AUTREV-01859; No of Pages 8
Autoimmunity Reviews xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Autoimmunity Reviews
journal homepage: www.elsevier.com/locate/autrev
Review
Zika virus and autoimmunity: From microcephaly to Guillain-Barré
syndrome, and beyond
Guglielmo Lucchese a, Darja Kanduc b,⁎
a
b
Brain and Language Laboratory, Freie Universität Berlin, 14195 Berlin, Germany
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy
a r t i c l e
i n f o
Article history:
Received 11 March 2016
Accepted 18 March 2016
Available online xxxx
Keywords:
Zika virus infection
Microcephaly
Centriolar and centrosomal proteins
Ocular anomalies
Brain calcification
Aicardi-Goutieres syndromes
Guillain-Barré-like syndromes
Peptide sharing
Crossreactivity
Autoimmunity
a b s t r a c t
Zika virus (ZIKV) infection during pregnancy may be linked to fetal neurological complications that include brain
damage and microcephaly. How the viral infection relates to fetal brain malformations is unknown. This study
analyzes ZIKV polyprotein for peptide sharing with human proteins that, when altered, associate with microcephaly and brain calcifications. Results highlight a vast viral versus human peptide commonality that, in particular, involves centriolar and centrosomal components canonically cataloged as microcephaly proteins,
i.e., C2CD3, CASC5, CP131, GCP4, KIF2A, STIL, and TBG. Likewise, a search for ZIKV peptide occurrences in
human proteins linked to Guillain-Barré-like syndromes also show a high, unexpected level of peptide sharing.
Of note, further analyses using the Immune Epitope DataBase (IEDB) resource show that many of the shared peptides are endowed with immunological potential. The data indicate that immune reactions following ZIKV infection might be a considerable source of crossreactions with brain-specific proteins and might contribute to the
ZIKV-associated neuropathologic sequelae.
© 2016 Elsevier B.V. All rights reserved.
Contents
1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.
Peptide sharing between ZIKV polyprotein and human proteins related to microcephaly . . . . . . . . . . . . . . . . .
3.
Peptide sharing between ZIKV polyprotein and human proteins related to altered brain calcification . . . . . . . . . . . .
4.
Peptide sharing between ZIKV polyprotein and human proteins related to myelin, (de)myelination, and axonal neuropathies
5.
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgemnts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Appendix A.
Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
In the context of emerging and re-emerging infectious diseases,
scientific and clinical attention was called recently [1–4] to ZIKV
infection. In particular, investigating the molecular determinants and
⁎ Corresponding author. E-Mails: [email protected] [email protected] Tel.:
+39-080-544-3321; Fax: +39-080-544-3317.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0
0
0
0
0
0
0
0
0
0
mechanisms that might relate acute ZIKV infection to fetal brain damage, i.e., microcephaly [2–4] appears of foremost importance for understanding ZIKV pathogenicity as well as for developing preventive/
therapeutic approaches.
Focusing on the ZIKV-induced immune responses as a possible link
to the viral pathologic sequela, this study analyzed the peptide sharing
between ZIKV polyprotein and human proteins associated with microcephaly, and used the Immune Epitope DataBase (IEDB) [5] to investigate the immunological potential of the shared peptides. The
http://dx.doi.org/10.1016/j.autrev.2016.03.020
1568-9972/© 2016 Elsevier B.V. All rights reserved.
Please cite this article as: Lucchese G, Kanduc D, Zika virus and autoimmunity: From microcephaly to Guillain-Barré syndrome, and beyond,
Autoimmun Rev (2016), http://dx.doi.org/10.1016/j.autrev.2016.03.020
2
G. Lucchese, D. Kanduc / Autoimmunity Reviews xxx (2016) xxx–xxx
underlying rationale is that common peptides between a pathogen and
the human host may lead to autoimmune pathologies through
crossreactivity phenomena following pathogen infection [6–8].
The results described here (i) document a relevant penta- and
hexapeptide sharing between ZIKV polyprotein and human proteins
that, when altered, are specifically associated with microcephaly, brain
calcifications, and Guillain-Barré-like syndromes, and (ii) support immune crossreactivity as a mechanism involved in the pathologies that
may associate with ZIKV active infection.
2. Peptide sharing between ZIKV polyprotein and human proteins
related to microcephaly
Penta- and hexapeptides were used as sequence probes based on the
fact that a peptide grouping formed by five-six amino acid (aa) residues
can induce highly specific antibodies, and that antigen–antibody
specific interaction may depend on just five-six aa of an antigenic
protein [9,10, and pertinent references therein].
Analyses were carried out on ZIKV polyprotein, 3419 aa, NCBI Ref Sequence: NC_012532.1 [11]. Peptide sharing between ZIKV polyprotein
and human microcephaly-related proteins was analyzed as follows.
A viral pentapeptide library was constructed by dissecting ZIKV
polyprotein primary sequence into pentapeptides offset by one residue
each other (that is, MKNPK, KNPKE, NPKEE, PKEEI, and so forth). Next,
each viral pentapeptide was analyzed for matches within a library
consisting of sequences of human proteins related to microcephaly.
The same procedure was applied when hexapeptides were used as
probes.
The microcephaly protein library was constructed at random by
using UniProtKB Database (www.uniprot.org/) [12] utilizing ‘microcephaly’ as a key word. The key word-guided search produced 199
human protein entries that directly or indirectly relate to the word ‘microcephaly’. Description of the 199 microcephaly-related proteins is
given in Supplementary Table 1. Any viral occurrence in the set of microcephaly protein library was termed a match. Microcephaly proteins
are reported as UniProtKB/Swiss-Prot entry names throughout the
paper, unless when discussed in detail. As a control, a set of proteins associated with Down syndrome, a genetic disease that has no links with
infectious agents and may present microcephaly as a phenotypic feature
[13], was used. Description of the human proteins associated with
Down syndrome is given in Supplementary Table 2.
Table 1 shows the viral versus human peptide overlap at the
hexapeptide level. It can be seen that 26 hexapeptides are shared
between the ZIKV polyprotein and 21 human microcephaly-related
proteins. No hexapeptide match was found in the comparison set of
proteins associated with Down syndrome.
Preliminarily, we observe that the level of peptide sharing shown in
Table 1 is high and mathematically unexpected, since the theoretical
probability of a sequence of 6 aa occurring at random in two proteins
is equal to 20−6, i.e., 1 in 64,000,000, if the number of protein
hexapeptides is ≪64,000,000 and assuming that all aa occur with the
same frequency.
From a functional point of view, the human proteins that host ZIKV
hexapeptides play crucial roles during neurodevelopment. De facto,
microcephaly and additional neurological and/or psychiatric disorders
may occur, following alterations of, for example:
• ACSF3 (acyl-CoA synthetase family member 3, mitochondrial) that is
fundamental in brain development and metabolism [14];
• CDKL5, a kinase that mediates phosphorylation of MECP2, a protein
that is involved in Rett syndrome [15];
• DCPS, a phosphatase decapping enzyme that can modulate pre-mRNA
splicing, and EDC, that enhances mRNA-decapping protein 3. DCPS
and EDC are involved in embryonic neurogenesis [16];
• the histone acetyltransferase KAT6B, which is crucial for neural
craniofacial and skeletal morphogenesis [17];
• PCL, a presynaptic protein that underlies pontocerebellar hypoplasia
type III [18];
• POMT1 that is involved in protein O-mannosylation. Defect of protein
O-mannosylation may cause failure of neuronal migration in developing brain [19,20];
• PQBP1 that plays a role in transcription and alternative splicing associated with neurite outgrowth. PQBP1 is highly expressed in the CNS
of embryonic or newborn rodents, with the peak around birth
[21–24];
• SEN54, a tRNA splicing enzyme that causes pontocerebellar hypoplasia [25];
• SERA (D-3-phosphoglycerate dehydrogenase), which is preferentially
expressed in the radial glia/astrocyte lineage and olfactory
ensheathing glia [26,27];
• the transcription factor SOX11 that is implicated in the embryonic
neurogenesis and in tissue modeling during development [28], as
well as in the differentiation of granule cells to granule neurons [29].
Moreover, inspection of Table 1 reveals that five human proteins
sharing peptides with ZIKV are also involved, when altered, in ocular
anomalies such as microphthalmia, poor vision, nystagmus, retinal
folding, retinal detachment, optic nerve hypoplasia, absence of retinal
vessels, round areas of chorioretinal atrophy (GCP4) [30], optic atrophy
(PCLO) [18], eye malformations, cystic retinal coloboma, cataract and
anterior chamber synechia (POMT1) [19,20], microphtalmia and ocular
colobomas (PQBP1) [23], and pediatric eye disorders (SOX11) [31,32].
These data appear of relevance in light of the reported association
between ZIKV infection and ocular anomalies [33,34].
Most impressingly in the context of the present study, we find that 7
out of the 21 human proteins listed in Table 1, i.e., C2CD3, CASC5, CP131,
GCP4, KIF2A, STIL, and TBG, are cataloged as microcephalic proteins in
the scientific literature. These proteins play fundamental roles in mitotic
spindle assembly and/or centriole biogenesis, and crucially participate
to the still unclear network of complex cellular processes involved in
brain growth [35–40]. Of note, using the keyword ‘microcephaly’ as a
search criterion underrates the effective number of the proteins that affect brain dimensions. Indeed, pericentriolar material 1 protein (PCM1)
is not cataloged as a microcephalic protein, but, if altered, is associated
with orbitofrontal gray matter volumetric deficits [41]. PCM1 shares
one hexapeptide (SCLLQT) and four pentapeptides (EETPV, ESSSS,
KMDKL, and SSSSP) with ZIKV.
In addition, as said above, a pentapeptide can represent a minimal
immune determinant [9,10]. Hence, a thorough investigation of the
ZIKV versus human peptide overlap at the 5-mer level highlights
additional specific matches that might be of pathological importance
in the ZIKV infection–microcephaly immune connection. As few
examples among the many we report that
• three ZIKV pentapeptide matches (EEALR, GSVKN, and SLIYT) are
found in microcephalin (MCPH1), a protein implicated in chromosome condensation, neurogenesis and regulation of the size of the
cerebral cortex [42], and
• eight ZIKV pentapeptide matches (AAQKR, AIFEE, GLLGL, KVRKD,
ILEEN, LGLLG, LTAVR, and STTAS) are shared with abnormal spindlelike microcephaly-associated protein (ASPM), which is a major
determinant of cerebral cortical size [43].
On the whole, Table 1 supports the possibility that crossreactions
between ZIKV and the human host may occur following immune
responses induced by ZIKV infection. The hypothesis of crossreactivity
as a main causal link between ZIKV and microcephaly receives further
support from the analysis of the immunologic potential of the peptide
sequences listed in Table 1. Indeed, a search through the IEDB resource
highlights that many of the shared hexapeptides listed in Table 1
(i.e., LAGASL, SSTATS, AAEMEE, ALAGAL, LLGLLG, EALGTL, and GCGRGG)
are part of immunopositive epitopes that have been experimentally
validated in humans (Table 2).
Please cite this article as: Lucchese G, Kanduc D, Zika virus and autoimmunity: From microcephaly to Guillain-Barré syndrome, and beyond,
Autoimmun Rev (2016), http://dx.doi.org/10.1016/j.autrev.2016.03.020
G. Lucchese, D. Kanduc / Autoimmunity Reviews xxx (2016) xxx–xxx
3
Table 1
Hexapeptide sharing between ZIKV polyprotein and human microcephaly-related proteins.
Hexapeptide(s) Human proteins1 and involvement in disease2
LGVPLL
GLQAAA
TRGPSL
SQLTPL
LAGASL
GKSVDM
SRGSAK
LGKRKR
RAGDIT
VEESDL
SSTATS
RGADTS
AAEMEE
SDLAKL
ALAGAL
VDRERE
LLGLLG
LAKLVI
MASDSR
REREHH
EALGTL
VALDES
GSASSL
GLIASL
GCGRGG
EIIKKF
1
2
ACSF3. Acyl-CoA synthetase family member 3, mitochondrial that catalyzes the initial reaction in fatty acid synthesis.
Malonic and methylmalonic aciduria. Clinical features include coma, ketoacidosis, hypoglycemia, microcephaly, dystonia, axial hypotonia, and seizures.
C2CD3. C2 Ca-dependent domain containing 3. Component of the centrioles.
Orofaciodigital syndrome. Malformations of the oral cavity, face and digits, severe microcephaly, cerebral malformations, the molar tooth sign, and intellectual
disability.
CASC5. Essential for spindle-assembly checkpoint signaling and for correct chromosome alignment.
Microcephaly defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight reduced, cerebral cortex small,
gyral pattern relatively well preserved.
CDKL5. Cyclin-dependent kinase-like 5.
Epileptic encephalopathy, characterized by features resembling Rett syndrome such as microcephaly, lack of speech development, stereotypic hand
movements.
CP131. CP131 interacts with the primary microcephaly associated protein CEP152 to promote centriole duplication. Contributes to build a microcephaly
protein complex critical for human neurodevelopment.
Microcephaly-linked protein
DCPS. Decapping enzyme can modulate pre-mRNA splicing
Al-Raqad syndrome: delayed psychomotor development, intellectual disability, poor/absent speech, microcephaly, hypotonia, growth delay.
EDC3. Enhancer of mRNA decapping 3 homolog,
Mental retardation: significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the
developmental period.
GCP4. Gamma-tubulin complex component 4, necessary for microtubule nucleation at the centrosome.
Microcephaly and chorioretinal dysplasia. Developmental delay and learning difficulties. OMIM: 616335
KAT6B. Histone acetyltransferase required for RUNX2-dependent transcriptional activation.
Ohdo syndrome: blepharophimosis, hypotonia. Skeletal problems: joint laxity, abnormal thumbs and toes. Cardiac defects in ~50% of cases. Dental anomalies.
Conductive or sensorineural deafness. Mental retardation, delayed motor milestones, and significantly impaired speech.
Genitopatellar syndrome: microcephaly, severe psychomotor retardation, and characteristic coarse facial features.
KIF2A. Kinesin-like protein KIF2A, required for normal brain development. Implicated in formation of bipolar mitotic spindles.
Cortical dysplasia and brain malformations due to aberrant neuronal migration and disturbed axonal guidance. Early-onset epilepsy, agyria, posterior or
frontal pachygyria, subcortical band heterotopia, and thin corpus callosum.
PCLO. Piccolo presynaptic protein.
Pontocerebellar hypoplasia: abnormally small cerebellum and brainstem, decreased cerebral white matter, a thin corpus callosum, seizures, short stature,
optic atrophy, progressive microcephaly, severe developmental delay.
POMT1. Protein O-mannosyl-transferase 1.
Muscular dystrophy, cobblestone lissencephaly and other brain anomalies, eye malformations, profound mental retardation, and death usually in the first
years of life. Included diseases are the more severe Walker-Warburg syndrome and the slightly less severe muscle-eye-brain disease.
PQBP1. Polyglutamine binding protein 1.
Renpenning syndrome: mental retardation, microcephaly, short stature, and small testes. Manifestations include ocular colobomas, cardiac malformations,
cleft palate.
PRKDC. DNA-dependent protein kinase catalytic subunit.
Immunodeficiency with/out neurologic abnormalities: reduced/absent T and B cells, recurrent candidiasis, infections. May associate with dysmorphic
features, microcephaly, seizures, impaired neurological functions.
SEN54. tRNA-splicing endonuclease subunit Sen54.
Pontocerebellar hypoplasias, small cerebellum and brainstem, neonatal encephalopathy, microcephaly, myoclonus and muscular hypertonia, inferior olivary
and pontine neuronal loss and a diffuse white matter gliosis.
SERA. D-3-phosphoglycerate dehydrogenase.
Phosphoglycerate dehydrogenase deficiency: neurometabolic disorder associated with microcephaly, psychomotor retardation, and seizures.
Neu-Laxova syndrome: characterized by ichthyosis, intrauterine growth restriction, microcephaly, short neck, limb deformities, hypoplastic lungs, edema.
Lissencephaly, cerebellar hypoplasia, abnormal corpus callosum.
SOX11. Transcription factor.
Mental retardation, with impairments in adaptive behavior during the developmental period, dysmorphic facial features, microcephaly, growth deficiency,
hypoplastic fifth toenails. Involved in ocular alterations.
STIL. SCL-interrupting locus protein. A pericentriolar and centrosomal protein.
Microcephaly defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight reduced and cerebral cortex
disproportionately small. Gyral pattern is relatively well preserved.
TBG1. Tubulin gamma-1 chain. Pericentriolar component that regulates centrosome duplication and spindle formation
Cortical dysplasia, a disorder of aberrant neuronal migration and disturbed axonal guidance. Clinical features: early-onset seizures, microcephaly, spastic
tetraplegia, malformations of cortical development, such as agyria, posterior or frontal pachygyria, thick cortex.
TF3B. Isoform 2. Transcription factor. Functions at RNA polIII U6 promoter for synthesis of short hairpin RNA.
Cerebello-facio-dental syndrome with cerebellar hypoplasia, delayed development, intellectual disability, dysmorphic features, microcephaly, and dental
anomalies.
VPS53. Vacuolar protein sorting-associated protein 53 homolog. Involved in cycling mannose 6-phosphate receptors.
Pontocerebellar hypoplasia characterized by cerebello-cerebral atrophy, mental retardation, microcephaly, spasticity, and early-onset epilepsy.
Proteins linked to microcephaly are indicated by UniProtKB/Swiss-Prot entry names and listed in alphabetical order.
Further details and references for disease involvement at http://www.uniprot.org/.
3. Peptide sharing between ZIKV polyprotein and human proteins
related to altered brain calcification
Fetal brain calcifications have been also reported in the pathologic
sequela associated with ZIKV infection [44]. Consequently, we also investigated whether the viral polyprotein might share sequences with
human proteins involved in altered brain calcification. Applying the
research paradigm described above for microcephaly, we captured
human proteins related to cerebral calcification from Uniprot (see
Supplementary Table 3), and then searched them for peptide sharing
with ZIKV.
Table 3 shows that 27 ZIKV pentapeptides are disseminated through
eleven human proteins, dysfunction of which are specifically linked to
brain calcifications. Once more, it has to be observed that the level of
peptide matching described in Table 3 is mathematically unexpected.
Indeed, the theoretical probability of a sequence of 5 aa occurring at
Please cite this article as: Lucchese G, Kanduc D, Zika virus and autoimmunity: From microcephaly to Guillain-Barré syndrome, and beyond,
Autoimmun Rev (2016), http://dx.doi.org/10.1016/j.autrev.2016.03.020
4
G. Lucchese, D. Kanduc / Autoimmunity Reviews xxx (2016) xxx–xxx
Table 2
Immunopositive epitopes containing sequences shared between
ZIKV polyprotein and human proteins linked to microcephaly.
IEDB ID1
Epitope2
26965
49766
49767
66127
85241
134959
143943
143946
156711
167912
179533
188921
189000
440581
451679
452923
459118
465596
467414
469330
469331
ilaptrvvAAEMEEa
ptrvvAAEMEEalrg
ptrvvAAEMEEamkg
trvvAAEMEEa
salsLAGASL
fsLLGLLGeiiyivl
ifsLLGLLGeityiv
imgynfsLLGLLGei
laptrvvAAEMEEal
gkvidlGCGRGGwcyyma
SSTATSgaavvspae
mntkiatrlsvfALAGALla
vfALAGALlagcatqqgtnt
sllsgALAGALak
aEALGTLmraw
aseALAGAL
sllsgALAGAL
glaEALGTL
kpwiglaEALGTL
pwiglaEALGTL
pwiglaEALGTLm
1
Epitopes listed according to IEDB ID number. Only epitopes that
had been experimentally validated as immunopositive in the human host are reported. Further details and references are available
at www.immuneepitope.org/.
2
Peptide sequences shared between ZIKV polyprotein and human
proteins in capital letters.
Table 3
Pentapeptide sharing between ZIKV polyprotein and human proteins related to brain
calcification.
Pentapeptide(s)
ASISD, ATIRK, LIASL,
SDLGY
ASCLL, LGVLV, PSLGL,
QLTPL, QTAIS
LSLKG, RLLSK
LGLTA, NTIME, RVIGL
RGGGT
PRAEA, TKGGP
VFKEK
AVPPG
EEEKE, GETLG, GSTIG,
KKRLR, YAATI
LGHGP
LAFLR, LSTAV
Human proteins1 and involvement in altered
calcification2
ANKH. Progressive ankylosis protein homolog
Craniometaphyseal dysplasia, hyperostosis and
sclerosis of the craniofacial bones
CTC1. CST complex subunit CTC1
Cerebroretinal microangiopathy with calcifications and
cysts
DSRAD. Double-stranded RNA-specific adenosine
deaminase.
Aicardi-Goutieres syndrome. Cerebral atrophy,
intracranial calcifications.
IFIH1. Interferon-induced helicase C domain containing
protein 1
Aicardi-Goutieres syndrome. Cerebral atrophy,
intracranial calcifications
ISG15. Ubiquitin-like protein ISG15
Basal ganglia calcification.
PGFRB. Platelet-derived growth factor receptor beta
precursor
Basal ganglia calcification, idiopathic.
RNH2B. Ribonuclease H2 subunit B
Aicardi-Goutieres syndrome. Cerebral atrophy,
intracranial calcifications.
RNH2C. Ribonuclease H2 subunit C
Aicardi-Goutieres syndrome. Cerebral atrophy,
intracranial calcifications.
S20A2. Sodium-dependent phosphate transporter 2.
Basal ganglia calcification, idiopathic.
SAMH1. Deoxynucleoside triphosphate
triphosphohydrolase SAMHD1
Aicardi-Goutieres syndrome. Cerebral atrophy,
intracranial calcifications.
TREX1. Three-prime repair exonuclease 1.
Aicardi-Goutieres syndrome. Cerebral atrophy,
intracranial calcifications.
1
Proteins linked to altered brain calcification were retrieved using ‘calcifications,
cerebral, intracranial’ as keywords (see Supplementary Table 3). Proteins are indicated by UniProtKB/Swiss-Prot entry names, and listed in alphabetical order.
2
Details and references for disease involvement at http://www.uniprot.org/.
random in two proteins is equal to 20−5, i.e., 1 in 3,200,000, if the number of protein pentapeptides is ≪ 3,200,000 and assuming that all aa
occur with the same frequency [6–10].
Moreover, it is of relevance that many of the proteins listed in
Table 3, i.e., DSRAD, IFIH1, RNH2B, RNH2C, SAMH1, and TREX1, characterize Aicardi-Goutieres syndromes that are phenotypically similar to in
utero viral infection and lead to severe neurological dysfunction,
progressive microcephaly, spasticity, dystonic posturing, profound
psychomotor retardation and often death in early childhood [45,46].
Analysis of the immunologic potential of the peptide sequences
listed in Table 3 is given in Table 4. It can be seen that 13 out of the 27
ZIKV pentapeptides disseminated throughout the eleven human proteins related to altered calcification repeatedly recur in 32 experimentally validated epitopes cataloged as immunopositive in the human
host at IEDB.
4. Peptide sharing between ZIKV polyprotein and human proteins
related to myelin, (de)myelination, and axonal neuropathies
Following reports linking ZIKV infection to GBS [47–49], we analyzed the peptide sharing between the virus and human proteins potentially related to GBS related proteins. GBS encompasses a spectrum of
neuropathies with variants and subtypes (i.e., Miller Fisher syndrome
and Bickerstaff’s brain-stem encephalitis) [50]. Basically, the pathologic
features of GBS support a classification that includes demyelinating and
axonal subtypes, i.e., acute inflammatory demyelinating
polyneuropathy and acute motor axonal neuropathy [51–53], so that
search keywords were myelin, (de)myelination, and axonal neuropathy.
Table 4
Immunopositive epitopes containing sequences shared between ZIKV
polyprotein and human proteins linked to brain calcifications.
IEDB ID1
Epitope2
67088
81065
88294
122542
122639
137659
140012
141396
152536
168001
169082
176289
181140
181156
182132
182330
195482
214887
222553
240330
241458
265471
267340
269797
275293
305148
341620
391759
418227
418643
419283
427060
tvngedvgAVPPGkf
dirdslsEEEKEllnriqvd
RVIGLcirismvisl
qPRAEAawqffmsdkplhla
vqhaplemgpqPRAEAawqf
kvclRLLSK
dkiqgknkrkRVIGLc
riLGVLVhl
fekskeQLTPLikkagtelvnf
sasslvngvvRLLSKpw
leaavkqaYAATIaa
kVFKEKhhsw
qrVFKEKvdtrakdp
tdttpfgqqrVFKEK
fskiGETLGqlfrhrapdsa
tsfaqqikrifskiGETLGq
iGETLGekwksrlna
LSLKGdqal
GETLGiigl
rsAVPPGadkkaeagagsate
rrsAVPPGadk
ddddddepEEEKEks
dgdesideEEEKEve
dnddddddepEEEKE
eddeeeeeeeEEEKE
gtdgdesideEEEKE
nddddddepEEEKEk
tdgdesideEEEKEv
iydpnLAFLR
VFKEKhhsw
neyQTAISeny
RVIGLglly
1
Epitopes listed according to IEDB ID number. Only epitopes that had
been experimentally validated as immunopositive in the human
host are reported. Further details and references are available at
www.immuneepitope.org/.
2
Peptide sequences shared between ZIKV polyprotein and human
proteins in capital letters.
Please cite this article as: Lucchese G, Kanduc D, Zika virus and autoimmunity: From microcephaly to Guillain-Barré syndrome, and beyond,
Autoimmun Rev (2016), http://dx.doi.org/10.1016/j.autrev.2016.03.020
G. Lucchese, D. Kanduc / Autoimmunity Reviews xxx (2016) xxx–xxx
Table 5
Peptide sharing between ZIKV polyprotein and human proteins related to myelin,
(de)myelination and/or axonal neuropathies.
Peptide(s)1
LLALA, EEARR, LWLLR
LLAVP, YLSTQV
FDLEN
SLGLD, MSWFS, MAVLV, MLLSL,
VSYVV
ASDSR, GALEA, ALGLT, YSLMA
ALAGA, PFGDS, LLALA, AARGY,
TQGSA
GSASS
LAGAL
LLTTA, LKGKG, RGYIS, GGGCA
ALAGA, SLFGG, IAACL, LLGLL,
RDLRL
LLLLT
GLDFSD, AFKSL, VQLLA, TKEEF,
QRGSG
LRGLP, PTQGS
LLGLL
GAALR
STSQK
ALEAE
EALIT, GIMLL
PALLV, VVAAE
AKFTC, VLTAVG, EEPML, GSASS
TPVGR, PVGRL, GAALG
VDGDT, AAAAR, DTVNM
VEEDG, SPGAG
NSFLV, ALAGG
Human proteins2 and relation to
(de)myelination processes and axonal
neuropathologies3
ABCD1. ATP-binding cassette sub-family D
member 1
Adrenoleukodystrophy. Progressive
multifocal demyelination of the central
nervous system.
ACATN. Acetyl-coenzyme A transporter 1.
Cerebral and cerebellar atrophy and
hypomyelination.
ACY2. Aspartoacylase.
White matter vacuolization and
demyelination that gives rise to a spongy
appearance.
ADCY6. Adenylate cyclase type 6.
Hypomyelination neuropathy –
arthrogryposis. Reduced fetal movements.
ANAG. Alpha-N-acetylglucosaminidase.
Axonal neuropathies.
ARSA Arylsulfatase A.
Intralysosomal storage of
cerebroside-3-sulfate, with a diffuse loss of
myelin in the CNS.
CC177. Myelin proteolipid protein-like
protein.
CGT. 2-Hydroxyacylsphingosine
1-beta-galactosyltransferase.
Synthesis of galactocerebrosides (abundant
in the myelin of the CNS and peripheral
nervous system)
CH60. 60 kDa heat shock protein,
mitochondrial precursor.
CLCN2. Chloride channel protein 2 (ClC-2).
Leukoencephalopathy. White matter
abnormalities on brain MRI suggesting
myelin microvacuolation.
CLD11. Claudin-11 (oligodendrocyte-specific
protein)
CMC1.
Global cerebral hypomyelination.
CN37. 2′,3′-cyclic-nucleotide
3′-phosphodiesterase.
CN37 is the third most abundant protein in
central nervous system myelin.
CNTN1. Contactin-1 precursor.
CNTP1. Contactin-associated protein 1
precursor.
CNTP2. Contactin-associated protein-like 2
precursor.
CTDP1. RNA polymerase II subunit A
C-terminal domain phosphatase.
Hypomyelination of the peripheral nervous
system.
CTL1. Choline transporter-like protein 1.
CXB1. Gap junction beta-1 protein.
Connexin-32.
Associated to both demyelinating and axonal
neuropathies.
CXG2. Gap junction gamma-2 protein.
Connexin-46.6.
Hypomyelinating leukodystrophy with
symptoms of Pelizaeus-Merzbacher
disease.
CXG3. Gap junction gamma-3
protein.Connexin-30.2.
DHTK1. Probable 2-oxoglutarate
dehydrogenase E1 component DHKTD1,
mitochondrial.
Axonal neuropathies.
DNJB2. DnaJ homolog subfamily B member 2.
Axonal neuropathies.
DPYL2. Dihydropyrimidinase-related protein
2. Collapsin response mediator protein 2,
Neurodegeneration
5
Table 5 (continued)
Peptide(s)1
Human proteins2 and relation to
(de)myelination processes and axonal
neuropathologies3
DHSGK, FATTL, SLRST
DRP2. Dystrophin-related protein 2.
Required for normal myelination and for
normal organization of the cytoplasm and the
formation of Cajal bands in myelinating
Schwann cells.
DYHC1. Cytoplasmic dynein 1 heavy chain 1,
Axonal neuropathy.
EGR2. E3 SUMO-protein ligase EGR2.
Hypomyelinating or amyelinating
neuropathies.
ENOG. Gamma-enolase.
ENPP6. Ectonucleotide
pyrophosphatase/phosphodiesterase family
member 6. Choline-specific
glycerophospho-diester phosphodiesterase.
EXOS8. Exosome complex component RRP43,
cerebellar and corpus callosum hypoplasia,
abnormal myelination of the central nervous
system, and spinal motor neuron disease.
EZRI. Ezrin (Cytovillin).
Expressed in cerebral cortex, basal ganglia,
hippocampus, hypophysis, and optic nerve.
Very strong staining is detected in the
Purkinje cell layer of the infant brain
compared to adult brain.
F168B. Myelin-associated neurite-outgrowth
inhibitor.
Expressed in the brain, within neuronal axonal
fibers and associated with myelin sheets,
FA2H. Fatty acid 2-hydroxylase.
Leukodystrophy.
FGD4. FYVE, RhoGEF and PH
domain-containing protein 4. peripheral
demyelinating neuropathies
FIG4. Polyphosphoinositide phosphatase-,
peripheral demyelinating neuropathies
GDAP1. Ganglioside-induced
differentiation-associated protein 1,
Axonal neuropathy. Vocal cord paresis.
GDIA. Rab GDP dissociation inhibitor alpha
(Oligophrenin-2).
GELS. Gelsolin. Gelsolin is specifically
enriched in myelin-forming cells.
GFAP. Glial fibrillary acidic protein.
Leukodystrophy with macrocephaly,
seizures, and psychomotor retardation
GNAO. Guanine nucleotide-binding protein
G(o) subunit alpha.
Epileptic encephalopathy. Brain
abnormalities, such as cerebral atrophy or
thin corpus callosum.
GPM6A. Neuronal membrane glycoprotein
M6-a.
Involved in neuronal differentiation,
including differentiation and migration of
neuronal stem cells.
GPR6. G-protein coupled receptor 6
(Sphingosine 1-phosphate receptor GPR6).
Blocks myelin inhibition in neurons.
F168B. Myelin-associated neurite-outgrowth
inhibitor
HS71A
HS90A
HSPB1. Heat shock protein beta-1.
Axonal neuropathy.
HSPB8. Heat shock protein beta-8,
Axonal neuropathy.
HTRA1 Serine protease HTRA1.
Demyelination of the cerebral white matter
with sparing of U fibers
HYCCI. Hyccin. Down-regulated by CTNNB1
protein A.
Leukodystrophy, hypomyelinating.
IFLST, GAGKT, SSSPE, EEEKE,
RRDLR, ENIKD
STTAS
MLELD
LLALA
KEVKK
EEARR, EFEAL
APAYS
RRLAA
ELGKR, LEERG
DGLSE, SLGLI
VVGLL
GESSS
AAAIF, GDSYI, GRARV, SLFGG,
TAMAA
LAGAL
VSRME
ALAGA, ILLMV
AALGA, TVSLG,VVAAE
APAYS
LRIIN
EEEKE, GPSLR, LVILL
APAYS, KTKDG
KTKDG
LLLGR
LLSLK, SSTSQ
(continued on next page)
Please cite this article as: Lucchese G, Kanduc D, Zika virus and autoimmunity: From microcephaly to Guillain-Barré syndrome, and beyond,
Autoimmun Rev (2016), http://dx.doi.org/10.1016/j.autrev.2016.03.020
6
G. Lucchese, D. Kanduc / Autoimmunity Reviews xxx (2016) xxx–xxx
Table 5 (continued)
Peptide(s)
1
CYSQL, GSQHS, SLTCLA
IPKSL, KNPKE, LVDRE, VFIYN
GQVVT
LEGDL, GKRKR, ARRAL
VLDLH
HSDLG, RRLLG, TEVEV
ASSLV
LKMDK, IKDTV
RRALK
EEIRR, HFSLG, RFEEC
GLKKR
ASAGI
ENEAL, EELEI
LAGAL, PALLV, SGKRS, AEMEE
AVLLR, DENHP, GPSLR, GLLIV,
LQDGL, REEGA, SEELE, SLGLI,
VLSMV
ESSSS, LIYTV, RPALL
VEFKD, ARRAL
EFGKA, FVVDGDT, GAGKT, LGLQR
CSAVPV
LVEED
KKSGI
ETLHG, PALLV
AAARA, AKVEV, EEEKE, GEAAA
EVEET, RDLRL, VRAAK
RPALL, ISALE, NSTHE, ALGAI,
VEGLG, LNDMG
PSLGL
LALGG, PRRLA, TAAGI, LLTRS
PSLGL, GTVSL
RLAAA, AGGFA, EVQLL, VTLGA,
GEAGA, GQVVT
VNPLG, LLVVL
KGIGK
VVDPI
TVDIE, RVILA, EDVNL
LTAVR, VPERA, GTLPG, RPASA,
GGGTG
ILAFL, LAAAV, LLALA, IPGLQ
ILAAL, PVILD
Table 5 (continued)
2
Human proteins and relation to
(de)myelination processes and axonal
neuropathologies3
IL7RA. Interleukin-7 receptor subunit alpha.
Multiple sclerosis
KIF1B. Kinesin-like protein KIF1B (Klp).
Axonal neuropathy.
LMNA. Prelamin-A/C.
Axonal neuropathy.
LMNB1. Lamin-B1 precursor.
Axonal neuropathy.
LRSM1. E3 ubiquitin-protein ligase LRSAM1.
Axonal neuropathy.
MAG. Myelin-associated glycoprotein
precursor
MAL. Myelin and lymphocyte protein
MERL. Merlin (Moesin-ezrin-radixin-like
protein) (Neurofibromin-2) (Schwannomin)
METK1. S-adenosylmethionine synthase
isoform type-1.
Brain demyelination due to methionine
adenosyltransferase deficiency.
MFN2. Mitofusin-2.
Axonal neuropathy.
MPZL3. Myelin protein zero-like protein 3
precursor
MRF Myelin regulatory factor
MRFL. Myelin regulatory factor-like
protein
MTMR2. Myotubularin-related protein 2.
Demyelination.
MTMR5. Myotubularin-related protein 5.
Demyelination.
MTMRD. Myotubularin-related protein 13
MYEF2. Myelin expression factor 2
MYO1D. Unconventional myosin-Id.
Expressed in myelinating oligodendrocytes.
MYPR. Myelin proteolipid protein
MYT1. Myelin transcription factor 1
MYT1L. Myelin transcription factor 1-like
protein
NDRG1. Protein NDRG1, Demyelinating
neuropathy.
NFH. Neurofilament heavy polypeptide
NFL. Neurofilament light polypeptide,
Demyelinating neuropathy.
NRCAM. Neuronal cell adhesion molecule
precursor.
Plays a role in the formation and
maintenance of the nodes of Ranvier on
myelinated axons.
OPALI. Opalin. Oligodendrocytic myelin
paranodal and inner loop protein.
P5CR2. Pyrroline-5-carboxylate reductase 2.
Leukodystrophy, hypomyelinating,
PARD3. Partitioning defective 3 homolog,
Modulates peripheral myelination
PRAX. Periaxin.
Demyelinating neuropathy.
PTPRC. Receptor-type tyrosine-protein
phosphatase C. Multiple sclerosis.
RPAC1. DNA-directed RNA polymerases I and
III subunit RPAC1.
Leukodystrophy, hypomyelinating
RPC1. DNA-directed RNA polymerase III
subunit RPC1.
Leukodystrophy, hypomyelinating
RPC2. DNA-directed RNA polymerase III
subunit RPC2
Leukodystrophy, hypomyelinating
RTN4R.Reticulon-4 receptor.
Receptor for myelin-associated glycoprotein
S3TC2. SH3 domain and tetratricopeptide
repeat-containing protein 2.
Demyelinating neuropathy.
SAP. Prosaposin.
Peptide(s)1
GAALR, ALRGL, LLGLL
ALEAE, GTRGP, PFAAG, EALRG,
IEPARI, RRGGG, GETLGE
VATGG, NAALG
GCGLF, TKNGS, GERAR, GVPLL,
ERLQR
TAVSA, YISTR
KGSLV, GDTAW
ALVAV, DIEMA
AEEVL
LKDGV
NGVQL, LVNGV, EKEWK
LVILL, AETDE, TLETI, ALKDG,
RGECH, ISRQD, LKDGR
TVEVQ
CRECT, EGLKK
FPDSN, DRRWCF, IILLV, VSRGS,
QLLYF
Human proteins2 and relation to
(de)myelination processes and axonal
neuropathologies3
Demyelination, periventricular white matter
abnormalities, peripheral neuropathy
SATT. Neutral amino acid transporter A.
Developmental delay, microcephaly and
hypomyelination.
SCRIB. Protein scribble homolog. Regulates
myelination and remyelination in the central
nervous system.
SDHA. Succinate dehydrogenase
[ubiquinone] flavoprotein subunit,
mitochondrial.
Progressive leukoencephalopathy.
SMBP2. DNA-binding protein SMUBP-2.
Axonal neuropathy.
STXB1. Syntaxin-binding protein 1.
Brain hypomyelination
SYAC. Alanine–tRNA ligase, cytoplasmic,
Axonal neuropathy
SYDC. Aspartate–tRNA ligase, cytoplasmic,
Hypomyelination and white matter lesions in
the cerebrum, brainstem, cerebellum, and
spinal cord.
SYG. Glycine–tRNA ligase,
Axonal neuropathy.
SYHC. Histidine–tRNA ligase, cytoplasmic,
Axonal neuropathy.
SYRC Arginine–tRNA ligase, cytoplasmic,
Leukodystrophy. Ataxia associated with
diffuse hypomyelination apparent on brain
MRI.
TEN4. Teneurin-4.
Regulates the myelination of small-diameter
axons in the central nervous system
TNR1A. Tumor necrosis factor receptor
superfamily member 1.
Multiple sclerosis.
TRIM2, Tripartite motif-containing protein 2.
Axonal neuropathy.
TRPV4. Transient receptor potential cation
channel subfamily V member 4.
Axonal neuropathy.
1
Hexa- and heptapeptides given bold.
Proteins were retrieved using ‘myelin, (de)myelination, axonal neuropathy’ as
keywords (see Supplementary Table 4). Proteins are indicated by UniProtKB/Swiss-Prot
entry names, and listed in alphabetical order.
3
Details and references for disease involvement at http://www.uniprot.org/.
2
The search was also extended to GBS autoantigens described in the
scientific-clinical literature such as: alpha-crystallin B chain (CRYAB)
[54]; contactin-1 (CNTN1) [55,56]; contactin-associated protein-like 1
(CNTP1) [56,57]; contactin-associated protein-like 2 (CNTP2) [58];
gliomedin (GLDN) [56,59]; heat shock proteins 27, 60, 70, and 90
(HSPB1, CH60, HS90A) [60]; moesin (MOES) [56,61]; neurofascin
(NFASC) [55,56,59]; and neuronal cell adhesion molecule (NRCAM)
[56]. On the whole, 140 protein entries were retrieved (see Supplementary Table 4) and analyzed for peptide sharing. Final results are reported in
Table 5 and document an extensive and intensive peptide overlap
between ZIKV and human proteins that may relate to demyelination
and axonal neuropathies.
Numerically, 216 peptide sequences – 207 pentapeptides, 8
hexapeptides, and 1 heptapeptide – recur for a total of 247 exact
matches throughout 99 human proteins that, when altered, are associated with myelin disorders and/or neuropathies. Such numbers and
the immunological potential of the peptide sharing shown in Table 6
point in favor of an autoimmune crossreactive connection between
ZIKV and Guillain-Barré-like syndromes. Indeed, a conspicuous number
of peptides shared between the virus and proteins associated, when
altered, with (de)myelination and axonal neuropathy are present in
Please cite this article as: Lucchese G, Kanduc D, Zika virus and autoimmunity: From microcephaly to Guillain-Barré syndrome, and beyond,
Autoimmun Rev (2016), http://dx.doi.org/10.1016/j.autrev.2016.03.020
G. Lucchese, D. Kanduc / Autoimmunity Reviews xxx (2016) xxx–xxx
Table 6
Immunopositive epitopes containing sequences shared between ZIKV polyprotein and human proteins linked to myelin, (de)myelination, axonal neuropathy.
IEDB ID1
10
2859
3500
9980
14278
15456
15968
18866
19121
19122
21271
21783
24302
25523
35458
36077
37528
37757
42819
43963
46576
47494
53027
54023
55116
55881
59561
62564
108957
133702
139759
150534
162369
162647
162824
162892
167116
176191
179920
180593
180632
180639
183353
Epitope2
IEDB ID1
Epitope2
IEDB ID1
Epitope2
aaAAAIFvi
ALRGLPiry
APAYSral
dRGYISqy
ESSSSdkp
fdRGYISq
fGDSYI
GCGLFg
GDSYIi
GDTAWd
gmGEAAAIF
GPSLRtttv
hlsLRGLPv
iCSAVPVhw
lEFEALgfl
lGDTAW
LLLLTvltv
llrSTSQK
mTKEEFtry
nGCGLF
nyaDRRWCF
PFGDSy
qysDRRWCF
RGYISqyf
RPASAgaml
rSLFGGmsw
sLVNGVvrl
syhDRRWCF
fLLGLLffv
srNSTHEmy
gLAAAVvav
RPASAwtly
gQRGSGssf
kEVEETata
laaaRLAAA
lpktGTVSL
kaGQVVTiw
KTKDGvvei
vvRDLRLra
lEFEALgfm
lsrNSTHEm
mailGDTAW
GESSSnpti
185419
194338
194401
207331
209443
209448
213577
217411
218007
218979
220742
222388
222457
236364
236420
238984
418547
420040
420168
420169
423807
424148
424246
427527
427966
434001
436455
436632
444417
446126
446920
446941
447041
447194
447525
447526
448964
451561
451914
452231
452911
452923
454329
rLKMDKlel
SLFGGsvkl
tLAAAVpki
ELGKRvqal
gesGAGKTw
GESSSrlgy
ktfTAAGI
raapAAAAR
rLKDGVlay
seeLLSLKy
vGAALRpaf
geadILAAL
geGLLIVkv
VRAAKfwk
aAPAYSral
RPASAgaml
sLLGLLvev
qnpqILAAL
SLRSTii
SLRSTiikk
aaaVVGLLy
avNGVQLhy
EEARRLLGy
stTAVSAry
twnAVLLRy
iagkLQDGL
apnsRPALL
aTLETIlrh
GPSLRgpal
laRPASAal
nlISALEea
npkESSSSl
PALLVsqi
qridEFEAL
RPALLall
rpalPALLV
STTASlskk
AAAARiqp
AEMEErfyr
ALAGGitmv
aRPALLlll
aseALAGAL
gSLGLIfal
455521
456221
456350
456552
457312
458233
458309
459912
464089
465337
467953
469571
470343
470554
470859
470894
475411
475912
476155
477146
477243
478632
478876
480858
481247
482780
483862
484166
485074
485755
485864
485938
486103
486146
486594
487020
487072
487689
488605
488606
488926
491193
492165
kLQDGLlhi
LLAVPvpgv
lLQDGLkdl
lprgLAGAL
nvvALVAV
rlvGIMLLl
RPASAnisl
tlDENHPsi
dpfRPALL
ftASAGIqv
LLTTAevvv
qpEGLKKtl
ryTPVGRsf
SLFGGkpmi
sPFGDSpl
spgsPSLGL
AETDEprll
apSSTSQel
ASSLVdtpk
eaagGEAAA
EEARRqsga
gidSSSPEv
gtaaAAAAR
klrEEARRk
KTKDGvrev
nrypASSLV
rEFGKAlql
RLAAAARek
ryiEGLKKR
sESSSSpsa
sfSPGAGaf
shlGESSSy
SLFGGtsgl
sLLALAGAv
ssgpGPSLR
sVSRGSslk
sygpGPSLR
trhKEVKKl
vVVDPIlsk
vVVDPIqsv
ypASSLVvv
frsNGVQLl
hrALVAVll
7
Moreover and of extreme relevance, a great number of the shared
peptides are part of epitopes that have been experimentally validated
as immunopositive in the human host (Tables 2, 4, and 6).
The data not only warrant collaborative multi-disciplinary research
efforts in order to further understand and define the dangerous autoimmune relationship between ZIKV and the human host, but also mandatorily warn against using vaccines based on entire ZIKV antigens to fight
ZIKV infection. Peptides unique to the virus appear to be the obliged
basis for designing effective and safe anti-ZIKV immunotherapies [62–
64].
Take-home messages
• ZIKV infection during pregnancy may cause fetus microcephaly and
other brain anomalies.
• ZIKV infection has also been related to Guillain-Barré-like syndromes
• How the viral infection relates to fetal brain malformations and to
Guillain-Barré-like syndromes is unknown.
• We describe a massive peptide sharing between ZIKV and human
proteins specifically related, when altered, to the ZIKV-induced pathologic sequela.
• Such a massive peptide sharing might lead to crossreactions with
consequent autoimmune diseases.
• Utilization of peptide sequences uniquely present in the pathogen
proteins and absent in the human host should be considered as the
molecular basis for developing an efficacious and safe anti-ZIKV
vaccine exempt from autoimmune crossreactions.
Conflicts of interest
None.
Acknowledgemnts
GL gratefully acknowledges support by the Deutscher Akademischer
Austauschdienst (DAAD), the Deutsche Forschungsgemeinschaft (DFG),
and the Freie Universität Berlin, Germany.
Appendix A. Supplementary data
1
Epitopes listed according to IEDB ID number. Only epitopes that had been experimentally validated as immunopositive in the human host are reported. Further details and
references are available at www.immuneepitope.org/.
2
Peptide sequences shared between ZIKV polyprotein and human proteins in capital
letters.
more than 500 epitopes that have been cataloged as immunopositive in
the human host at IEDB (data not shown). Using the epitope aa length
as a filter, Table 6 is restricted to n-mer sequences with n b 9.
5. Conclusions
On the whole, this study powerfully supports an autoimmune etiological component for the brain damage and the neurodevelopmental
disturbances recently described in infants following in utero ZIKV infection. De facto, the vast, intense, and widesprad peptide sharing illustrated in Tables 1 and 3 clearly demonstrates that, under conditions of
immunoreactogenicity, prenatal exposure to ZIKV infection might result
in anti-viral immune responses crossreacting with human proteins that,
if attacked, may lead to microcephaly, ocular anomalies, brain calcification, and neurodevelopmental disorders. In parallel, the concomitant
massive peptide overlap between ZIKV polyprotein and human proteins
linked to myelin, (de)myelination, and axonal neuropathy (Table 5)
provides an equally robust argument for a crossreactivity mechanism
as a link between ZIKV infection and Guillain-Barré-like syndromes.
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.autrev.2016.03.020.
References
[1] MacFadden DR, Bogoch II. Zika virus infection. CMAJ Feb 8 2016.
[2] Rubin EJ, Greene MF, Baden LR. Zika virus and microcephaly. N Engl J Med Feb 2016;
10.
[3] Mlakar J, Korva M, Tul N, Popović M, Poljšak-Prijatelj M, Mraz J, et al. Zika virus
associated with microcephaly. N Engl J Med Feb 2016;10.
[4] Schuler-Faccini L, Ribeiro EM, Feitosa IM, Horovitz DD, Cavalcanti DP, Pessoa A, et al.
Possible association between Zika virus infection and microcephaly—Brazil. MMWR
Morb Mortal Wkly Rep. 2016, 65; 2015. p. 59–62.
[5] Peters B, Sidney J, Bourne P, Bui HH, Buus S, Doh G, et al. The Immune Epitope DataBase and analysis resource: from vision to blueprint. PLoS Biol 2005;3, e91.
[6] Lucchese G, Capone G, Kanduc D. Peptide sharing between influenza A H1N1 hemagglutinin and human axon guidance proteins. Schizophr Bull 2014;40:362–75.
[7] Lucchese G, Spinosa JP, Kanduc D. The peptide network between tetanus toxin and
human proteins associated with epilepsy. Epilepsy Res Treat 2014;2014:236309.
[8] Lucchese G, Kanduc D. Potential crossreactivity of human immune responses against
HCMV glycoprotein B. Curr Drug Discov Technol Jan 28 2016.
[9] Frank A. Immunology and Evolution of Infectious Disease. Princeton (NJ): Princeton
University Press; 2002.
[10] Kanduc D. Pentapeptides as minimal functional units in cell biology and immunology. Curr Protein Pept Sci 2013;14:111–20.
[11] Kuno G, Chang GJ. Full-length sequencing and genomic characterization of Bagaza,
Kedougou, and Zika viruses. Arch Virol 2007;152:687–96.
[12] UniProt Consortium. The universal protein resource (UniProt) 2009. Nucleic Acids
Res 2009;37:D169–74.
[13] Korenberg JR, Chen X-N, Schipper R, Sun Z, Gonsky R, Gerwehr S, et al. Down
syndrome phenotypes: the consequences of chromosomal imbalance. Proc Natl
Acad Sci 1994;91:4997–5001.
Please cite this article as: Lucchese G, Kanduc D, Zika virus and autoimmunity: From microcephaly to Guillain-Barré syndrome, and beyond,
Autoimmun Rev (2016), http://dx.doi.org/10.1016/j.autrev.2016.03.020
8
G. Lucchese, D. Kanduc / Autoimmunity Reviews xxx (2016) xxx–xxx
[14] Celato A, Mitola C, Tolve M, Giannini MT, De Leo S, Carducci C, et al. A new case of
malonic aciduria with a presymptomatic diagnosis and an early treatment. Brain
Dev 2013;35:675–80.
[15] Mari F, Azimonti S, Bertani I, Bolognese F, Colombo E, Caselli R, et al. CDKL5
belongs to the same molecular pathway of MeCP2 and it is responsible for the
early-onset seizure variant of Rett syndrome. Hum Mol Genet 2005;14:1935–46.
[16] Ahmed I, Buchert R, Zhou M, Jiao X, Mittal K, Sheikh TI, et al. Mutations in DCPS and
EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA
decapping in neurodevelopment. Hum Mol Genet 2015;24:3172–80.
[17] Kraft M, Cirstea IC, Voss AK, Thomas T, Goehring I, Sheikh BN, et al. Disruption of the
histone acetyltransferase MYST4 leads to a Noonan syndrome-like phenotype and
hyperactivated MAPK signaling in humans and mice. J Clin Invest 2011;121:
3479–91.
[18] Ahmed MY, Chioza BA, Rajab A, Schmitz-Abe K, Al-Khayat A, Al-Turki S, et al. Loss of
PCLO function underlies pontocerebellar hypoplasia type III. Neurology 2015;84:
1745–50.
[19] Beltrán-Valero de Bernabé D, Currier S, Steinbrecher A, Celli J, van Beusekom E, van
der Zwaag B, et al. Mutations in the O-mannosyltransferase gene POMT1 give rise to
the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum
Genet 2002;71:1033–43.
[20] Devisme L, Bouchet C, Gonzalès M, Alanio E, Bazin A, Bessières B, et al. Cobblestone
lissencephaly: neuropathological subtypes and correlations with genes of
dystroglycanopathies. Brain 2012;135:469–82.
[21] Wang Q, Moore MJ, Adelmant G, Marto JA, Silver PA. PQBP1, a factor linked to intellectual disability, affects alternative splicing associated with neurite outgrowth.
Genes Dev 2013;27:615–26.
[22] Qi Y, Hoshino M, Wada Y-I, Marubuchi S, Yoshimura N, Kanazawa I, et al. PQBP-1 is
expressed predominantly in the central nervous system during development. Eur J
Neurosci 2005;22:1277–86.
[23] Martínez-Garay I, Tomás M, Oltra S, Ramser J, Moltó MD, Prieto F, et al. A two base
pair deletion in the PQBP1 gene is associated with microphthalmia, microcephaly,
and mental retardation. Eur J Hum Genet 2007;15:29–34.
[24] Ito H, Shiwaku H, Yoshida C, Homma H, Luo H, Chen X, et al. In utero gene therapy
rescues microcephaly caused by Pqbp1-hypofunction in neural stem progenitor
cells. Mol Psychiatry 2015;20:459–71.
[25] Budde BS, Namavar Y, Barth PG, Poll-The BT, Nürnberg G, Becker C, et al. tRNA
splicing endonuclease mutations cause pontocerebellar hypoplasia. Nat Genet
2008;40:1113–8.
[26] Klomp LW, de Koning TJ, Malingré HE, van Beurden EA, Brink M, Opdam FL, et al.
Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency—a
neurometabolic disorder associated with reduced L-serine biosynthesis. Am J Hum
Genet 2000;67:1389–99.
[27] Yamasaki M, Yamada K, Furuya S, Mitoma J, Hirabayashi Y, Watanabe M. 3Phosphoglycerate dehydrogenase, a key enzyme for l-serine biosynthesis, is
preferentially expressed in the radial glia/astrocyte lineage and olfactory
ensheathing glia in the mouse brain. J Neurosci 2001;21:7691–704.
[28] Tsurusaki Y, Koshimizu E, Ohashi H, Phadke S, Kou I, Shiina M, et al. De novo SOX11
mutations cause Coffin-Siris syndrome. Nat Commun 2014;5:4011.
[29] Rex M, Church R, Tointon K, Ichihashi RM, Mokhtar S, Uwanogho D, et al. Granule
cell development in the cerebellum is punctuated by changes in Sox gene
expression. Mol Brain Res 1998;55:28–34.
[30] Scheidecker S, Etard C, Haren L, Stoetzel C, Hull S, Arno G, et al. Mutations in
TUBGCP4 alter microtubule organization via the γ-tubulin ring complex in
autosomal-recessive microcephaly with chorioretinopathy. Am J Hum Genet 2015;
96:666–74.
[31] Pillai-Kastoori L, Wen W, Wilson SG, Strachan E, Lo-Castro A, Fichera M, et al. Sox11
is required to maintain proper levels of Hedgehog signaling during vertebrate ocular
morphogenesis. PLoS Genet 2014;10, e1004491.
[32] Wurm A, Sock E, Fuchshofer R, Wegner M, Tamm ER. Anterior segment dysgenesis
in the eyes of mice deficient for the high-mobility-group transcription factor
Sox11. Exp Eye Res 2008;86:895–907.
[33] de Paula Freitas B, de Oliveira Dias JR, Prazeres J, Sacramento GA, Ko AI, Maia M, et al.
Ocular findings in infants with microcephaly associated with presumed Zika virus
congenital infection in Salvador, Brazil. JAMA Ophthalmol Feb 9 2016.
[34] Jampol LM, Goldstein DA. Zika virus infection and the eye. JAMA Ophthalmol 2016.
[35] Balestra FR, Strnad P, Flückiger I, Gönczy P. Discovering regulators of centriole
biogenesis through siRNA-based functional genomics in human cells. Dev Cell
2013;25:555–71.
[36] Kodani A, Yu TW, Johnson JR, Jayaraman D, Johnson TL, Al-Gazali L, et al. Centriolar
satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote
centriole duplication. Elife 2015;4, e07519.
[37] Sir JH, Barr AR, Nicholas AK, Carvalho OP, Khurshid M, Sossick A, et al. A primary
microcephaly protein complex forms a ring around parental centrioles. Nat Genet
2011;43:1147–53.
[38] Morris-Rosendahl DJ, Kaindl AM. What next-generation sequencing (NGS) technology has enabled us to learn about primary autosomal recessive microcephaly
(MCPH). Mol Cell Probes 2015;29:271–81.
[39] Cox J, Jackson AP, Bond J, Woods CG. What primary microcephaly can tell us about
brain growth. Trends Mol Med 2006;12:358–66.
[40] Nigg EA, Čajánek L, Arquint C. The centrosome duplication cycle in health and
disease. FEBS Lett 2014;588:2366–72.
[41] Gurling HM, Critchley H, Datta SR, McQuillin A, Blaveri E, Thirumalai S, et al. Genetic
association and brain morphology studies and the chromosome 8p22 pericentriolar
material 1 (PCM1) gene in susceptibility to schizophrenia. Arch Gen Psychiatry
2006;63:844–54.
[42] Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM, et al. Identification of
microcephalin, a protein implicated in determining the size of the human brain.
Am J Hum Genet 2002;71:136–42.
[43] Bond J, Roberts E, Mochida GH, Hampshire DJ, Scott S, Askham JM, et al. ASPM is a
major determinant of cerebral cortical size. Nat Genet 2002;32:316–20.
[44] Brasil P, Pereira Jr JP, Raja Gabaglia C, Damasceno L, Wakimoto M, Ribeiro Nogueira
RM, et al. Zika virus infection in pregnant women in Rio de Janeiro—preliminary
report. N Engl J Med Mar 2016;4.
[45] Rice G, Patrick T, Parmar R, Taylor CF, Aeby A, Aicardi J, et al. Clinical and molecular
phenotype of Aicardi-Goutieres syndrome. Am J Hum Genet Oct 2007;81(4):
713–25.
[46] Lee-Kirsch MA, Wolf C, Günther C. Aicardi-Goutières syndrome: a model disease for
systemic autoimmunity. Clin Exp Immunol 2014;175:17–24.
[47] Smith DW, Mackenzie J. Zika virus and Guillain-Barré syndrome: another viral cause
to add to the list. Lancet Feb 2016;29.
[48] Cao-Lormeau VM, Blake A, Mons S, Lastère S, Roche C, Vanhomwegen J, et al.
Guillain-Barré syndrome outbreak associated with Zika virus infection in French
Polynesia: a case-control study. Lancet Feb 2016;29.
[49] Brasil P, Pereira Jr JP, Raja Gabaglia C, Damasceno L, Wakimoto M, Ribeiro, et al. Zika
virus infection in pregnant women in Rio de Janeiro—preliminary report. N Engl J
Med Mar 4 2016.
[50] Wakerley BR, Uncini A, Yuki N, GBS Classification Group. Guillain-Barré and Miller
Fisher syndromes—new diagnostic classification. Nat Rev Neurol 2014;10:537–44.
[51] Yuki N, Hartung HP. Guillain-Barré syndrome. N Engl J Med 2012;366(24):
2294–304.
[52] Asbury AK, Arnason BG, Adams RD. The inflammatory lesion in idiopathic polyneuritis: its role in pathogenesis. Medicine (Baltimore) 1969;48:173–215.
[53] McKhann GM, Cornblath DR, Griffin JW, et al. Acute motor axonal neuropathy: a
frequent cause of acute flaccid paralysis in China. Ann Neurol 1993;33:333–42.
[54] Wanschitz J, Ehling R, Löscher WN, Künz B, Deisenhammer F, Kuhle J, et al. Intrathecal anti-alphaB-crystallin IgG antibody responses: potential inflammatory markers
in Guillain-Barré syndrome. J Neurol 2008;255:917–24.
[55] Querol L, Illa I. Paranodal and other autoantibodies in chronic inflammatory
neuropathies. Curr Opin Neurol Oct 2015;28(5):474–9.
[56] Stathopoulos P, Alexopoulos H, Dalakas MC. Autoimmune antigenic targets at the
node of Ranvier in demyelinating disorders. Nat Rev Neurol Mar 2015;11(3):
143–56.
[57] Querol L, Nogales-Gadea G, Rojas-Garcia R, Martinez-Hernandez E, Diaz-Manera J,
Suárez-Calvet X, et al. Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann Neurol Mar 2013;73(3):370–80.
[58] Rosch RE, Bamford A, Hacohen Y, Wraige E, Vincent A, Mewasingh L, et al. GuillainBarré syndrome associated with CASPR2 antibodies: two paediatric cases. J Peripher
Nerv Syst 2014;19:246–9.
[59] Devaux JJ, Odaka M, Yuki N. Nodal proteins are target antigens in Guillain-Barré syndrome. J Peripher Nerv Syst 2012;17:62–71.
[60] Yonekura K, Yokota S, Tanaka S, Kubota H, Fujii N, Matsumoto H, et al. Prevalence of
anti-heat shock protein antibodies in cerebrospinal fluids of patients with GuillainBarré syndrome. J Neuroimmunol 2004;156:204–9.
[61] Sawai S, Satoh M, Mori M, Misawa S, Sogawa K, Kazami T, et al. Moesin is a possible
target molecule for cytomegalovirus-related Guillain-Barré syndrome. Neurology
2014;83:113–7.
[62] Kanduc D. The self/nonself issue: a confrontation between proteomes. Self Nonself
2010;1:255–8.
[63] Kanduc D, Lucchese A, Mittelman A. Non-redundant peptidomes from DAPs:
towards “the vaccine”? Autoimmun Rev 2007;6:290–4.
[64] Kanduc D. Peptide cross-reactivity: the original sin of vaccines. Front Biosci 2012;4:
1393–401.
Please cite this article as: Lucchese G, Kanduc D, Zika virus and autoimmunity: From microcephaly to Guillain-Barré syndrome, and beyond,
Autoimmun Rev (2016), http://dx.doi.org/10.1016/j.autrev.2016.03.020