phagocytosis. 
7KH0SURWHLQKDVDOVREHHQLPSOLFDWHGLQWKHLQWHUQDOL]D-
tion process, which involves cytoskeletal rearrangements.
It is possible that these proteins provide an intraepithelial
refuge for the organism, sheltered from phagocytes and
humoral antibodies. Another intracellular bacterium,
Mycobacterium tuberculosis, infects the CNS and causes
different manifestations of disease, like meningitis, space-
SURWHLQ S DQG WKH DWD[LD WHODQJLHFWDVLDPXWDWHG $70
occupying lesions in the brain parenchyma, and focal disease
kinase, triggering caspase dependent-apoptosis.36 The pres-
of the spinal cord and its osseous structures. In previous
ence of the capsule also prevents the binding of iC3b (a
studies of S. agalactiae meningitisR[LGDWLYHGDPDJHZDV
FRPSOHPHQW IDFWRU WKDW VWLPXODWHV SKDJRF\WRVLV DQG )F
elevated and enzymatic defense was decreased. 71)Ş
(which stimulates receptor-mediated phagocytose) to the
,/ş ,/ DQG F\WRNLQHLQGXFHG QHXWURSKLO FKHPRDWWUDF-
bacterial cell surface, affecting antiphagocytic activity.
WDQW&,1&OHYHOVZHUHLQFUHDVHGLQWKHÀUVWKRXUVDIWHU
Pathogens such as S. pneumoniae, N. meningitidis, E. coli
neonatal meningitis induction, prior to BBB breakdown in the
K1 and +LQÁXHQ]DH use this pathogenic mechanism.
KLSSRFDPSXVDQGFRUWH[ In infant rats with pneumococ-
The virulence of other bacteria is based on the produc-
FDOPHQLQJLWLVWKHSHDNRISURLQÁDPPDWRU\F\WRNLQHDQG
tion of enzymes such as coagulase, proteolytic enzymes,
chemokine production was also associated with a disrup-
hyaluronidase, neuraminidase and catalase. Hemolysin
tion of the BBB.6071)ŞDQG&,1&OHYHOVZHUHLQFUHDVHG
and cytolysin from Streptococcus have the ability to cause
in the blood from jugular veins in comparison with arterial
LQÁDPPDWRU\DFWLYDWLRQDQGWKHVHVDPHHQ]\PHVSURGXFHG
EORRG LQ WKH ÀUVW KRXUV DIWHU SQHXPRFRFFDO PHQLQJLWLV
by S. agalactiae LQGXFH FKHPRNLQHV DQG ,&$0 LQ EUDLQ
induction, indicating their production in the CNS.610RUHRYHU
microvascular endothelium cells.36 Teichoic acids present in
animals that survived bacterial meningitis showed impair-
*UDPEDFWHULDFDQLQGXFH71)ŞDQG12SURGXFWLRQDVZHOO
ments of memory and learning, depressive-like-behavior and
DVWKHH[SUHVVLRQRI,&$0([RWR[LQVDUHDOVRSURGXFHG
DQ[LHW\OLNHV\PSWRPV
by some bacteria as part of their growth and metabolism,
ZKLOHHQGRWR[LQVDUHSDUWRIWKHH[WHUQDOSRUWLRQRI*UDP Behavioral disorders
(-) bacteria. S. pneumoniae bacterial compounds like pep-
tidoglycans and lipoteichoic acids are recognized in the CNS Neuronal infection causes intense an inflammatory host
by TLR2.7KHH[RWR[LQSQHXPRO\VLQLVUHFRJQL]HGE\7/522 LPPXQH UHVSRQVH LW LV SRWHQWLDOO\ IDWDO DQG FRQWULEXWHV WR
DQGEDFWHULDO'1$LVUHFRJQL]HGE\7/5ZKLFKLVDQLQWUD- neurological symptoms.1 There are several studies describing
FHOOXODU353DFWLYDWHGE\&S* Pneumolysin and H2O2 are DSUREDEOHUROHRIF\WRNLQHVDQGR[LGDWLYHVWUHVVLQEHKDYLRUDO
produced and released by pneumococcus, causing neuronal disorders. Epidemiological research over the last twenty
cell death through mitochondrial damage. This damage years has indicated that the risk for schizophrenia is enhanced
OHDGVWRWKHUHOHDVHRIDSRSWRVLVLQGXFLQJIDFWRU$,)LQWR
WKHF\WRVRO$,)LQGXFHVDSRSWRVLVE\DFDVSDVHLQGHSHQGHQW
pathway. When pneumococcal cell wall compounds are
released, they activate the host immune response and a
ODUJHQXPEHURISRO\PRUSKRQXFOHDUFHOOVDUHDWWUDFWHGS
DQG$70FRQYHUJHRQPLWRFKRQGULDWRLQLWLDWHWKHUHOHDVHRI
cytocrome-c, which is necessary to form the apoptosome
LQRIIVSULQJH[SRVHGWRYLUDORUEDFWHULDOLQIHFWLRQVLQXWHUR
possibly by a disruption in the programmed maturation of the
brain in prenatal and early neonatal life. This association
EHWZHHQ SUHQDWDO H[SRVXUH WR EDFWHULDO LQIHFWLRQ DQG ULVN
RI VFKL]RSKUHQLD ZDV HYDOXDWHG IRU H[DPSOH LQ WKH
Copenhagen Perinatal Cohort, which showed that prenatal
H[SRVXUH WR EDFWHULDO LQIHFWLRQV LQ SUHJQDQW ZRPHQ ZHUH
$SDI DQG DFWLYDWH FDVSDVH UHVXOWLQJ LQ DFWLYDWLRQ RI
caspase-3 and caspase-dependent apoptosis.36 S. agalactiae
produces lipoteichoic acid that is through to activate TLR2,
ZKLOH 7/5 DQGRU 7/5 LQWHUDFW ZLWK PLFURELDO 51$2 In
vitro, L. monocytogenes cell wall components such as lipo-
WHLFKRLFDFLGVDUHUHFRJQL]HGE\7/5ZLWKWKHKHOSRI&'
correlated with an increased risk of schizophrenia in their
offspring. It has been proposed that this association might
be mediated through transplacental passage of maternally
produced cytokines in response to these bacterial infec-
tions. Individuals with meningitis during childhood had a
IROG LQFUHDVHG ULVN IRU VFKL]RSKUHQLD DQG D IROG
Pathophysiology of bacterial infection 85

increased risk for psychosis in adulthood when compared Disclosures

to their siblings without childhood meningitis. The im-
Tatiana Barichello
mune system may signal the CNS through the action of
Employment: Laboratório de Microbiologia Experimental e Instituto
cytokines, which have also been implicated in the develop- Nacional de Ciência e Tecnologia Translacional em Medicina, Programa
PHQW RI VFKL]RSKUHQLD )RU LQVWDQFH ,/ş LV FDSDEOH RI de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul
inducing the differentiation of mesencephalic progenitor &DWDULQHQVH&ULFL~PD6&%UD]LO
Jaqueline S. Generoso
cells into dopaminergic neurons. IL-6 is highly effec-
Employment: Laboratório de Microbiologia Experimental e Instituto
tive in decreasing the survival of fetal brain serotonergic Nacional de Ciência e Tecnologia Translacional em Medicina, Programa
neurons and is increased in patients with schizophrenia. de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul
7KHUHZDVDVLJQLÀFDQWDVVRFLDWLRQEHWZHHQPDWHUQDO,/ &DWDULQHQVH&ULFL~PD6&%UD]LO
Graziele Milioli
levels during the second trimester of pregnancy and the Employment: Laboratório de Microbiologia Experimental e Instituto
risk of schizophrenia in the offspring. Cytokines in the Nacional de Ciência e Tecnologia Translacional em Medicina, Programa
CNS are also implicated to depressive disorders. Animals de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul
subjected to pneumococcal meningitis and sepsis models &DWDULQHQVH&ULFL~PD6&%UD]LO
Samuel G. Elias
had increased levels of pro-inflammatory cytokines in Employment: Laboratório de Microbiologia Experimental e Instituto
parallel with depressive-like behavior. Interestingly, Nacional de Ciência e Tecnologia Translacional em Medicina, Programa
treatment with imipramine reversed these depressive-like de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul
V\PSWRPVDQGGHFUHDVHG71)ŞOHYHOVLQWKHFRUWH[GD\V &DWDULQHQVH&ULFL~PD6&%UD]LO
Antônio Lúcio Teixeira
after pneumococcal meningitis induction.  Impairment Employment: Laboratório Interdisciplinar de Investigação Médica,
of learning and memory has also been demonstrated in Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo
bacterial meningitis in a neonatal animal model. Neonatal +RUL]RQWH0*%UD]LO
* Modest
Wistar rats subjected to S. agalactiae meningitis showed


6LJQLÀFDQW
aversive memory impairment in adulthood and a decrease


6LJQLÀFDQW$PRXQWVJLYHQWRWKHDXWKRU
VLQVWLWXWLRQRUWRDFROOHDJXHIRU
RI WKH EUDLQGHULYHG QHXURWURSKLF IDFWRU %'1) OHYHOV LQ
WKHKLSSRFDPSXVDQGFRUWH[)XUWKHUPRUHWKHGHFUHDVHG
%'1)OHYHOVLQWKHKLSSRFDPSXVZHUHFRUUHODWHGZLWKPHPRU\
impairment in adult animals subjected to pneumococ-
cal meningitis in the neonatal period. Other neuronal
disorders are also related to bacterial infection. Obsessive-
FRPSXOVLYH GLVRUGHU RU ´WLFµ GLVRUGHUV DUH H[DPSOHV RI
pediatric neuropsychiatric disorders that have been associ-
ated with autoimmune disease secondary to S. pyogenes,
D JURXS $ şKHPRO\WLF VWUHSWRFRFFDO LQIHFWLRQ The
involvement of the host immune response is suggested by
TXDQWLWDWLYH FKDQJHV LQ FLUFXODWLQJ OHYHOV RI 71)Ş ,/ş
and IL-6 levels in these patients. Pathogenic mechanisms
include antibodies targeting the streptococcal epitope
*OF1$F FURVVUHDFWLQJ ZLWK QHXURQDO PROHFXOHV OLNH WXEX-
lin, lysoganglioside and dopamine receptors. Cytokines
have an important role in the pathophysiology of brain
infections, and they are implicated in a variety of common
diseases that have been associated with production of cyto-
kines, such as psychiatric disorders.
Conclusion
8QGHUVWDQGLQJWKHLQWHUDFWLRQVEHWZHHQWKHFRPSOH[QHW-
ZRUNVRIF\WRNLQHVRWKHULQÁDPPDWRU\PHGLDWRUVDQGOHXNR-
cytes, and bacterial virulence factors may help to establish
more effective therapeutic strategies for CNS infections and,
WKHUHIRUHDEHWWHURXWFRPHIRUDIIHFWHGVXEMHFWV0RUHRYHU
these diseases highlight the role of the immune system in the
pathophysiology of psychiatric disorders, which represents
an interesting research venue.
Acknowledgments
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)$3(0,*81(6&1(1$6&SURMHFW3521(;SURJUDP&13T
research in which the author has participation, not directly to the author.
References
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