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Shashank Tripathi, Vinod R. M. T. Balasubramaniam, Julia A. Brown, Ignacio Mena, Alesha Grant, Susana V. Bardina, Kevin Maringer, Megan C. Schwarz, Ana M. Maestre, Marion Sourisseau, Randy A. Albrecht, Florian Krammer, Matthew J. Evans, Ana Fernandez-Sesma, Jean K. Lim, Adolfo García-Sastre
A novel Zika virus mouse model reveals strain specific differences in virus pathogenesis and host inflammatory immune responses
www.plospathogens.org
www.plospathogens.org
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2.1259 0 Td
([)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
-36.0337 -1.2983 Td
(7)Tj
0 g
(].)Tj
1.2585 0 Td
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4.218 0 Td
(determinants)Tj
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(and)Tj
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(new)Tj
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1.8765 0 Td
[(\n)12()]TJ
1.0148 0 Td
[( )-13(\n)14()7()20()]TJ
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(,)Tj
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2.2677 0 Td
[()1()]TJ
1.0772 0 Td
[( )-13(\n)15( )3()]TJ
/F8 1 Tf
1.8198 0 Td
(and)Tj
/F12 1 Tf
1.7348 0 Td
[(\n)12()]TJ
1.0148 0 Td
[( )-13(\n)15( )3()]TJ
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1.8198 0 Td
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(ZIKV)Tj
-32.9497 -1.2983 Td
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3.7927 0 Td
(and)Tj
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([)Tj
0.83 0.64 0.02 0 k
(2)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2642 0 Td
(8)Tj
0 g
(].)Tj
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(ZIKV)Tj
2.5342 0 Td
([)Tj
0.83 0.64 0.02 0 k
(9)Tj
0 g
(].)Tj
/F12 1 Tf
1.5987 0 Td
[()-16()]TJ
1.2359 0 Td
[( )-13(\n)15( )3()]TJ
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-34.5144 -1.2983 Td
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1.0261 0 Td
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(III)Tj
1.2416 0 Td
(IFN)Tj
1.8255 0 Td
([)Tj
0.83 0.64 0.02 0 k
(10)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.7347 0 Td
(11)Tj
0 g
(].)Tj
1.7348 0 Td
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1.1112 0 Td
(the)Tj
1.4683 0 Td
(last)Tj
1.5591 0 Td
(year)Tj
1.9049 0 Td
(there)Tj
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(extensive)Tj
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-34.2309 -1.3039 Td
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1.0261 0 Td
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3.3165 0 Td
(new)Tj
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(animal)Tj
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(ZIKV)Tj
2.5284 0 Td
(pathogenesis)Tj
5.3518 0 Td
([)Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(].)Tj
1.6044 0 Td
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1.2019 0 Td
(the)Tj
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-32.3771 -1.2983 Td
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3.8835 0 Td
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2.143 0 Td
[()8()]TJ
0.907 0 Td
[()11()]TJ
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-35.6369 -1.2982 Td
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(and)Tj
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3.2485 0 Td
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1.7802 0 Td
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3.6567 0 Td
(mice)Tj
2.1543 0 Td
(were)Tj
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-36.3569 -1.2983 Td
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5.4198 0 Td
(ZIKV)Tj
2.5284 0 Td
(infections)Tj
4.1499 0 Td
([)Tj
0.83 0.64 0.02 0 k
(4)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2643 0 Td
(12)Tj
0 g
(].)Tj
1.7348 0 Td
(Later,)Tj
2.5115 0 Td
(ZIKV)Tj
2.5284 0 Td
(infection)Tj
3.7928 0 Td
(and)Tj
1.7291 0 Td
(disease)Tj
3.016 0 Td
(symptoms)Tj
4.3597 0 Td
(were)Tj
2.126 0 Td
(dem-)Tj
-35.1607 -1.3039 Td
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3.9911 0 Td
(in)Tj
1.0318 0 Td
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3.6623 0 Td
(mice,)Tj
2.3755 0 Td
(rhesus)Tj
2.7949 0 Td
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3.7871 0 Td
(and)Tj
1.7348 0 Td
(chicken)Tj
3.3278 0 Td
(embryos)Tj
3.6624 0 Td
([)Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2642 0 Td
(13)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(17)Tj
0 g
(].)Tj
3.2031 0 Td
(Similar)Tj
3.1011 0 Td
(to)Tj
1.0261 0 Td
(den-)Tj
-34.9622 -1.2983 Td
(gue)Tj
1.6327 0 Td
(viruses,)Tj
3.2145 0 Td
(ZIKV)Tj
2.5285 0 Td
(does)Tj
2.0409 0 Td
(not)Tj
1.5704 0 Td
(cause)Tj
2.3924 0 Td
(infection)Tj
3.7927 0 Td
(and)Tj
1.7291 0 Td
(disease)Tj
3.0161 0 Td
(in)Tj
1.0375 0 Td
(wild)Tj
1.9445 0 Td
(type)Tj
1.9162 0 Td
(adult)Tj
2.2507 0 Td
(mice.)Tj
2.3811 0 Td
(To)Tj
1.338 0 Td
(overcome)Tj
-32.7853 -1.2983 Td
(this)Tj
1.6724 0 Td
(limitation,)Tj
4.3993 0 Td
(scientists)Tj
3.8268 0 Td
(have)Tj
2.0636 0 Td
(used)Tj
2.0579 0 Td
(immunocompromised,)Tj
9.479 0 Td
(neonatal)Tj
3.6624 0 Td
(or)Tj
1.0998 0 Td
(special)Tj
2.8913 0 Td
(mouse)Tj
2.8573 0 Td
(strains)Tj
-34.0098 -1.3039 Td
(such)Tj
2.0579 0 Td
(as)Tj
1.0148 0 Td
(SJL)Tj
1.5647 0 Td
(strain)Tj
2.5001 0 Td
(to)Tj
1.0262 0 Td
(study)Tj
2.3867 0 Td
(ZIKV)Tj
2.5285 0 Td
(pathogenesis)Tj
5.3575 0 Td
([)Tj
0.83 0.64 0.02 0 k
(13)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.7348 0 Td
(14)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.3946 0 Td
(17)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(19)Tj
0 g
(].)Tj
3.2088 0 Td
(Although)Tj
4.0025 0 Td
(mice)Tj
2.1543 0 Td
(are)Tj
1.4513 0 Td
(significantly)Tj
-32.3827 -1.2982 Td
(different)Tj
3.6566 0 Td
(than)Tj
2.0296 0 Td
(humans,)Tj
3.6624 0 Td
(especially)Tj
4.0138 0 Td
(in)Tj
1.0375 0 Td
(their)Tj
2.1089 0 Td
(placental)Tj
3.7928 0 Td
(anatomy)Tj
3.7133 0 Td
(and)Tj
1.7291 0 Td
(gestation)Tj
3.8268 0 Td
(period,)Tj
3.0557 0 Td
(scientists)Tj
-32.6265 -1.2983 Td
(have)Tj
2.0579 0 Td
(demonstrated)Tj
5.76 0 Td
(their)Tj
2.1089 0 Td
(utility)Tj
2.5795 0 Td
(in)Tj
1.0375 0 Td
(reproducing)Tj
5.1704 0 Td
(ZIKV)Tj
2.5285 0 Td
(pathogenesis)Tj
5.3517 0 Td
(consistent)Tj
4.2576 0 Td
(with)Tj
1.9956 0 Td
(that)Tj
1.7802 0 Td
(in)Tj
-34.6278 -1.3039 Td
(humans)Tj
3.4355 0 Td
([)Tj
0.83 0.64 0.02 0 k
(20)Tj
0 g
(].)Tj
2.0806 0 Td
(Mouse)Tj
2.931 0 Td
(models)Tj
3.1011 0 Td
(have)Tj
2.0636 0 Td
(been)Tj
2.1203 0 Td
(used)Tj
2.0636 0 Td
(to)Tj
1.0205 0 Td
(demonstrate)Tj
5.2327 0 Td
(ZIKV)Tj
2.5342 0 Td
(ability)Tj
2.6929 0 Td
(to)Tj
1.0261 0 Td
(cause)Tj
2.3868 0 Td
(fetal)Tj
1.9105 0 Td
(abnor-)Tj
-34.5994 -1.2983 Td
(malities,)Tj
3.5602 0 Td
(deterioration)Tj
5.4652 0 Td
(of)Tj
1.0148 0 Td
(gonadal)Tj
3.3845 0 Td
(tissue)Tj
2.4548 0 Td
(and)Tj
1.7348 0 Td
(infection)Tj
3.7871 0 Td
(through)Tj
3.4469 0 Td
(sexual)Tj
2.6759 0 Td
(route)Tj
2.3471 0 Td
([)Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2642 0 Td
(13)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.3946 0 Td
(21)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(28)Tj
0 g
(].)Tj
-32.5301 -1.2983 Td
(Immunocompromised)Tj
9.3259 0 Td
(mouse)Tj
2.8573 0 Td
(models)Tj
3.1067 0 Td
(have)Tj
2.058 0 Td
(been)Tj
2.1259 0 Td
(useful)Tj
2.5909 0 Td
(in)Tj
1.0375 0 Td
(recapitulating)Tj
5.7429 0 Td
(the)Tj
1.4684 0 Td
(neurotropic)Tj
-30.3135 -1.2982 Td
(nature)Tj
2.8232 0 Td
(of)Tj
1.0148 0 Td
(ZIKV)Tj
2.5285 0 Td
(infection)Tj
3.7928 0 Td
(and)Tj
1.7291 0 Td
(in)Tj
1.0375 0 Td
(demonstrating)Tj
6.0887 0 Td
(a)Tj
0.652 0 Td
(critical)Tj
2.9537 0 Td
(role)Tj
1.7688 0 Td
(of)Tj
1.0148 0 Td
(IFN)Tj
1.8198 0 Td
(induction)Tj
4.1386 0 Td
(and)Tj
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(signaling)Tj
-33.0914 -1.3039 Td
(for)Tj
1.3832 0 Td
(protection)Tj
4.3824 0 Td
(against)Tj
3.0274 0 Td
(ZIKV)Tj
2.5285 0 Td
([)Tj
0.83 0.64 0.02 0 k
(14)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.7404 0 Td
(17)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.3947 0 Td
(18)Tj
0 g
(].)Tj
-13.2604 -1.2983 Td
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1.1111 0 Td
(an)Tj
1.2019 0 Td
(earlier)Tj
2.7553 0 Td
(report,)Tj
2.9367 0 Td
(we)Tj
1.3266 0 Td
(showed)Tj
3.2541 0 Td
(that)Tj
1.7745 0 Td
(ZIKV)Tj
2.5285 0 Td
(targets)Tj
2.8743 0 Td
(human)Tj
3.0784 0 Td
(STAT2)Tj
3.0784 0 Td
(for)Tj
1.3833 0 Td
(degradation,)Tj
5.2497 0 Td
(thereby)Tj
-33.749 -1.2983 Td
(reducing)Tj
3.7757 0 Td
(induction)Tj
4.1329 0 Td
(of)Tj
1.0148 0 Td
(IFN)Tj
1.8255 0 Td
(stimulated)Tj
4.422 0 Td
(genes)Tj
2.4434 0 Td
(\(ISGs\))Tj
2.7893 0 Td
(and)Tj
1.7348 0 Td
(subsequent)Tj
4.6998 0 Td
(antiviral)Tj
3.5433 0 Td
(responses)Tj
4.0932 0 Td
(in)Tj
-34.4747 -1.3039 Td
(human)Tj
3.0784 0 Td
(cells,)Tj
2.1429 0 Td
(but)Tj
1.5534 0 Td
(not)Tj
1.5761 0 Td
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(mouse)Tj
2.8629 0 Td
(cells)Tj
1.9163 0 Td
([)Tj
0.83 0.64 0.02 0 k
(29)Tj
0 g
(].)Tj
2.0806 0 Td
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2.5625 0 Td
(findings)Tj
3.4979 0 Td
(were)Tj
2.1203 0 Td
(corroborated)Tj
5.4708 0 Td
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1.1792 0 Td
(another)Tj
3.3336 0 Td
(study)Tj
-34.4067 -1.2982 Td
(which)Tj
2.6475 0 Td
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1.7688 0 Td
(concluded)Tj
4.3767 0 Td
(proteasomal)Tj
5.1363 0 Td
(targeting)Tj
3.7927 0 Td
(of)Tj
1.0148 0 Td
(STAT2)Tj
3.0784 0 Td
(by)Tj
1.1793 0 Td
(ZIKV)Tj
2.5341 0 Td
(NS5)Tj
1.9049 0 Td
(protein)Tj
3.1521 0 Td
([)Tj
0.83 0.64 0.02 0 k
(30)Tj
0 g
(].)Tj
2.0806 0 Td
(Following)Tj
-32.6662 -1.2983 Td
(up)Tj
1.2642 0 Td
(on)Tj
1.2756 0 Td
(these)Tj
2.2507 0 Td
(observations)Tj
5.261 0 Td
(we)Tj
1.3323 0 Td
(now)Tj
1.9559 0 Td
(demonstrate)Tj
5.2327 0 Td
(that)Tj
1.7802 0 Td
(ZIKV)Tj
2.5285 0 Td
(challenge)Tj
3.9571 0 Td
(in)Tj
/F12 1 Tf
1.0375 0 Td
[()10()11()22()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 498.7842 282.8409 cm
BT
/F12 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 508.2519 278.4188 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(mice)Tj
2.1486 0 Td
(results)Tj
2.8119 0 Td
(in)Tj
-35.7842 -1.3039 Td
(ZIKV)Tj
2.5285 0 Td
(infection)Tj
3.7927 0 Td
(and)Tj
1.7292 0 Td
(spread)Tj
2.8516 0 Td
(to)Tj
1.0261 0 Td
(CNS,)Tj
2.3244 0 Td
(gonads)Tj
3.0614 0 Td
(and)Tj
1.7291 0 Td
(other)Tj
2.3471 0 Td
(vital)Tj
1.9219 0 Td
(organs,)Tj
3.1351 0 Td
(with)Tj
1.9956 0 Td
(manifestation)Tj
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(of)Tj
1.0148 0 Td
(neu-)Tj
-35.172 -1.2982 Td
(rological)Tj
3.685 0 Td
(symptoms.)Tj
4.5865 0 Td
(Further)Tj
3.2654 0 Td
(we)Tj
1.3266 0 Td
(have)Tj
2.0637 0 Td
(used)Tj
2.0579 0 Td
(the)Tj
/F12 1 Tf
1.4683 0 Td
[()10()11()22()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 404.6173 256.8188 cm
BT
/F12 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 414.0283 252.3968 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(mouse)Tj
2.8573 0 Td
(model)Tj
2.7439 0 Td
(to)Tj
1.0261 0 Td
(compare)Tj
3.719 0 Td
(the)Tj
1.4684 0 Td
(virulence)Tj
-33.2161 -1.2982 Td
(and)Tj
1.7291 0 Td
(pathogenesis)Tj
5.3518 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.6576 0 Td
(panel)Tj
2.3868 0 Td
(of)Tj
1.0148 0 Td
(ZIKV)Tj
2.5285 0 Td
(strains)Tj
2.863 0 Td
(representing)Tj
5.2382 0 Td
(different)Tj
3.6567 0 Td
(lineages)Tj
3.3902 0 Td
(and)Tj
1.7292 0 Td
(spatio-tempo-)Tj
-31.5607 -1.3039 Td
(ral)Tj
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3.6397 0 Td
(resulted)Tj
3.4016 0 Td
(in)Tj
1.0318 0 Td
(80%)Tj
1.9332 0 Td
(lethality)Tj
3.4129 0 Td
(in)Tj
1.0374 0 Td
(5)Tj
0.6973 0 Td
(week)Tj
2.245 0 Td
(old)Tj
/F12 1 Tf
1.5023 0 Td
[()23()-8()6()16()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 559.2188 620.844 cm
BT
/F13 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 603.3826 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(mice)Tj
2.1543 0 Td
(by)Tj
1.1792 0 Td
(day)Tj
1.6384 0 Td
(14)Tj
1.1679 0 Td
([)Tj
0.83 0.64 0.02 0 k
(17)Tj
0 g
(].)Tj
2.0806 0 Td
(WT)Tj
1.7971 0 Td
(mice)Tj
2.1543 0 Td
(were)Tj
2.1203 0 Td
(refractory)Tj
4.1613 0 Td
(to)Tj
1.0261 0 Td
(ZIKV)Tj
2.5285 0 Td
(infection)Tj
3.7927 0 Td
(and)Tj
1.7292 0 Td
(did)Tj
1.542 0 Td
(not)Tj
1.576 0 Td
(display)Tj
3.0274 0 Td
(any)Tj
1.6555 0 Td
(signs)Tj
-35.3308 -1.2982 Td
(of)Tj
1.0147 0 Td
(disease)Tj
3.0161 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(1a,)Tj
1.355 0 Td
(1b)Tj
1.2019 0 Td
(and)Tj
1.7291 0 Td
(1c)Tj
0 g
(\).)Tj
1.6894 0 Td
(ZIKV)Tj
2.5285 0 Td
(RNA)Tj
2.262 0 Td
(measurements)Tj
6.0321 0 Td
(on)Tj
1.2756 0 Td
(day)Tj
1.6328 0 Td
(6)Tj
0.6973 0 Td
(post)Tj
1.9048 0 Td
(infection)Tj
3.7871 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(brain,)Tj
-34.452 -1.2983 Td
(ovary,)Tj
2.6645 0 Td
(spleen)Tj
2.7439 0 Td
(and)Tj
1.7291 0 Td
(liver)Tj
1.9843 0 Td
(of)Tj
/F12 1 Tf
1.0148 0 Td
[()10()11()22()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 321.3921 581.8393 cm
BT
/F12 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 330.8031 577.4173 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(and)Tj
/F12 1 Tf
1.7291 0 Td
[()23()-8()6()16()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 372.4724 581.8393 cm
BT
/F12 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 381.8834 577.4173 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(mice)Tj
2.1543 0 Td
(showed)Tj
3.2541 0 Td
(the)Tj
1.4684 0 Td
(highest)Tj
3.0897 0 Td
(viral)Tj
1.9956 0 Td
(RNA)Tj
2.262 0 Td
(levels)Tj
2.3754 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
-35.8182 -1.3039 Td
(brain,)Tj
2.5682 0 Td
(followed)Tj
3.651 0 Td
(by)Tj
1.1792 0 Td
(ovary,)Tj
2.6645 0 Td
(spleen)Tj
2.7383 0 Td
(and)Tj
1.7291 0 Td
(minimum)Tj
4.2915 0 Td
(levels)Tj
2.3754 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.4684 0 Td
(liver)Tj
1.9842 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8142 0 Td
(1d)Tj
0 g
(\).)Tj
1.7915 0 Td
(Interestingly,)Tj
5.4878 0 Td
(despite)Tj
-34.7751 -1.2982 Td
(delayed)Tj
3.2541 0 Td
(lethality,)Tj
3.6454 0 Td
(the)Tj
1.4683 0 Td
(viral)Tj
1.9956 0 Td
(RNA)Tj
2.262 0 Td
(levels)Tj
2.3698 0 Td
(in)Tj
/F12 1 Tf
1.0374 0 Td
[()23()-8()6()16()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 384.7181 555.8173 cm
BT
/F12 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 394.1291 551.3952 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(mice)Tj
2.1543 0 Td
(were)Tj
2.1259 0 Td
(higher)Tj
2.8007 0 Td
(than)Tj
/F12 1 Tf
2.0295 0 Td
[()10()11()22()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 505.2472 555.8173 cm
BT
/F12 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 514.6582 551.3952 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(mice)Tj
2.1543 0 Td
(in)Tj
1.0374 0 Td
(all)Tj
1.1452 0 Td
(the)Tj
-35.8012 -1.2982 Td
(organs)Tj
2.9083 0 Td
(tested,)Tj
2.7779 0 Td
(except)Tj
2.7666 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4684 0 Td
(brain.)Tj
2.5738 0 Td
(In)Tj
1.1112 0 Td
(addition,)Tj
3.821 0 Td
(we)Tj
1.3267 0 Td
(also)Tj
1.7688 0 Td
(evaluated)Tj
3.9911 0 Td
(viremia)Tj
3.2542 0 Td
(and)Tj
1.7348 0 Td
(viral)Tj
1.9898 0 Td
(RNA)Tj
2.262 0 Td
(levels)Tj
-34.7921 -1.3039 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.474 0 Td
(brain)Tj
2.3471 0 Td
(and)Tj
1.7291 0 Td
(ovaries)Tj
3.0387 0 Td
(of)Tj
/F12 1 Tf
1.0148 0 Td
[()10()11()22()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 326.3811 529.8519 cm
BT
/F12 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 335.8488 525.3732 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(mice)Tj
2.1543 0 Td
(on)Tj
1.2699 0 Td
(days)Tj
2.0012 0 Td
(2,)Tj
0.9184 0 Td
(4)Tj
0.6974 0 Td
(and)Tj
1.7291 0 Td
(6)Tj
0.6973 0 Td
(post)Tj
1.9049 0 Td
(infection)Tj
3.787 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(S1)Tj
1.5137 0 Td
(Fig)Tj
0 g
(\).)Tj
2.0466 0 Td
(We)Tj
1.6101 0 Td
(observed)Tj
-33.9134 -1.2982 Td
(that)Tj
1.7745 0 Td
(Uganda)Tj
3.3675 0 Td
(ZIKV)Tj
2.5285 0 Td
(reached)Tj
3.3505 0 Td
(maximum)Tj
4.3766 0 Td
(RNA)Tj
2.262 0 Td
(levels)Tj
2.3755 0 Td
(in)Tj
1.0318 0 Td
(serum)Tj
2.7269 0 Td
(\(up)Tj
1.6044 0 Td
(to)Tj
1.0261 0 Td
(10^)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 479.3385 516.8692 cm
BT
/F8 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(9)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 485.1212 512.3905 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(ZIKV)Tj
2.5284 0 Td
(RNA)Tj
2.2621 0 Td
(copies/ml\))Tj
-33.3011 -1.2982 Td
(as)Tj
1.0148 0 Td
(early)Tj
2.1486 0 Td
(as)Tj
1.0148 0 Td
(2)Tj
0.6973 0 Td
(days)Tj
1.9956 0 Td
(post)Tj
1.9049 0 Td
(infection)Tj
3.7927 0 Td
(and)Tj
1.7291 0 Td
(showed)Tj
3.2485 0 Td
(slightly)Tj
3.0898 0 Td
(reduced)Tj
3.4412 0 Td
(levels)Tj
2.3754 0 Td
(by)Tj
1.1849 0 Td
(day)Tj
1.6326 0 Td
(6)Tj
0.6973 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(S1a)Tj
1.9446 0 Td
(Fig)Tj
0 g
(\).)Tj
2.0466 0 Td
(In)Tj
1.1112 0 Td
(com-)Tj
-35.0699 -1.2983 Td
(parison)Tj
3.2258 0 Td
(ZIKV)Tj
2.5285 0 Td
(RNA)Tj
2.262 0 Td
(kept)Tj
1.9559 0 Td
(on)Tj
1.2756 0 Td
(increasing)Tj
4.3313 0 Td
(in)Tj
1.0318 0 Td
(brain)Tj
2.3471 0 Td
(tissue)Tj
2.4604 0 Td
(from)Tj
2.2054 0 Td
(day)Tj
1.6384 0 Td
(2)Tj
0.6973 0 Td
(to)Tj
1.0205 0 Td
(day)Tj
1.6383 0 Td
(6)Tj
0.6973 0 Td
(post)Tj
1.8992 0 Td
(infection)Tj
3.7927 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(S1b)Tj
-35.0075 -1.3039 Td
(Fig)Tj
0 g
(\).)Tj
2.0466 0 Td
(In)Tj
1.1055 0 Td
(the)Tj
1.4683 0 Td
(ovaries)Tj
3.0387 0 Td
(ZIKV)Tj
2.5285 0 Td
(reached)Tj
3.3562 0 Td
(maximum)Tj
4.371 0 Td
(copy)Tj
2.1203 0 Td
(numbers)Tj
3.7814 0 Td
(by)Tj
1.1792 0 Td
(day)Tj
1.6384 0 Td
(4)Tj
0.6973 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(S1C)Tj
2.1713 0 Td
(Fig)Tj
0 g
(\).)Tj
2.0466 0 Td
(These)Tj
2.5681 0 Td
(trends)Tj
-34.1174 -1.2983 Td
(of)Tj
1.0148 0 Td
(temporal)Tj
3.838 0 Td
(changes)Tj
3.4016 0 Td
(in)Tj
1.0375 0 Td
(ZIKV)Tj
2.5285 0 Td
(RNA)Tj
2.262 0 Td
(in)Tj
1.0318 0 Td
(different)Tj
3.6567 0 Td
(organs)Tj
2.9083 0 Td
(are)Tj
1.4513 0 Td
(similar)Tj
2.9821 0 Td
(to)Tj
1.0261 0 Td
(what)Tj
2.1655 0 Td
(has)Tj
1.5421 0 Td
(been)Tj
2.1203 0 Td
(reported)Tj
3.6623 0 Td
(in)Tj
/F12 1 Tf
-36.6289 -1.2982 Td
[()23()-8()6()16()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 224.3905 451.8425 cm
BT
/F13 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 233.8015 447.4204 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(mice)Tj
2.1543 0 Td
([)Tj
0.83 0.64 0.02 0 k
(17)Tj
0 g
(].)Tj
2.0749 0 Td
(Taken)Tj
2.7326 0 Td
(together,)Tj
/F12 1 Tf
3.7644 0 Td
[()10()11()22()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 361.0771 451.8425 cm
BT
/F12 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 370.4881 447.4204 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(mice)Tj
2.1543 0 Td
(support)Tj
3.3222 0 Td
(ZIKV)Tj
2.5284 0 Td
(infection,)Tj
4.0139 0 Td
(with)Tj
2.0012 0 Td
(virus)Tj
2.1997 0 Td
(spread)Tj
2.8573 0 Td
(to)Tj
-36.1244 -1.3039 Td
(CNS,)Tj
2.3187 0 Td
(gonads,)Tj
3.2882 0 Td
(spleen)Tj
2.7439 0 Td
(and)Tj
1.7291 0 Td
(liver.)Tj
2.2054 0 Td
(In)Tj
1.1111 0 Td
(comparison)Tj
/F12 1 Tf
4.9776 0 Td
[()23()-8()6()16()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 408.0755 438.8598 cm
BT
/F12 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 417.5433 434.3811 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(mice)Tj
2.1543 0 Td
(show)Tj
2.296 0 Td
(a)Tj
0.6576 0 Td
(delayed)Tj
3.2542 0 Td
(onset)Tj
2.3584 0 Td
(of)Tj
1.0148 0 Td
(disease,)Tj
-33.4882 -1.2982 Td
(but)Tj
1.5534 0 Td
(higher)Tj
2.8006 0 Td
(viral)Tj
1.9956 0 Td
(RNA)Tj
2.262 0 Td
(levels)Tj
2.3754 0 Td
(in)Tj
1.0318 0 Td
(most)Tj
2.2054 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(sample)Tj
3.0217 0 Td
(tissues.)Tj
3.0443 0 Td
(In)Tj
1.1055 0 Td
(addition)Tj
3.6 0 Td
(to)Tj
1.0261 0 Td
(STAT2)Tj
3.0784 0 Td
(independent)Tj
-31.589 -1.2983 Td
(signaling)Tj
3.8211 0 Td
(of)Tj
1.0148 0 Td
(IFN)Tj
1.8255 0 Td
(through)Tj
3.4469 0 Td
(the)Tj
1.4683 0 Td
(type)Tj
1.9106 0 Td
(I)Tj
0.5612 0 Td
(IFN)Tj
1.8255 0 Td
(receptor,)Tj
3.7814 0 Td
(the)Tj
/F12 1 Tf
1.4684 0 Td
[()10()11()22()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 431.2629 412.8377 cm
BT
/F12 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 440.7307 408.4157 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(and)Tj
/F12 1 Tf
1.7291 0 Td
[()23()-8()6()16()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 482.4 412.8377 cm
BT
/F12 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 491.811 408.4157 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(differ)Tj
2.3867 0 Td
(in)Tj
1.0375 0 Td
(their)Tj
2.1033 0 Td
(ability)Tj
-34.7071 -1.3039 Td
(to)Tj
1.0261 0 Td
(support)Tj
3.3165 0 Td
(type)Tj
1.9162 0 Td
(I)Tj
0.5613 0 Td
(and)Tj
1.7291 0 Td
(III)Tj
1.2416 0 Td
(IFN)Tj
1.8198 0 Td
(signaling)Tj
3.8268 0 Td
([)Tj
0.83 0.64 0.02 0 k
(31)Tj
0 g
(],)Tj
2.0749 0 Td
(which)Tj
2.6476 0 Td
(may)Tj
1.9332 0 Td
(explain)Tj
3.1181 0 Td
(their)Tj
2.1089 0 Td
(differential)Tj
4.6034 0 Td
(susceptibility)Tj
-31.9235 -1.2982 Td
(to)Tj
1.0261 0 Td
(ZIKV)Tj
2.5285 0 Td
(induced)Tj
3.4639 0 Td
(disease.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 347.9811 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Phylogenetic)Tj
5.8724 0 Td
(and)Tj
1.8662 0 Td
(amino)Tj
2.9055 0 Td
(acid)Tj
2.0315 0 Td
(variance)Tj
3.9497 0 Td
(analysis)Tj
3.7843 0 Td
(of)Tj
1.0441 0 Td
(ZIKV)Tj
2.4331 0 Td
(strains)Tj
3.1323 0 Td
(selected)Tj
-27.0191 -1.1669 Td
(for)Tj
1.3748 0 Td
(comparison)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 317.0267 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Phylogenetically,)Tj
6.9675 0 Td
(ZIKV)Tj
2.5285 0 Td
(can)Tj
1.627 0 Td
(be)Tj
1.1509 0 Td
(divided)Tj
3.2145 0 Td
(into)Tj
1.8425 0 Td
(African)Tj
3.2371 0 Td
(and)Tj
1.7291 0 Td
(Asian)Tj
2.5172 0 Td
(lineages)Tj
3.3902 0 Td
([)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2586 0 Td
(7)Tj
0 g
(].)Tj
1.2585 0 Td
(The)Tj
1.7859 0 Td
(African)Tj
3.2371 0 Td
(line-)Tj
-35.7446 -1.3039 Td
(age)Tj
1.542 0 Td
(viruses)Tj
2.9877 0 Td
(have)Tj
2.0579 0 Td
(caused)Tj
2.9197 0 Td
(sporadic)Tj
3.6283 0 Td
(human)Tj
3.0784 0 Td
(infections)Tj
4.1499 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(last)Tj
1.5591 0 Td
(century,)Tj
3.4922 0 Td
(resulting)Tj
3.7304 0 Td
(in)Tj
1.0375 0 Td
(mild,)Tj
2.3017 0 Td
(febrile)Tj
-34.9906 -1.2982 Td
(disease)Tj
3.016 0 Td
(symptoms)Tj
4.3597 0 Td
([)Tj
0.83 0.64 0.02 0 k
(7)Tj
0 g
(].)Tj
1.5987 0 Td
(The)Tj
1.7858 0 Td
(Asian)Tj
2.5115 0 Td
(lineage)Tj
3.0274 0 Td
(has)Tj
1.542 0 Td
(however)Tj
3.617 0 Td
(emerged)Tj
3.6737 0 Td
(at)Tj
0.9524 0 Td
(a)Tj
0.652 0 Td
(larger)Tj
2.5341 0 Td
(scale)Tj
2.1033 0 Td
(displaying)Tj
4.3086 0 Td
(vec-)Tj
-35.6822 -1.2983 Td
(tor-borne)Tj
4.1045 0 Td
(as)Tj
1.0148 0 Td
(well)Tj
1.8198 0 Td
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