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Nicole Stichling, Maarit Suomalainen, Justin W. Flatt, Markus Schmid, Martin Pacesa, Silvio Hemmi, Wolfgang Jungraithmayr, Mareike D. Maler, Marina A. Freudenberg, Andreas Plückthun, Tobias May, Mario Köster, György Fejer, Urs F. Greber
Lung macrophage scavenger receptor SR-A6 (MARCO) is an adenovirus type-specific virus entry receptor
www.plospathogens.org
www.plospathogens.org
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(additional)Tj
4.218 0 Td
(cues)Tj
1.9332 0 Td
(from)Tj
2.1826 0 Td
(the)Tj
1.4514 0 Td
(cell,)Tj
-34.4237 -1.3039 Td
(enable)Tj
2.7665 0 Td
(the)Tj
1.4514 0 Td
(virus)Tj
2.1713 0 Td
(to)Tj
1.0148 0 Td
(penetrate)Tj
3.9004 0 Td
(into)Tj
1.8199 0 Td
(the)Tj
1.4513 0 Td
(cytosol)Tj
2.9764 0 Td
([)Tj
0.83 0.64 0.02 0 k
(22)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(24)Tj
0 g
(].)Tj
3.4979 0 Td
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1.6044 0 Td
(example,)Tj
3.7304 0 Td
(the)Tj
1.4513 0 Td
(coxsackie)Tj
3.9685 0 Td
(adenovirus)Tj
-31.8045 -1.2982 Td
(receptor)Tj
3.5092 0 Td
(\(CAR\))Tj
2.8346 0 Td
(mediates)Tj
3.7304 0 Td
(initial)Tj
2.5058 0 Td
(attachment)Tj
4.6658 0 Td
(of)Tj
1.0035 0 Td
(species)Tj
2.9537 0 Td
(A)Tj
0.8957 0 Td
(and)Tj
1.7178 0 Td
(C)Tj
0.8731 0 Td
(HAdVs)Tj
3.2258 0 Td
(to)Tj
1.0148 0 Td
(non-immune)Tj
5.5218 0 Td
(cells)Tj
-34.452 -1.2983 Td
([)Tj
0.83 0.64 0.02 0 k
(25)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(27)Tj
0 g
(],)Tj
3.4979 0 Td
(distinct)Tj
3.1634 0 Td
(from)Tj
2.1827 0 Td
(the)Tj
1.4513 0 Td
(membrane)Tj
4.5184 0 Td
(cofactor)Tj
3.4242 0 Td
(protein)Tj
3.1125 0 Td
(CD46,)Tj
2.7666 0 Td
(or)Tj
1.0828 0 Td
(desmoglein-2,)Tj
5.7826 0 Td
(which)Tj
2.6249 0 Td
(are)Tj
1.4286 0 Td
(the)Tj
-35.0359 -1.2983 Td
(main)Tj
2.262 0 Td
(receptors)Tj
3.8664 0 Td
(for)Tj
1.3663 0 Td
(species)Tj
2.9537 0 Td
(D)Tj
0.9524 0 Td
(and)Tj
1.7121 0 Td
(B)Tj
0.7937 0 Td
(viruses,)Tj
3.1635 0 Td
(respectively)Tj
4.8132 0 Td
([)Tj
0.83 0.64 0.02 0 k
(28)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(30)Tj
0 g
(].)Tj
3.4979 0 Td
(CAR)Tj
2.1713 0 Td
(engages)Tj
3.2995 0 Td
(retrograde)Tj
4.354 0 Td
(acto-)Tj
-35.206 -1.3039 Td
(myosin)Tj
3.1407 0 Td
(mediated)Tj
3.8948 0 Td
(transport)Tj
3.8721 0 Td
(and)Tj
1.7121 0 Td
(exerts)Tj
2.5285 0 Td
(mechanical)Tj
4.7055 0 Td
(stress)Tj
2.3641 0 Td
(on)Tj
1.2585 0 Td
(HAdV-C5)Tj
4.3427 0 Td
(against)Tj
2.9877 0 Td
(the)Tj
1.4513 0 Td
(holding)Tj
3.2655 0 Td
(force)Tj
-35.5235 -1.2982 Td
(of)Tj
1.0034 0 Td
(the)Tj
1.4513 0 Td
(secondary)Tj
4.218 0 Td
(integrin)Tj
3.3618 0 Td
(receptors,)Tj
4.0819 0 Td
(which)Tj
2.6192 0 Td
(leads)Tj
2.1827 0 Td
(to)Tj
1.0148 0 Td
(the)Tj
1.4513 0 Td
(exposure)Tj
3.7644 0 Td
(of)Tj
1.0034 0 Td
(the)Tj
1.4514 0 Td
(membrane)Tj
4.524 0 Td
(lytic)Tj
1.8765 0 Td
(protein)Tj
-34.0041 -1.2983 Td
(of)Tj
1.0034 0 Td
(the)Tj
1.4513 0 Td
(virion)Tj
2.5966 0 Td
([)Tj
0.83 0.64 0.02 0 k
(31)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.7121 0 Td
(32)Tj
0 g
(].)Tj
1.7178 0 Td
(CAR,)Tj
2.3867 0 Td
(CD46)Tj
2.5455 0 Td
(and)Tj
1.7121 0 Td
(DSG-2)Tj
2.948 0 Td
(interactions)Tj
4.8926 0 Td
(with)Tj
1.9729 0 Td
(HAdV)Tj
2.8743 0 Td
(are)Tj
1.4287 0 Td
(mediated)Tj
3.8947 0 Td
(by)Tj
1.1679 0 Td
(the)Tj
-34.3046 -1.3039 Td
(globular)Tj
3.4752 0 Td
(head)Tj
2.109 0 Td
(domain)Tj
3.2881 0 Td
(\(knob\))Tj
2.9254 0 Td
(of)Tj
1.0034 0 Td
(the)Tj
1.4514 0 Td
(fiber)Tj
2.0466 0 Td
(which)Tj
2.6192 0 Td
(protrudes)Tj
4.0705 0 Td
(from)Tj
2.1826 0 Td
(the)Tj
1.4514 0 Td
(vertex)Tj
2.6192 0 Td
(of)Tj
1.0034 0 Td
(the)Tj
1.4514 0 Td
(icosahedral)Tj
-31.6968 -1.2983 Td
(virion)Tj
2.5965 0 Td
([)Tj
0.83 0.64 0.02 0 k
(33)Tj
0 g
(].)Tj
2.0466 0 Td
(Yet,)Tj
1.7801 0 Td
(CAR)Tj
2.1713 0 Td
(and)Tj
1.7122 0 Td
(DSG-2)Tj
2.9423 0 Td
(are)Tj
1.4287 0 Td
(not)Tj
1.559 0 Td
(expressed)Tj
4.0365 0 Td
(on)Tj
1.2643 0 Td
(macrophages,)Tj
5.6579 0 Td
(and)Tj
1.7121 0 Td
(although)Tj
3.7077 0 Td
(CD46)Tj
2.5455 0 Td
(is)Tj
0.839 0 Td
(a)Tj
-35.9997 -1.2983 Td
(ubiquitously)Tj
5.1476 0 Td
(expressed)Tj
4.0365 0 Td
(protein)Tj
3.1125 0 Td
(in)Tj
1.0261 0 Td
(humans,)Tj
3.6227 0 Td
(its)Tj
1.1281 0 Td
(expression)Tj
4.405 0 Td
(in)Tj
1.0205 0 Td
(mouse)Tj
2.829 0 Td
(is)Tj
0.839 0 Td
(restricted)Tj
3.9231 0 Td
(to)Tj
1.0148 0 Td
(testis)Tj
2.194 0 Td
([)Tj
0.83 0.64 0.02 0 k
(34)Tj
0 g
(].)Tj
-0.004 Tc
-33.1027 -1.3039 Td
(HAdVs)Tj
3.2598 0 Td
(are)Tj
1.4456 0 Td
(non-enveloped,)Tj
6.4743 0 Td
(double)Tj
2.9594 0 Td
(stranded)Tj
3.7077 0 Td
(DNA)Tj
2.3811 0 Td
(viruses.)Tj
3.2088 0 Td
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2.2393 0 Td
(replicate)Tj
3.6227 0 Td
(in)Tj
1.0374 0 Td
(the)Tj
1.4684 0 Td
(host)Tj
1.9162 0 Td
(cell)Tj
-34.9169 -1.2982 Td
(nucleus.)Tj
3.5035 0 Td
(Their)Tj
2.4208 0 Td
(outer)Tj
2.3471 0 Td
(surface)Tj
3.0501 0 Td
(is)Tj
0.8447 0 Td
(composed)Tj
4.3086 0 Td
(of)Tj
1.0148 0 Td
(three)Tj
2.262 0 Td
(main)Tj
2.2904 0 Td
(proteins,)Tj
3.7417 0 Td
(hexon,)Tj
2.914 0 Td
(penton)Tj
3.0671 0 Td
(base)Tj
1.9445 0 Td
(and)Tj
1.7292 0 Td
(fiber.)Tj
-35.4385 -1.2983 Td
(Penton)Tj
3.101 0 Td
(base)Tj
1.9503 0 Td
(and)Tj
1.7291 0 Td
(fiber)Tj
2.0749 0 Td
(localize)Tj
3.1805 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.4684 0 Td
(capsid)Tj
2.7495 0 Td
(vertices,)Tj
3.4696 0 Td
(whereas)Tj
3.4469 0 Td
(the)Tj
1.4684 0 Td
(structural)Tj
4.0818 0 Td
(framework)Tj
4.6148 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
-35.3761 -1.3039 Td
(capsid)Tj
2.7495 0 Td
(is)Tj
0.8504 0 Td
(formed)Tj
3.1521 0 Td
(by)Tj
1.1849 0 Td
(hexons)Tj
3.0501 0 Td
([)Tj
0.83 0.64 0.02 0 k
(35)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.7404 0 Td
(36)Tj
0 g
(].)Tj
1.7348 0 Td
(HAdVs)Tj
3.2542 0 Td
(are)Tj
1.4513 0 Td
(classified)Tj
3.8154 0 Td
(into)Tj
1.8425 0 Td
(seven)Tj
2.4321 0 Td
(species)Tj
2.9934 0 Td
(A)Tj
0.9071 0 Td
(to)Tj
1.0261 0 Td
(G)Tj
0.9354 0 Td
(with)Tj
1.9956 0 Td
(more)Tj
-35.1153 -1.2983 Td
(than)Tj
2.0295 0 Td
(50)Tj
1.1679 0 Td
(serotypes,)Tj
4.1669 0 Td
(and)Tj
1.7291 0 Td
(nearly)Tj
2.6986 0 Td
(70)Tj
1.1679 0 Td
(bioinformatically)Tj
7.1092 0 Td
(defined)Tj
3.2258 0 Td
(types)Tj
2.2734 0 Td
([)Tj
0.83 0.64 0.02 0 k
(37)Tj
0 g
(].)Tj
2.0749 0 Td
(HAdV)Tj
2.897 0 Td
(infections)Tj
4.1499 0 Td
(in)Tj
-34.6901 -1.2982 Td
(immuno-competent)Tj
8.3167 0 Td
(hosts)Tj
2.2791 0 Td
(manifest)Tj
3.6567 0 Td
(with)Tj
2.0012 0 Td
(mild)Tj
2.0806 0 Td
(respiratory)Tj
4.5921 0 Td
(\(HAdV-B,)Tj
4.3937 0 Td
(-C,)Tj
1.457 0 Td
(-E\),)Tj
1.7064 0 Td
(ocular)Tj
2.7269 0 Td
(\(HAdV-B,)Tj
-33.2104 -1.2983 Td
(-D,)Tj
1.5306 0 Td
(-F\))Tj
1.44 0 Td
(or)Tj
1.0942 0 Td
(gastrointestinal)Tj
6.3496 0 Td
(infections)Tj
4.1555 0 Td
(\(HAdV-F\).)Tj
4.6772 0 Td
(The)Tj
1.7801 0 Td
(widespread)Tj
4.7622 0 Td
(application)Tj
4.6771 0 Td
(of)Tj
1.0148 0 Td
(HAdV-based)Tj
-31.4813 -1.3039 Td
(vectors)Tj
3.0557 0 Td
(in)Tj
1.0375 0 Td
(gene)Tj
2.0806 0 Td
(therapy,)Tj
3.4752 0 Td
(cancer)Tj
2.8403 0 Td
(gene)Tj
2.0806 0 Td
(therapy)Tj
3.2485 0 Td
(and)Tj
1.7291 0 Td
(vaccination)Tj
4.8302 0 Td
(enhances)Tj
3.9062 0 Td
(the)Tj
1.474 0 Td
(medical)Tj
3.3618 0 Td
(impor-)Tj
-33.1197 -1.2983 Td
(tance)Tj
2.347 0 Td
(of)Tj
1.0148 0 Td
(these)Tj
2.2564 0 Td
(viruses)Tj
2.982 0 Td
([)Tj
0.83 0.64 0.02 0 k
(38)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(40)Tj
0 g
(].)Tj
-7.404 -1.2983 Td
(HAdV-C5)Tj
4.388 0 Td
(based)Tj
2.4718 0 Td
(toxicity)Tj
3.2031 0 Td
(is)Tj
0.8447 0 Td
(strongly)Tj
3.4753 0 Td
(linked)Tj
2.7269 0 Td
(to)Tj
1.0261 0 Td
(innate)Tj
2.7383 0 Td
(immune)Tj
3.6283 0 Td
(responses)Tj
4.0932 0 Td
(against)Tj
3.0274 0 Td
(the)Tj
1.4683 0 Td
(virions)Tj
-34.2876 -1.3039 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
(41)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(43)Tj
0 g
(].)Tj
3.2032 0 Td
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5.5785 0 Td
(are)Tj
1.4513 0 Td
(central)Tj
2.9651 0 Td
(actors)Tj
2.6135 0 Td
(in)Tj
1.0375 0 Td
(these)Tj
2.2507 0 Td
(responses.)Tj
4.3199 0 Td
(For)Tj
1.6271 0 Td
(example,)Tj
3.7757 0 Td
(intravenous)Tj
-30.5572 -1.2982 Td
(administration)Tj
6.1681 0 Td
(of)Tj
1.0148 0 Td
(HAdV-C5-derived)Tj
7.7272 0 Td
(vectors)Tj
3.0557 0 Td
(into)Tj
1.8425 0 Td
(mice)Tj
2.1487 0 Td
(leads)Tj
2.211 0 Td
(to)Tj
1.0261 0 Td
(rapid)Tj
2.3358 0 Td
(capture)Tj
3.2144 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(vector)Tj
2.6929 0 Td
(par-)Tj
-35.9204 -1.2983 Td
(ticles)Tj
2.2393 0 Td
(by)Tj
1.1792 0 Td
(the)Tj
1.4683 0 Td
(liver)Tj
1.9843 0 Td
(resident)Tj
3.4412 0 Td
(macrophages,)Tj
5.7316 0 Td
(the)Tj
1.4684 0 Td
(Kupffer)Tj
3.3108 0 Td
(cells,)Tj
2.143 0 Td
(as)Tj
1.0148 0 Td
(well)Tj
1.8198 0 Td
(as)Tj
1.0148 0 Td
(by)Tj
1.1849 0 Td
(the)Tj
1.4683 0 Td
(spleen)Tj
2.7383 0 Td
(marginal)Tj
-32.207 -1.3039 Td
(zone)Tj
2.1032 0 Td
(macrophages)Tj
5.4936 0 Td
(and)Tj
1.7234 0 Td
(myeloid)Tj
3.4583 0 Td
(dendritic)Tj
3.8664 0 Td
(cells,)Tj
2.1373 0 Td
(and)Tj
1.7178 0 Td
(these)Tj
2.245 0 Td
(cells)Tj
1.9162 0 Td
(contribute)Tj
4.3823 0 Td
(to)Tj
1.0148 0 Td
(the)Tj
1.4627 0 Td
(vector-induced)Tj
-31.521 -1.2983 Td
(early)Tj
2.1486 0 Td
(production)Tj
4.7168 0 Td
(of)Tj
1.0148 0 Td
(proinflammatory)Tj
7.1036 0 Td
(cytokines,)Tj
4.2236 0 Td
(such)Tj
2.0636 0 Td
(as)Tj
1.0148 0 Td
(type)Tj
1.9105 0 Td
(I)Tj
0.5613 0 Td
(IFNs,)Tj
2.4094 0 Td
(interleukin-1)Tj
/F11 1 Tf
()Tj
/F6 1 Tf
6.0321 0 Td
(\(IL-1)Tj
/F11 1 Tf
()Tj
/F6 1 Tf
(\),)Tj
-33.1991 -1.2983 Td
(interleukin-6)Tj
5.4651 0 Td
(\(IL-6\))Tj
2.6022 0 Td
(and)Tj
1.7291 0 Td
(tumor)Tj
2.7439 0 Td
(necrosis)Tj
3.4866 0 Td
(factor)Tj
2.5399 0 Td
(\(TNF\))Tj
2.7779 0 Td
([)Tj
0.83 0.64 0.02 0 k
(10)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.7348 0 Td
(44)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(46)Tj
0 g
(].)Tj
3.2031 0 Td
(Furthermore,)Tj
5.6183 0 Td
(lung)Tj
2.0069 0 Td
(macro-)Tj
-33.9078 -1.2982 Td
(phages)Tj
2.948 0 Td
(capture)Tj
3.2144 0 Td
(HAdV-C5-derived)Tj
7.7329 0 Td
(vectors)Tj
3.0557 0 Td
(administered)Tj
5.4879 0 Td
(via)Tj
1.3776 0 Td
(the)Tj
1.4683 0 Td
(respiratory)Tj
4.5978 0 Td
(tract)Tj
2.0466 0 Td
(and)Tj
1.7291 0 Td
(respond)Tj
-33.6583 -1.3039 Td
(with)Tj
1.9955 0 Td
(a)Tj
0.652 0 Td
(rapid)Tj
2.3414 0 Td
(induction)Tj
4.1329 0 Td
(of)Tj
1.0148 0 Td
(TNF)Tj
2.0976 0 Td
(and)Tj
1.7291 0 Td
(IL-6)Tj
1.9219 0 Td
([)Tj
0.83 0.64 0.02 0 k
(47)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.7405 0 Td
(48)Tj
0 g
(].)Tj
1.7348 0 Td
(Finally,)Tj
3.1691 0 Td
(mouse)Tj
2.8629 0 Td
(alveolar)Tj
3.3336 0 Td
(macrophage-like)Tj
6.9278 0 Td
(MPI)Tj
-35.6539 -1.2983 Td
(cells)Tj
1.9218 0 Td
(produce)Tj
3.515 0 Td
(robust)Tj
2.7949 0 Td
(levels)Tj
2.3754 0 Td
(of)Tj
1.0148 0 Td
(cytokines)Tj
3.9968 0 Td
(upon)Tj
2.3188 0 Td
(inoculation)Tj
4.7962 0 Td
(with)Tj
2.0012 0 Td
(early)Tj
2.1487 0 Td
(gene)Tj
2.0806 0 Td
(expression)Tj
4.4617 0 Td
(defective)Tj
-33.4259 -1.2983 Td
(HAdV-C5_dE1_GFP)Tj
8.7476 0 Td
([)Tj
0.83 0.64 0.02 0 k
(49)Tj
0 g
(].)Tj
2.0806 0 Td
(These)Tj
2.5682 0 Td
(acute)Tj
2.3244 0 Td
(phase)Tj
2.4831 0 Td
(macrophage)Tj
5.142 0 Td
(responses)Tj
4.0932 0 Td
(are)Tj
1.4514 0 Td
(directly)Tj
3.2315 0 Td
(triggered)Tj
3.8324 0 Td
(by)Tj
-35.9544 -1.3039 Td
(the)Tj
1.4683 0 Td
(incoming)Tj
4.0648 0 Td
(virions,)Tj
3.2258 0 Td
(and)Tj
1.7292 0 Td
(critically)Tj
3.651 0 Td
(require)Tj
3.1124 0 Td
(interaction)Tj
4.6091 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(incoming)Tj
4.0649 0 Td
(viral)Tj
1.9956 0 Td
(genome)Tj
3.4072 0 Td
(with)Tj
1.9956 0 Td
(the)Tj
-35.807 -1.2982 Td
(cytoplasmic)Tj
4.9719 0 Td
(DNA)Tj
2.3754 0 Td
(sensor)Tj
2.7949 0 Td
(cyclic)Tj
2.4548 0 Td
(GMP-AMP)Tj
4.8756 0 Td
(synthase)Tj
3.6283 0 Td
(\(cGAS\))Tj
3.1975 0 Td
(and/or)Tj
2.9367 0 Td
(the)Tj
1.474 0 Td
(endosomal)Tj
4.5921 0 Td
(DNA)Tj
2.3754 0 Td
(sen-)Tj
-35.6766 -1.2983 Td
(sor)Tj
1.4569 0 Td
(Toll-like)Tj
3.617 0 Td
(receptor)Tj
3.5547 0 Td
(9)Tj
0.6973 0 Td
(\(TLR9\))Tj
3.1464 0 Td
([)Tj
0.83 0.64 0.02 0 k
(44)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.7348 0 Td
(50)Tj
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6.7521 0 Td
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(\(BMM\),)Tj
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(HAdV-C)Tj
-33.3182 -1.304 Td
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(49)Tj
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(HAdV-C5)Tj
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(in)Tj
-34.4974 -1.3039 Td
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(HAdV-C5_dE1_GFP)Tj
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2.7836 0 Td
(\(Msr1\),)Tj
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(SR-B1)Tj
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(\(SCAR-B1\))Tj
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(or)Tj
1.0828 0 Td
(SR-B2)Tj
2.6759 0 Td
(\(CD36\).)Tj
3.4129 0 Td
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-35.5405 -1.2982 Td
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4.8755 0 Td
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4.0932 0 Td
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(Fig)Tj
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(1B)Tj
0 g
(\).)Tj
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(SR-A6)Tj
2.7836 0 Td
(shRNA)Tj
3.1068 0 Td
(reduced)Tj
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(SR-A1)Tj
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1.7007 0 Td
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(SR-A1)Tj
2.7836 0 Td
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1.0772 0 Td
(SR-B2)Tj
2.6816 0 Td
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3.4582 0 Td
(actually)Tj
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(boosted)Tj
-30.7103 -1.3039 Td
(HAdV-C5_dE1_GFP)Tj
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(infection)Tj
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3.3675 0 Td
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3.3619 0 Td
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1.0091 0 Td
(be)Tj
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1.0091 0 Td
(the)Tj
1.44 0 Td
(SR-A6)Tj
2.7836 0 Td
(shRNA)Tj
3.1067 0 Td
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3.7134 0 Td
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1.321 0 Td
(exclude)Tj
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(off-target)Tj
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(56)Tj
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(shRNA)Tj
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(bases)Tj
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(9)Tj
0.686 0 Td
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1.0091 0 Td
(11)Tj
1.1509 0 Td
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(replaced)Tj
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(owing)Tj
2.6476 0 Td
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(transduction)Tj
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(MPI-2)Tj
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(cells)Tj
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(SR-A6_C911)Tj
5.3235 0 Td
(shRNA)Tj
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1.6157 0 Td
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(parental)Tj
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(and)Tj
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(infection)Tj
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(\()Tj
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(Fig)Tj
1.7858 0 Td
(1C)Tj
0 g
(\),)Tj
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(shRNA.)Tj
3.3222 0 Td
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(MPI-2)Tj
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(cells)Tj
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(notion,)Tj
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Q
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1 j
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BT
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1 TL
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(-/-)Tj
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Q
q
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