ライフサイエンスコーパス: EEEV

1 EEEV efficiently utilizes both the VEEV-specific FXR pro

2 EEEV has a positive-sense RNA genome that, in infected c

3 EEEV HVD contains short linear motifs that recruit host

4 EEEV infection, which can cause severe encephalitis with

5 EEEV is a biodefence concern because of its potential fo

6 EEEV neurovirulence is influenced by the interaction of

7 EEEV-33 and EEEV-143 protect against disease following s

8 Unlike similar viruses such as SARS-CoV-2, EEEV replicates efficiently in neurons, producing progen

9 , we observed 70% protection when 10x LD(50) EEEV FL93-939-infected C57BL/6 mice were treated prophyl

10 ine elicited neutralizing antibodies against EEEV and protected against aerosol exposure to a North A

11 neutralizing human antibody response against EEEV and can facilitate development of vaccines and cand

12 understand the human immune response against EEEV.

13 Whereas all EEEV strains show conservation of two VLDLR-binding site

14 lpha/beta induction in vivo, which may allow EEEV to evade the host's innate immune responses and the

15 is new study demonstrate that North American EEEV exhibits a high level of redundancy in using host f

16 These residues are highly conserved among EEEV strains, and therefore a change in these residues m

17 low-density lipoprotein receptor (VLDLR), an EEEV receptor protein.

18 EEEV-33 and EEEV-143 protect against disease following stringent let

19 of two highly neutralizing mAbs, EEEV-33 and EEEV-143, were solved in complex with chimeric Sindbis/E

20 haviruses, can cause fatal encephalitis, and EEEV is a select agent of concern in biodefense.

21 at each site contributes to both EEEV-HS and EEEV-protein receptor interactions, providing evidence t

22 ssays (rRT-PCRs) for VEEV complex, MADV, and EEEV using whole-genome sequences.

23 ine encephalitis virus (WEEV) from SINV- and EEEV-like ancestors.

24 ately 35-amino-acid-long peptide of VEEV and EEEV capsid proteins plays the most critical role in the

25 nses and protected mice from lethal VEEV and EEEV challenges at 1 month postvaccination as well as le

26 single-dose protection from lethal VEEV and EEEV challenges, demonstrating the potential for a multi

27 est that the New World alphaviruses VEEV and EEEV developed an alternative mechanism of transcription

28 ure of rISFV vectors expressing the VEEV and EEEV E2/E1 glycoproteins also provided durable, single-d

29 attenuate virulence and express the VEEV and EEEV E2/E1 surface glycoproteins as vaccine antigens.

30 BDGR-49, potently reduced cellular VEEV and EEEV titers by >7 log at 1 muM and exhibited suitable in

31 ainst the encephalitic alphaviruses VEEV and EEEV, both of which can cause fatal disease.

32 astern equine encephalitis viruses (VEEV and EEEV, respectively) are mosquito-borne, neuroinvasive hu

33 es of attenuated vaccine strains of VEEV and EEEV.

34 in receptor-dependent infection in vitro and EEEV replication in animals.

35 n equine encephalitis virus (VEEV, WEEV, and EEEV) cause a febrile illness that may result in fatal n

36 Administration of one dose of anti-EEEV mAb protected mice from lethal subcutaneous or aero

37 basis for neutralization by protective anti-EEEV mAbs and suggest a path forward for treatment and v

38 and LDLR have also been shown to function as EEEV receptors.

39 Previous studies associated EEEV-HS interactions with three positively charged amino

40 public health threat, to date no attenuated EEEV variants have been applied as live EEEV vaccines.

41 tly been reported to be critical for binding EEEV to the very-low-density lipoprotein receptor (VLDLR

42 We show that each site contributes to both EEEV-HS and EEEV-protein receptor interactions, providin

43 Finally, when cell lines containing EEEV replicons encoding capsid were selected, replicons

44 In contrast, EEEV replicates poorly in lymphoid tissues, preferential

45 Our investigation demonstrated EEEV transmission through SOT.

46 y to induce detectable disease, the designed EEEV mutants remained highly immunogenic and, after a si

47 o induce transcriptional shutoff, diminished EEEV's ability to develop viremia.

48 the EEEV HS binding domain may arise during EEEV sylvatic cycles and that this variation may influen

49 Venezuelan (VEEV), Eastern (EEEV), and Western (WEEV) equine encephalitis viruses ar

50 ruses, including Venezuelan (VEEV), eastern (EEEV), and western equine encephalitis viruses, constitu

51 necessary or sufficient to support efficient EEEV infection.

52 ed mutants attractive vaccine candidates for EEEV infection.

53 This region is also critical for EEEV pathogenesis.

54 ed prior to organ recovery were positive for EEEV RNA.

55 eceptor 2 (ApoER2) as cellular receptors for EEEV and a distantly related alphavirus, Semliki Forest

56 tion and properties of a trans-replicase for EEEV.

57 ave previously identified those specific for EEEV.

58 Formalin-inactivated vaccines for EEEV and WEEV are also poorly immunogenic and no longer

59 functioning in transcription inhibition from EEEV-like virus.

60 In hamsters, EEEV replicates in visceral organs, produces viremia, an

61 To determine how EEEV may evade innate immune responses, we screened indi

62 Other identified EEEV nsP3 HVD-interacting host proteins are also capable

63 vely characterizes host ribosome activity in EEEV replication via a model parameter defining ribosome

64 Thus, multiple HS-binding sites exist in EEEV E2, and these sites overlap functionally with prote

65 unction of the hypervariable domain (HVD) in EEEV nsP3 for the assembly of viral replication complexe

66 ied HVD-binding factors are also involved in EEEV replication, but their roles are not as critical as

67 s processing products have a leading role in EEEV template RNA recognition.

68 ations in the nuclear localization signal in EEEV capsid protein have an additional negative effect o

69 RNAs, we found that translation of incoming EEEV genomes was almost completely inhibited in myeloid,

70 ate immune responses, we screened individual EEEV proteins for the ability to rescue the growth of a

71 f the capsid were introduced into infectious EEEV, the mutants exhibited delayed replication in Vero

72 y proteins with multiple LA3 repeats inhibit EEEV infection in cell culture and in mice.

73 In 2019, the largest EEEV outbreak in the United States for more than 50 year

74 There are no licensed EEEV vaccines or therapeutics for human use, warranting

75 ated EEEV variants have been applied as live EEEV vaccines.

76 etransplant organ donor evaluation and local EEEV surveillance.

77 nstructions of two highly neutralizing mAbs, EEEV-33 and EEEV-143, were solved in complex with chimer

78 cellular FXR and G3BP protein families, made EEEV cease to be neurovirulent.

79 ty of blood-filtering phagocytes to modulate EEEV viremia.IMPORTANCEVirus-GAG interactions have long

80 After infection with most EEEV strains, higher viremia levels and shorter survival

81 es: one that circulates in North America (NA EEEV) and the Caribbean and three that circulate in Cent

82 s lower and more consistent than that for NA EEEV (2.7 x 10(-4)), which exhibited considerable rate v

83 The single, monophyletic NA EEEV lineage exhibited mainly temporally associated rela

84 rames of all available SA EEEV and recent NA EEEV isolates were sequenced and used in evolutionary an

85 ed in the brain, liver, and muscle of the NA EEEV-infected animals at the time of euthanasia or death

86 rain lesions described for human EEE, the NA EEEV-infected animals developed meningoencephalitis in t

87 The NA EEEV-infected animals either died or were euthanized on

88 ut there was no detectable viremia in the NA EEEV-infected animals.

89 Unlike many alphaviruses, NA-EEEV infection of mice yields limited signs of febrile i

90 of HS receptors by naturally circulating NA-EEEV strains.

91 ivation of the major HS binding domain in NA-EEEV E2 demonstrated that the HS binding increased brain

92 We propose that HS binding by natural NA-EEEV strains alters tropism in vivo to antagonize/evade

93 d the extreme neurovirulence of wild-type NA-EEEV may be a consequence.

94 We demonstrate that wild-type NA-EEEV strain FL91-4679 uses HS as an attachment receptor

95 erican eastern equine encephalitis virus (NA-EEEV) is uniquely neurovirulent among encephalitic alpha

96 erican eastern equine encephalitis virus (NA-EEEV) isolates and demonstrated that naturally circulati

97 primary HS binding site of wild-type (WT) NA-EEEV viruses.

98 s (mAbs) isolated from a survivor of natural EEEV infection with potent (<20 pM) inhibitory activity

99 us cross-reactive) from survivors of natural EEEV infection.

100 Neuroinvasive EEEV infection directly contributed to the death of 1 or

101 inimal VLDLR decoy receptor that neutralizes EEEV infection and protects mice from lethal challenge.

102 ) twice per day for 6 days for VEEV, but not EEEV or WEEV.

103 The ability of EEEV P123 to form functional RNA replicases with heterol

104 with potent (<20 pM) inhibitory activity of EEEV.

105 Clinicians should be aware of EEEV as a cause of transplant-associated encephalitis.

106 similar to those described in human cases of EEEV.

107 Although the general characteristics of EEEV infection within the host cell are well-studied, it

108 Using this system, the compatibility of EEEV replicase components with counterparts from other a

109 e found that the month of first detection of EEEV in mosquito surveillance data and vector index (abu

110 urther investigate the viral determinants of EEEV vascular clearance and evaluate their role in virem

111 se in cases in 2019, although the ecology of EEEV is complex and further data is required to explore

112 VEEV, the more rapid and efficient entry of EEEV and WEEV by this route into the central nervous sys

113 There was no evidence of EEEV infection among donors of the 8 blood products tran

114 rom the donor and recipients for evidence of EEEV infection by multiple assays.

115 Each constraint contributes to the extent of EEEV inhibition for blockade of virus entry, fusion, and

116 and FXR protein families in the nsP3 HVD of EEEV make the virus avirulent for mice.

117 IMPORTANCE Infection of EEEV in humans can cause serious neurologic disease with

118 l cells facilitates binding and infection of EEEV, Western equine encephalitis virus, and Semliki For

119 Here, we demonstrate that infectivity of EEEV for myeloid lineage cells including DCs and macroph

120 Thus, alterations of interactions of EEEV HVD and likely HVDs of other alphaviruses with host

121 of the outbreak, we sequenced 80 isolates of EEEV and combined them with existing genomic data.

122 ic health threat, the molecular mechanism of EEEV replication and interaction with hosts is poorly un

123 es and altered virulence in a mouse model of EEEV disease.

124 contributes to the extreme neurovirulence of EEEV.

125 ost gene expression and to the protection of EEEV from the antiviral effects of IFNs.

126 usly demonstrated that the capsid protein of EEEV is a potent inhibitor of host cell gene expression

127 tified a region within the capsid protein of EEEV that contributes to the inhibition of host gene exp

128 the exceptionally high replication rates of EEEV and suggest a new means of its attenuation and new

129 ibe critical features for the recognition of EEEV by these mAbs including the epitope-paratope intera

130 Cryo-EM reconstructions of EEEV bound to a protective antibody at acidic and neutra

131 Cryo-EM reconstructions of EEEV in complex with these Fab fragments reveal structur

132 ot affect vRC formation; however, removal of EEEV's ability to interact with both protein families ha

133 The replicase of EEEV was also successfully reconstructed from P123 and n

134 explanation for the efficient replication of EEEV and may contribute to its highly pathogenic phenoty

135 The replication of EEEV has a unique requirement for host factors but is po

136 The template RNA of EEEV was shown to be replicated by replicases of diverse

137 In this study, we developed a set of EEEV mutants that contained combinations of deletions in

138 nce receptor interaction and the severity of EEEV disease.

139 e highly pathogenic North American strain of EEEV.

140 North American and South American strains of EEEV produce neurologic disease that resembles that asso

141 yoelectron microscopy (cryo-EM) structure of EEEV complexed with the HS analog heparin.

142 tiple cryo-electron microscopy structures of EEEV-VLDLR complexes and performing mutagenesis and func

143 Mosquito-borne transmission of EEEV to the organ donor was the likely source of infecti

144 The altered tropism of EEEV correlated with an almost complete avoidance of ser

145 In this regard, the tropisms of EEEV and VEEV differ dramatically, likely contributing t

146 osol exposure to a North American variety of EEEV.

147 tested the effects of these modifications on EEEV infection in vivo These mutations had cumulative ne

148 al and nonstructural protein gene regions on EEEV virulence.

149 ere contributes significantly to research on EEEV, providing a safe and versatile tool for studying t

150 ethal intranasal challenge of VEEV, WEEV, or EEEV in BALB/c mouse model.

151 ous or aerosol challenge with VEEV, WEEV, or EEEV was demonstrated out to 12 months after vaccination

152 sol challenge of mice with highly pathogenic EEEV.

153 We found laboratory evidence of recent EEEV infection in all organ recipients and the common do

154 nary and mosquito surveillance showed recent EEEV activity in counties nearby the organ donor's count

155 t inhibition of genome translation restricts EEEV infectivity for myeloid but not mesenchymal lineage

156 iological evidence that some, if not all, SA EEEV strains are attenuated for humans.

157 t circulate in Central and South America (SA EEEV).

158 city and ecology, and propose that NA and SA EEEV be reclassified as distinct species in the EEE comp

159 ding upon the sequences used, with NA and SA EEEV diverging ca. 922 to 4,856 years ago and the two ma

160 divergences between members of the NA and SA EEEV lineages, consistent with major differences in path

161 tein open reading frames of all available SA EEEV and recent NA EEEV isolates were sequenced and used

162 In contrast, SA EEEV comprised three divergent lineages, two consisting

163 nucleotide substitution rate per year for SA EEEV (1.2 x 10(-4)) was lower and more consistent than t

164 . 922 to 4,856 years ago and the two main SA EEEV lineages diverging ca. 577 to 2,927 years ago.

165 A phylogenetic comparison of SA EEEV and Venezuelan equine encephalitis viruses (VEEV) d

166 The SA EEEV-infected animals developed peak viremia titers of 2

167 to anorexia and neurologic signs, but the SA EEEV-infected animals remained healthy and survived.

168 were solved in complex with chimeric Sindbis/EEEV virions to 7.2 angstrom and 8.3 angstrom, respectiv

169 uction of the chimeric virus, Sindbis (SINV)/EEEV, in complex with a potently neutralizing and effica

170 d that the WT and decreased GAG-binding SINV-EEEV virions traffic similarly from a subcutaneous inocu

171 dispersal of wild-type (WT) and mutant SINV-EEEV virions from the inoculation site to the draining l

172 tutions promotes prolonged retention of SINV-EEEV particles in the murine blood circulation in an exp

173 dbis-eastern equine encephalitis virus (SINV-EEEV) particles can be removed from the murine blood cir

174 the removal of enhanced GAG-binding WT SINV-EEEV virions from the blood circulation in a reductionis

175 An analysis of stable EEEV replicons expressing mutant capsid proteins corrobo

176 describe use of the golden hamster to study EEEV-induced acute vasculitis and encephalitis.

177 functions for treatment against subcutaneous EEEV challenge.

178 host proteins are also capable of supporting EEEV replication, albeit with a dramatically lower effic

179 WEEV infections and 30 to 70% in symptomatic EEEV infections.

180 Our new study demonstrates that EEEV exhibits a unique level of redundancy in the use of

181 ese observations in vivo, demonstrating that EEEV is compromised in its ability to replicate within l

182 We determined that EEEV infection of myeloid lineage cells was restricted a

183 e VLDLR ligand-binding domain and found that EEEV and SFV interact with the same cellular receptor th

184 ates the experimental data and predicts that EEEV rapidly concentrates host ribosomes densely on vira

185 genesis and functional studies, we show that EEEV uses multiple sites (E1/E2 cleft and E2 A domain) t

186 The EEEV replicase, on the other hand, demonstrated limited

187 The EEEV trans-replicase developed here contributes signific

188 ine monoclonal antibodies (mAbs) against the EEEV E2 glycoprotein, several of which have 'elite' acti

189 Infection of HEK293T cells harboring the EEEV template RNA with EEEV or Western equine encephalit

190 esults suggest that natural variation in the EEEV HS binding domain may arise during EEEV sylvatic cy

191 opy (cryo-EM) to determine structures of the EEEV and SFV spike glycoproteins bound to the VLDLR liga

192 Only expression of the EEEV capsid facilitated NDV-GFP replication.

193 An electrostatic map of the EEEV E1/E2 heterotrimer based upon the recent Chikunguny

194 ll, this study defines viral features of the EEEV E2 glycoprotein that influence tissue-specific vira

195 The hypervariable domain of the EEEV nsP3 protein interacts with all of the members of t

196 We identified two large basic patches on the EEEV E2 glycoprotein which contain two known GAG-binding

197 Similarly, the EEEV replicon and V/W/E combination vaccine elicited neu

198 conservation of two VLDLR-binding sites, the EEEV PE-6 strain and a few other EEE complex members fea

199 a was exceptionally high in 2019, as was the EEEV infection rate.

200 At the same time, EEEV infection resulted only in a limited activation of

201 change in these residues might be linked to EEEV neurovirulence.

202 contribution of each HS interaction site to EEEV HS- and protein receptor-dependent infection in vit

203 heterologous nsP4s was more efficient using EEEV template RNA than heterologous alphavirus template

204 developed a trivalent vaccine against VEEV, EEEV, and WEEV using a combination of attenuated chimeri

205 bination of attenuated chimeric Sindbis-VEEV/EEEV/WEEV viruses to streamline production and an H(2)O(

206 roduces 10-fold higher viremia than virulent EEEV strains.

207 including Eastern equine encephalitis virus (EEEV) and Semliki Forest virus (SFV).

208 trains of eastern equine encephalitis virus (EEEV) bind heparan sulfate (HS) receptors and this inter

209 Eastern equine encephalitis virus (EEEV) causes a rare but severe disease in horses and hum

210 Eastern equine encephalitis virus (EEEV) causes human encephalitis in North America (NA), b

211 Eastern equine encephalitis virus (EEEV) causes sporadic but often severe cases of human an

212 Eastern equine encephalitis virus (EEEV) causes sporadic epidemics of human and equine dise

213 Eastern equine encephalitis virus (EEEV) infection was identified during testing of endomyo

214 Eastern equine encephalitis virus (EEEV) is a human and veterinary pathogen that causes spo

215 Eastern equine encephalitis virus (EEEV) is a mosquito-transmitted alphavirus that can caus

216 Eastern equine encephalitis virus (EEEV) is a mosquito-transmitted alphavirus with a high c

217 Eastern equine encephalitis virus (EEEV) is a representative member of the New World alphav

218 Eastern equine encephalitis virus (EEEV) is an arthropod-borne, positive-sense RNA alphavir

219 MPORTANCE Eastern equine encephalitis virus (EEEV) is one of the most pathogenic New World alphavirus

220 Eastern equine encephalitis virus (EEEV) is one of the most virulent viruses endemic to Nor

221 Eastern equine encephalitis virus (EEEV) is the most pathogenic member of the Alphavirus ge

222 Eastern equine encephalitis virus (EEEV) is the most virulent alphavirus that infects human

223 hree anti-Eastern equine encephalitis virus (EEEV) neutralizing human mAbs targeting overlapping epit

224 Eastern equine encephalitis virus (EEEV) produces the most severe human arboviral disease i

225 Eastern equine encephalitis virus (EEEV) produces the most severe human arboviral diseases

226 ssing the Eastern equine encephalitis virus (EEEV) structural proteins and identify LDLR as a candida

227 ctures of eastern equine encephalitis virus (EEEV) under acidic conditions.

228 Eastern equine encephalitis virus (EEEV) usually cycles between Culiseta melanura mosquitoe

229 WEEV), or eastern equine encephalitis virus (EEEV) when given individually or in combination (V/W/E)

230 Eastern equine encephalitis virus (EEEV), a mosquito-borne icosahedral alphavirus found mai

231 s (VEEV), eastern equine encephalitis virus (EEEV), and western equine encephalitis virus (WEEV) are

232 VEEV) and eastern equine encephalitis virus (EEEV), evolved separately from those of the Old World, i

233 Eastern equine encephalitis virus (EEEV), Madariaga virus (MADV), and Venezuelan equine enc

234 WEEV) and eastern equine encephalitis virus (EEEV), two New World alphaviruses, can cause fatal encep

235 VEEV) and Eastern equine encephalitis virus (EEEV), which have demonstrated potential for natural dis

236 EEV), and eastern equine encephalitis virus (EEEV).

237 viruses (Eastern equine encephalitis virus [EEEV], Western equine encephalitis virus [WEEV], Venezue

238 ging from Eastern equine encephalitis virus [EEEV]-specific to alphavirus cross-reactive) from surviv

239 and Venezuelan equine encephalitis viruses (EEEV and VEEV, respectively) cause severe morbidity and

240 for a variety of vertebrate hosts, in which EEEV induces a highly debilitating disease, and the outc

241 ng intranasal or subcutaneous challenge with EEEV.

242 T cells harboring the EEEV template RNA with EEEV or Western equine encephalitis virus prominently ac

243 nst subsequent infection with wild-type (wt) EEEV.