1 title: dysregulation of rna editing may help explain ...1 1 title: dysregulation of rna editing...

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Title: Dysregulation of RNA editing may help explain pathogenicity mechanisms of 1

congenital Zika syndrome and Guillain-Barre syndrome 2

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Helen Piontkivska 1, 2, *, Noel-Marie Plonski 2, Michael M. Miyamoto 3, and Marta L. 4

Wayne 3, 4 5

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1 Department of Biological Sciences and 2 School of Biomedical Sciences, Kent State University, 7

Kent, OH 44242, USA 8

3 Department of Biology, University of Florida, Gainesville, FL 32611, USA 9

4 Emerging Pathogens Institute, University of Florida, Gainesville, FL 32611, USA 10

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* Corresponding Author 12

Helen Piontkivska 13

Department of Biological Sciences 14

Kent State University 15

Kent, OH 44242, USA 16

Telephone: (330) 672-3620 17

Fax: (330) 672-3713 18

E-mail: [email protected] 19

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PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.27401v1 | CC BY 4.0 Open Access | rec: 3 Dec 2018, publ: 3 Dec 2018

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Abbreviations: 21

ADAR, Adenosine Deaminases Acting on RNA 22

AGS6, Aicardi-Goutieres syndrome 6 23

ALS, amyotrophic lateral sclerosis 24

CDC, Centers for Disease Control and Prevention 25

CDI, inhibitory Ca2+-feedback 26

CMV, cytomegalovirus 27

CZS, Congenital Zika syndrome 28

GBS, Guillain-Barre syndrome 29

IFN, interferon 30

ISGs, interferon-stimulated genes 31

ISREs, interferon-sensitive response elements 32

WNV, West Nile virus 33

Zika virus (ZIKV) 34

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Abstract: 36

Many Zika virus (ZIKV) pathogenesis-related studies have focused primarily on virus-driven 37

pathology and neurotoxicity, instead of considering the possibility of pathogenesis as an 38

(unintended) consequence of host innate immunity: specifically, as the side-effect of an 39

otherwise well-functioning machine. The hypothesis presented here suggests a new way of 40

thinking about the role of host immune mechanisms in disease pathogenesis, focusing on 41

dysregulation of post-transcriptional RNA editing as a candidate driver of a broad range of 42

observed neurodevelopmental defects and neurodegenerative clinical symptoms in both infants 43

and adults linked with ZIKV infections. We collect and synthesize existing evidence of ZIKV-44

mediated changes in expression of adenosine deaminases that act on RNA (ADARs), known 45

links between abnormal RNA editing and pathogenesis, as well as ideas for potential 46

translational applications, including genomic profile-based molecular diagnostic tools and/or 47

treatment strategies. 48

49

50


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Introduction: ZIKV as a causative agent for an emergent public health crisis 51

Following discovery of a link between Zika Virus (ZIKV, a flavivirus) infection in pregnancy 52

and microcephaly in infants in 2015 [1], this public health crisis continues to present a significant 53

hazard to human health. The Global Disease Burden study estimated that ~7·60 million ZIKV 54

infections occurred in 2016, most of which were in Latin America and the Caribbean [2]. While 55

the vast majority of these cases were asymptomatic infections, with only a small portion 56

resulting in Zika-attributable Guillain-Barré syndrome (GBS) and congenital Zika syndrome 57

(CZS) births, infants born with the CZS will face life-long profound disability [3] and their 58

families face extreme economic burdens as well. Already over 6900 pregnancies with ZIKV 59

infected mothers have been recorded in the US and the US territories as of July 17, 2018 (CDC), 60

from which over 300 infants were born with CZS. Nor are adults immune: known consequences 61

of ZIKV infection in adults include GBS [4, 5], a debilitating peripheral neuropathy that is 62

potentially life-threatening and costly to treat [6]. However, there is currently no available vaccine 63

for ZIKV, nor antiviral treatments. The efficacy of prevention strategies, such as protecting 64

oneself from mosquito bites or sexual abstinence during confirmed infection, is compromised by 65

the frequently asymptomatic nature of ZIKV infection [7] as well as the wiliness of mosquitoes. 66

In the absence of effective prevention, insights into the mechanisms behind ZIKV-associated 67

pathogenesis are critical to the development of treatments that can ameliorate potential ZIKV 68

sequelae. 69

70

What is congenital Zika syndrome (CZS)? 71

The link between ZIKV infection in pregnancy and congenital Zika syndrome (CZS) is a 72

particularly pressing concern, in part because we do not yet fully understand the extent of 73

neurodevelopmental defects – particularly those not obvious at birth - associated with it [8]. CZS 74

includes a broad range of neurodevelopmental defects beyond microcephaly [9, 10], including 75

ocular [11] and auditory defects [12]. The overall risk of ZIKV-linked birth defects has been 76

estimated at up to ~15% for infections in the 1st trimester [13], potentially impacting thousands of 77

infants in the US and US territories alone. However, the risk extends into infections that occur 78

later in pregnancy [14], and central nervous system defects may be present without microcephaly 79

[15, 16]. A recent CDC report showed an increase in prevalence of birth defects potentially 80

consistent with CZS in US areas with documented local ZIKV transmission [8]. Flash flooding 81


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accompanying major hurricanes (such as those associated with 2017 hurricanes Harvey, Irma 82

and Maria in TX, FL and PR, respectively) and the diverse set of ZIKV transmission routes, 83

including non-vector-borne transmission via sexual contact and bodily fluids, such as sweat, 84

saliva or tears [17], likely expand the portion of ZIKV-exposed US population, similar to the 85

observed expansion of West Nile virus (WNV) infections following hurricane Katrina in 2005 86

[18]. 87

88

ZIKV-mediated pathogenesis? 89

Despite major efforts focused on ZIKV research over the last three years, our understanding of 90

ZIKV-mediated pathogenesis remains limited, in part because the symptoms and sequelae of 91

ZIKV infection span from asymptomatic to major birth defects in infants, as well as severe 92

adverse outcomes in some adults. Below we highlight a broad variety of clinical symptoms and 93

outcomes associated with ZIKV infection, with the explicit purpose of identifying connectedness 94

of ZIKV sequelae across different life stages. For in-depth comprehensive surveys focused on 95

fetal or adult outcomes, we refer the reader to the following studies [9, 19, 20]. 96

97

What do we know so far? On the one hand, most ZIKV infections in adults are benign and self-98

limiting [21], with as many as 80% having asymptomatic infections [7]. It is worth noting that 99

these asymptomatic carriers are still capable of infecting others [19]. Moreover, the risk of 100

neurodevelopmental fetal defects appears to be similar between symptomatic and asymptomatic 101

pregnant women [19]. While relatively few pediatric-focused studies of ZIKV infections are 102

available, the available evidence suggests that the majority of acute ZIKV infections in children 103

are similarly mild in nature to adult ones [22], although recent reports have begun to associate 104

ZIKV with other clinical issues, such as acute abdominal symptoms [23] or post-infection 105

vasculitis resulting in pediatric stroke [24]. 106

107

During pregnancy, ZIKV poses a substantial risk of fetal neurodevelopmental defects, resulting 108

in profound long-term disability and immense costs of future care, influencing individuals and 109

communities [21, 25]. The full spectrum of CZS is still being elucidated, coupled with concerns 110

that ZIKV-related outcomes are underreported, particularly when ZIKV infections result in later 111

onset of developmental delays and learning disabilities without visible microcephaly [26], or 112


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includes other systemic abnormalities that manifest postnatally, such as dysphagia [27], seizures 113

[28], and hearing loss [29]. For example, recent evidence suggests that ZIKV infection in 114

pregnancy may have been linked with microcephaly and other neurodevelopmental defects in the 115

US (Hawaii) as early as 2007, with several (likely travel-related) births in 2009 and 2011 being 116

definitively linked to maternal ZIKV-positive antibodies [30]. In part due to lack of long term, 117

longitudinal studies, the long-term consequences of an in utero ZIKV infection are poorly 118

understood, particularly in infants lacking visible symptoms of CZS and/or from asymptomatic 119

infections; however, there are reported cases of CZS being diagnosed post-birth because the 120

infants showed neurodevelopmental delays and developed postnatal microcephaly [31, 32]. Recent 121

abnormal imaging from normocephalic infants from ZIKV-positive pregnancies [33] and pregnant 122

pigtail macaques [16] further underscores challenges associated with detection of ZIKV-mediated 123

brain injury that may appear subtle, yet could have profound neurocognitive and psychiatric 124

consequences later. 125

126

In addition to causing severe neurodevelopmental defects in prenatal infections, ZIKV infections 127

have also been linked to severe neurotoxicity in some adults, including Guillain-Barre Syndrome 128

(GBS) [4, 5, 34]. GBS is an acute paralytic neuropathy, an inflammatory disorder of the peripheral 129

nervous system, and is one of the leading causes of acute flaccid paralysis worldwide [35, 36]. 130

Despite recent progress in immunotherapy [37], GBS remains a life-threatening condition, often 131

requiring complex and expensive care [38]. Up to 20% of GBS cases result in severe disability, or 132

even death [36], while many other patients experience ongoing motor or sensory issues, fatigue 133

and pain [39]. Compared to other morbidities, ZIKV-triggered GBS represents a very small 134

fraction of the global disease burden [3]. Nonetheless, GBS is associated with substantial risks 135

(including death) as well as financial costs for affected individuals [21]. Moreover, there are 136

challenges with early GBS diagnosis, particular in atypical presentations and/or pediatric patients 137

[38]. For example, cranial nerve enhancement - thought to be a part of GBS in pediatric patients 138

[40] - was recently described from an imaging study of seemingly normal infant born after ZIKV-139

positive pregnancy. However, not all infants from ZIKV-positive pregnancies receive the 140

recommended postnatal imaging [13, 41]. Moreover, the molecular mechanisms behind GBS 141

remain poorly understood [5, 42]. In addition to its association with GBS, the list of neurological 142


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and other consequences of ZIKV infection in adults and children – including 143

meningoencephalitis, paresis, and vasculitis - keeps growing [11, 24, 43]. 144

145

In other words, ZIKV infection appears to be associated with a broad and disparate range of 146

clinical and subclinical symptoms and outcomes. We would like to propose a novel hypothesis 147

that can help explain the multitude of diverse ZIKV infection outcomes both pre- and post-148

natally. While it requires experimental validation, this hypothesis is firmly grounded in evidence 149

from multiple areas of study, and allows us to make connections between previously un-150

connectable observations. It also enables us to generate new, testable hypotheses that may enable 151

development of effective treatment and prevention strategies. 152

153

Hypothesis: Connecting the dots 154

We now build the case that ZIKV-mediated pathogenicity – both fetal and adult - is due to 155

dysregulation of the activity of the RNA-editing enzymes, ADARs (Adenosine Deaminases 156

Acting on RNA), which in turn leads to inappropriate levels of post-transcriptional editing of 157

key proteins involved in metabolism of calcium and other ions, and homeostasis in neural 158

cells, thereby triggering a cascade of diverse neurological effects (Figure 1). We propose that 159

viral-triggered dysregulation of ADAR editing results in a handful of amino acid changes in key 160

neural proteins involved in ion transport and neurotransmitter metabolism. Either an excess or a 161

paucity of developmentally-appropriate edits lead to changes in ion permeability and excitability, 162

ultimately resulting in excitotoxicity and neuronal demise [44-46]. 163

164

What are ADARs? 165

ADARs (adenosine deaminases that act on RNA) are RNA editing enzymes that deaminate 166

adenosines (A) to produce inosines (I) within double-stranded RNAs [47]. These A-to-I changes 167

are translated as A-to-G substitutions in mRNA transcripts, thereby modulating proteome 168

diversity and expression by introducing nonsynonymous (amino acid changing) substitutions or 169

splice site changes, and serving as a mechanism of dynamic and nuanced post-transcriptional 170

regulation of gene expression [48]. There are three mammalian ADAR loci - ADAR, ADARB1 171

and ADARB2 [49]. Only ADAR and ADARB1 have proven deaminase activity [50], while 172

ADARB2 is thought to play a regulatory role through competition with other ADARs for 173


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substrate [51]. It should be noted that expression and editing activities of one family member can 174

be influenced by expression and editing activities of the other ADARs [52, 53]. ADARs play a 175

particularly prominent role in the nervous system as the majority of ADAR editing target genes 176

are expressed in the nervous system, including brain [49]. 177

178

ADAR expression is elevated in ZIKV-infected cells that exhibit cytopathic effects 179

This piece of evidence comes from a recent study that examined consequences of ZIKV infection 180

in three cell lines of primary human neural stem cells originally derived from three individual 181

fetal brains [54]. Two lines (K048 and K054) exhibited signs of reduced neuronal differentiation 182

(which is consistent with other ZIKV infected brain studies, including in vivo), while such signs 183

were not noticed in the third line, G010 [54]. Differential gene expression analysis showed global 184

similarities in transcriptome changes in K048 and K054, which were not shared with G010, 185

particularly among genes involved in innate immune pathways [54]. Their supplementary list of 186

differentially expressed genes reported that ADAR gene expression increased significantly in 187

K048 and K054 cells in response to ZIKV infection, while remained the same in G010 cells 188

(with 1.63 and 1.1-fold change, with the false discovery rate P values < 0.05 in K048 and K054, 189

but not in G010, respectively). In other words, only the cells with the observable cytopathic 190

effects exhibited an increase in ADAR expression (of course, the relationship between 191

expression and editing may not necessarily be linear [55]). While no significant change in 192

expression of ADARB1 and ADARB2 was reported, it should be noted that changes in the 193

ADAR gene expression can interfere with specific editing activity of the other ADARB1 enzyme 194

[52, 56]. 195

196

Our re-analysis of the McGrath et al. (2017) transcriptome data [54] shows that ADAR editing 197

activity per se, not merely expression of ADAR, appears to be higher in the cells with more 198

prominent cytopathic effects. Using the SnpEff variant annotation tool implemented in GATK, 199

we tallied nucleotide changes between mock and ZIKV-infected cells and found that ZIKV-200

infected samples harbor significantly higher numbers of A-to-G-changes (i.e., changes that can 201

be attributed to ADAR activity) in K048 cells compared to mock-infected cells (Mood’s median 202

test, P = 0.014). However, no significant differences were observed in K054 cells, where 203

cytopathic effects were not as prominent as in K048, and in G010 cells (P > 0.05). An alternative 204


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variant calling was performed using GATK Haplotype caller, and the distribution of missense A-205

to-G variants was examined in K048 cells, which had the highest read depth. Of the genes with 206

variants not shared between mock and ZIKV-infected cells (in other words, those less likely to 207

be genetic polymorphisms), there was a significantly higher fraction of genes with variants in at 208

least 2 samples in ZIKV-infected cells compared to mock-infected cells (10 versus 70 in mock 209

cell, and 59 versus 127 in ZIKV-infected cells), including well-known editing target GRIA3. 210

However, these preliminary analyses have significant limitations, one of which is the significant 211

difference in sequencing depth between samples (K048 had twice as many reads as the other two 212

cell lines) Thus, these preliminary findings offer only an initial glimpse into the potential effects 213

of ADAR editing in ZIKV infection, and require further experimental confirmation, including 214

careful validation of editing changes (if any) of specific key neural genes and/or whether 215

potential differences of normal editing patterns among individuals may be contributing to 216

pathogenesis mechanisms. Nonetheless, these preliminary findings are consistent with the 217

proposed hypothesis about the role of dysregulated editing changes in ZIKV infections; although 218

it remains to be determined whether these changes result from the redirection of ADAR p150 219

editing activity away from the host editome to ZIKV, or through changes in normal host editing 220

patterns because of increased ADAR p150 editing activity and/or interference between different 221

ADARs. 222

223

Appropriate ADAR editing is required for proper neuronal development 224

Severe CNS phenotypes are observed in ADAR knockouts and ADAR deficiency or loss of 225

function studies (e.g., [57]), including embryonic lethality [58], epilepsy, motor neuron death [59], 226

microcephaly and neural tube defects [60], as well as shortened life-span in worms [61]. Likewise, 227

decreased ADARB1 editing activity plays a role in the pathogenesis of a common motor neuron 228

disease, sporadic amyotrophic lateral sclerosis (ALS) [62], and various brain and neurological 229

cancers [52, 63]. 230

231

Mutations and polymorphisms in ADAR loci, such as the ADARB2 locus polymorphisms, have 232

been implicated in complex neurological phenotypes such as migraines [64], autism [65], and 233

genetic epilepsy [66]. Likewise, mutations in the ADAR gene that affect efficacy of RNA binding 234

and/or of A-to-I editing [67] have been associated with a rare human Mendelian disease, Aicardi-235


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Goutieres syndrome (AGS6) [68]. In its typical form, the damage caused by AGS resembles 236

neurodevelopmental pathology due to in utero infection [69], and is associated with an increased 237

level of interferon and upregulation of interferon-stimulated genes [70]. 238

239

ADAR editing is enriched in the nervous system [71]. One prominent example of ADAR editing 240

in the brain is the Q/R site of the glutamate receptor subunit GRIA2 (also known as GluA2), 241

where virtually complete (~100%) editing [72] of genomic glutamine codon 607 (Q607) to 242

arginine (R) results in multiple changes of the receptor properties, including cellular permeability 243

to calcium (Ca2+) [73]. Underediting of Q607R GRIA2 site (e.g., in the case of ADARB1 244

deficiency) results in increased influx of calcium, and neuronal death [74]. GRIA2 has an 245

additional ADAR editing site, R764G, which is edited mostly by ADAR, and results in different 246

electrophysiological properties. Editing at R764G gradually increases during neural 247

development, with the edited isoform fraction in adult brains ranging from 50% to 85% [75]. 248

249

Another well-documented ADAR editing event (via ADARB1) results in I-to-M, Q-to-R, and Y-250

to-C amino acid changes in the mammalian calcium voltage-gated channel subunit alpha1 D 251

channel CACNA1D (also known as CaV1.3) within the IQ domain, a calmodulin-binding site 252

responsible for regulating sensitivity to inhibitory Ca2+-feedback (CDI) [76]. Edited CACNA1D 253

proteins are expressed in both brain tissue and the surface membranes of primary neurons; 254

neurons with edited CACNA1D proteins show decreased CDI, as part of likely selective fine-255

tuning of Ca2+ feedback for low-voltage activated Ca2+ influx [76]. 256

257

GRIA2 and CACNA1D are not the only ADAR editing targets critical for neural function. 258

Functionally relevant editing targets include other glutamate receptors, such as glutamate 259

receptor subunit GRIA3 (also known as GluA3) [77], receptors for other neurotransmitters, 260

including excitatory and inhibitory neurotransmitters, such as serotonin 2C receptor 5HT2CR [78] 261

and the alpha3 subunit of gamma-aminobutyric acid (GABA) receptor (Gabra3) [79], respectively, 262

as well as ion channels (e.g., voltage-dependent potassium channel KCNA1 [80]), and 263

microRNAs [81]. Disruption of editing of these targets is known to lead to changes in excitability, 264

kinetics and other crucial functions of these receptors and ion channels, ultimately resulting in 265

neurodevelopmental defects, decreased proliferation and neuronal death [45]. In other words, 266


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seemingly minor amino acid changes in these proteins have the potential to significantly change 267

electrophysiology, calcium permeability and metabolism, among other properties, in neural (and 268

likely glial) cells, thus initiating a broad array of downstream neurophysiological changes such 269

as those observed in CZS and GBS. Indeed, because of glutamate’s fundamental role as a major 270

excitatory neurotransmitter in as many as 80 to 90% of brain neurons, most neurons and many 271

glial cells have glutamate receptors in their membranes [82]. Glutamatergic signaling also plays a 272

critical role in regulation of neural development, including neurotoxic effects of increased 273

calcium permeability due to, for example, inappropriate editing of GRIA2 [83]. 274

275

These examples offer a potential common explanation to the breadth of the observed clinical 276

symptoms and defects in both fetal and adult ZIKV infections, where variation in specific 277

manifestations across developmental stage at the time of infection can be attributed to the 278

nuanced spatio-temporal regulation of ADAR editing – and/or its infection-mediated 279

dysregulation, particularly in neural cells [84]. 280

281

ADAR is part of the antiviral response 282

Expression of ADARs, specifically, the ADAR1 p150 isoform, is regulated by interferon as part 283

of cell-autonomous immunity [85], with ADAR editing playing a role in an anti-viral activity, as 284

part of the innate immune response [86]. Recent experimental ZIKV studies have shown that the 285

interferon (IFN) type I response plays a role in ZIKV infection, that is that in human ZIKV 286

infections, expression of IFN cytokines increases, followed by increased expression of IFN-287

regulated genes, including ADARs [54]. Because the interactions between ZIKV and IFN pathway 288

activation are complex (e.g., may include mechanisms that suppress IFN signaling, such as 289

through action of viral NS5 protein [87], or by targeting STAT1 [88] and STAT2 [89]), and may 290

vary between ZIKV strains and/or specific variants of human genes or combination of the two 291

phenomena, that may help explain why not all ZIKV-positive pregnancies – or even fetuses from 292

the same pregnancy – show neurodevelopmental defects [90]. 293

294

Our recent work showed that ADAR editing plays a role in the molecular evolution of RNA 295

viruses [91], including ZIKV [92]. These results indicate that ADAR editing is active during ZIKV 296

infection. While it remains to be determined whether observed ADAR editing footprints were 297


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due to ADAR action in the mosquito or mammalian host (or both) [92], studies of the mammalian 298

immune response support the hypothesis that ADAR (specifically, the IFN-induced ADARp150 299

isoform) is activated in ZIKV infections. 300

Dysregulation of ADAR editing could potentially contribute to ZIKV pathogenesis via decreased 301

host editing (i.e., if ADAR editing activity is re-directed from the host editome to ZIKV) or via 302

increased host editing due to elevated expression of ADAR p150. ADAR p150 might directly 303

alter editing patterns, or do so indirectly if a stoichiometric change between ADAR p150 and 304

other ADARs modifies editing patterns. As noted previously, in mice both ADAR and ADARB1 305

knockouts can be fatal, e.g., due to underediting of key transcripts such as GRIA2 [58, 74, 93]. There 306

is mounting evidence that off-target editing by ADAR is also deleterious in humans [94]. 307

308

Thus, one of the potential explanations for mechanisms of congenital Zika syndrome may be 309

attributed to the disruption of editing and regulatory function of ADAR genes due to ZIKV-310

mediated IFN pathway activation (Figure 1). Specifically, physiological consequences of ADAR 311

editing dysregulation may be particularly critical for key synaptic signaling proteins, which in 312

turn result in shifts in calcium metabolism and homeostasis in the developing brain. For example, 313

changes in ADAR editing patterns can be linked to changes in (i) calcium permeability, and thus, 314

channel conductivity of GRIA2 and GRIA3 [95], and (ii) changes in how multiple isoforms of 5-315

HT2C – that have different binding affinities and functional potencies of agonists [96] – are 316

distributed within the brain. Appropriate ADAR editing thus could influence synaptic 317

transmission, as well as regulation of cell proliferation and neuronal differentiation [97], in 318

proliferative zones of the developing brain [98]. The changes of 5-HT2C editing have been linked 319

to mental disorders and suicide [99], although the full extent of editing consequences remains to 320

be elucidated [100]. Dysregulation of ADAR activity can also be potentially connected to the 321

neurodegeneration observed in GBS, where IFN-triggered elevated expression of ADAR results 322

in abnormal editing of proteins involved in synaptic signaling, thereby changing the ion 323

homeostasis of neurons, and hence, triggering the subsequent cascade of effects, similar to what 324

is observed in CZS. 325

326

327

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Conclusions and prospects 329

We posit that the experimental evidence from both the CZS and the GBS cases available so far is 330

consistent with the expectations of the hypothesis presented here. However, a causal link 331

between ADAR editing and subsequent neurodevelopmental or neurodegenerative sequelae in 332

CZS or GBS remains to be demonstrated. A critical first step would be to document ADAR 333

expression and ADAR editing levels in ZIKV infection in pregnancy and GBS, including self-334

regulation aspects of ADAR loci themselves [101], as well as expression and activity of calcium 335

homeostasis and metabolism proteins. Simultaneously, we need to elucidate the patterns and 336

regulatory processes involved in nuanced spatio-temporal changes in ADAR editing in brain 337

development during normal as well as ZIKV-positive pregnancies, and how these changes are 338

linked to observed clinical symptoms, because we still have only a limited understanding of the 339

complex regulation of ADAR editing across cells, tissues, developmental stages and individuals. 340

The observation of differential editing activity and its ramp-up during brain development [102] 341

must be supplemented by deeper understanding of how editing is regulated during different 342

stages of brain development and/or different locations in the CNS. This can be greatly aided by 343

the recently developed single-cell transcriptomics approaches [103]. 344

Understanding how ADAR editing influences brain development and function may lead to 345

development of treatment strategies that can be applied to newly infected ZIKV-positive 346

pregnant women, as well as to infants born or later diagnosed with CZS. It is likely that in utero 347

treatment strategies would vary depending on the stage of pregnancy (stemming from the 348

changing role of ADAR-edited proteins) at different stages of prenatal development. Treatment 349

strategies might range from (tailored) applications of existing immunotherapies to regulate 350

expression of interferon and/or other players of the cell-autonomous immunity pathway that are 351

upstream regulators of ADAR expression [85], to development of biomarkers of editing as well as 352

compounds targeting the editing process itself [104]. Similarly, we need to better understand the 353

role of ADAR editing and the functional implications of it (including quantitative aspects of how 354

much gets edited during any given time) on its respective targets during neurodegeneration of 355

GBS. 356

357

There might be an opportunity to intervene in the regulation of ADAR editing during/shortly 358

after ZIKV infection with the aim of preventing/diminishing the spectrum of ZIKV 359


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pathogenic/neurodevelopmental sequelae. For example, during pregnancy, within two-three 360

weeks of diagnosed ZIKV infection (i.e., within two-three weeks after the initial rash appears 361

[105]) a short course of drugs leading to the suppression of the type I interferon pathway can be 362

expected to result in down-regulation (or prevention of activation) of fetal ADAR activity. This 363

can be achieved by administering treatments currently used, e.g., to treat lupus [106]. Decisions to 364

use such treatments will be complicated by the fact that not all pregnant women exhibit clinical 365

signs of ZIKV infection [19]. However, the timing of asymptomatic infections can be inferred if 366

there is a finite window of exposure, by definition problematic in ZIKV-endemic areas. A similar 367

course of treatment can be applied if the early GBS symptoms were to appear a few weeks post-368

ZIKV infection (similar to that in HCV infections, [107]). Furthermore, the role of the recently 369

discovered member of the type III interferon pathway in the immune response needs to be 370

considered too [108]. Additionally, development of treatments specifically aimed at the reversal 371

of deleterious editing effects can also be pursued, e.g., via a combination of short-term 372

stimulation of expression of ADAR editing targets, administration of antagonists to the edited 373

protein versions and/or suppression of ADAR editing. 374

375

The same molecular mechanism postulated here to explain ZIKV pathogenesis may underlie 376

other conditions. For example, the increased editing of the calcium channel CaV1.3 has been 377

observed in dopamine-containing neurons affected in Parkinson’s disease, a second most 378

frequent neurodegenerative disease in the world [109], in which degeneration and death of these 379

(‘dopaminergic’) neurons is associated with motor symptoms of the disease [110]. Currently we 380

have neither a cure for it, nor a firm understanding of its underlying mechanisms [110, 111], 381

although it appears that (some form of) calcium dysregulation likely plays a prominent role [112]. 382

This dysregulation would result in oxidative and proteolytic stress and neuroinflammation that 383

may lead to mitochondrial dysfunction or vice versa [112, 113]. Evidence suggests that even in early 384

stages of Parkinson’s the calcium homeostasis is disturbed, in part attributable to what appears to 385

be a shift in cells reliance on (editable) CaV1.3 in lieu of CaV1.2 [114]. It is unclear whether the 386

changes in channel kinetics are due to CaV1.3 editing, and/or differential expression of 387

alternatively spliced isoforms CaV1.3 [115], as the study lacked the needed antibody resolution 388

[114]. In either case, this scenario offers an explanation of yet another neurodegenerative condition 389

(in addition to GBS) with unclear aetiology that could potentially be linked to possible changes 390


15

in ADAR editing patterns induced by prior infections (e.g., [116]), likely of minor viral variety, 391

which have mild to subclinical symptoms that nonetheless have the potential to (over)activate 392

ADARs as part of cell-autonomous immunity. Could changes in edited calcium channels also 393

explain the brain calcification observed following prenatal CMV (a herpesvirus) infection [117]? 394

Interestingly, brain calcification is also a common finding in CZS infants, born with or without 395

microcephaly [32], again suggesting a role for ADAR editing in ZIKV pathogenesis. 396

Ultimately, we would like to call for systematic, concerted and broad efforts to understand the 397

nuances of spatio-temporal distribution of ADARs and associated editing activity throughout the 398

brain and primary neurons, both in pregnancy and postnatally, as well the influence of viral 399

infections (including ZIKV) on such activity and subsequent clinical consequences. 400

401

Funding 402

This work was partially supported Kent State University Research Council Seed Award, and 403

Brain Health Institute Pilot Award to HP. MLW was supported by the National Institutes of 404

Health grant number GM083192. 405

406

407


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Figure 1.

A

B

408


17

409

Figure 1. Simplified (A) and detailed (B) summaries of our new hypothesis linking ZIKV 410

infection to congenital Zika syndrome and Guillain-Barre syndrome. (B) Overview of ZIKV 411

infection and the proposed mechanistic model of ZIKV-mediated pathogenesis. Upon infection, 412

ZIKV activates Toll-like-Receptor 3 (TLR3), which in turn activates the interferon (IFN) 413

pathway [118, 119]. Interferon-sensitive response elements (ISREs) upregulate interferon-stimulated 414

genes (ISGs), including the ADAR p150 isoform [85]. Thus, in addition to ADAR editing of viral 415

RNA as part of cell-autonomous immunity, ZIKV-driven activation of ADARp150 may also 416

lead to dysregulation of ADAR editing within host cells. These changes in levels of ADAR 417

editing may be due to increased abundance of ADAR p150 enzyme copies and/or due to 418

interference between ADAR p150 and other ADARs, e.g., through substrate competition with 419

ADARB1 [52, 101]. In turn, ZIKV-induced changes in editing patterns of host transcripts – such as 420

neurotransmitter receptors and transporters - can result in physiological changes in host proteins, 421

such as changes in ion permeability and excitability as illustrated by GRIA2 and GRIA3 [73, 77], in 422

turn leading to excitotoxicity and neuronal demise [45, 46]. Artistic drawing is by Peggy Muddles, 423

@vexedmuddler. 424

425


18

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1 title: dysregulation of rna editing may help explain ...1 1 title: dysregulation of rna editing...

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