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Man Shun Fu, Carolina Coelho, Carlos M. De Leon-Rodriguez, Diego C. P. Rossi, Emma Camacho, Eric H. Jung, Madhura Kulkarni, Arturo Casadevall
Cryptococcus neoformans urease affects the outcome of intracellular pathogenesis by modulating phagolysosomal pH
www.plospathogens.org
www.plospathogens.org
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(a)Tj
0.652 0 Td
(general)Tj
3.1351 0 Td
(virulence)Tj
3.9061 0 Td
(factor)Tj
2.5398 0 Td
(for)Tj
1.389 0 Td
(many)Tj
2.4774 0 Td
(bacterial)Tj
3.6227 0 Td
(pathogens,)Tj
4.5297 0 Td
(such)Tj
2.058 0 Td
(as)Tj
/F14 1 Tf
1.0148 0 Td
[()31()15()12()4()7()]TJ
-34.4974 -1.2983 Td
[()4()6()-4()11()2()]TJ
2.6021 0 Td
[()12()3()4()11()-9()]TJ
/F8 1 Tf
2.4605 0 Td
([)Tj
0.83 0.64 0.02 0 k
(37)Tj
0 g
(],)Tj
2.0749 0 Td
(and)Tj
1.7292 0 Td
(fungal)Tj
2.7325 0 Td
(pathogens)Tj
/F14 1 Tf
4.303 0 Td
[()13()-20()-13()12()11()4()7()4()7()1()-4( )]TJ
/F8 1 Tf
5.3121 0 Td
(spp.)Tj
1.8425 0 Td
(and)Tj
/F14 1 Tf
1.7291 0 Td
[()-2()4()7()1()4()12()4()11()4()4()8( )]TJ
5.0287 0 Td
[()4()7( )-3()6()4( )10()12()]TJ
/F8 1 Tf
3.821 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
-33.6356 -1.3039 Td
(Urease)Tj
2.9706 0 Td
(catalyzes)Tj
3.7077 0 Td
(the)Tj
1.4684 0 Td
(hydrolysis)Tj
4.2973 0 Td
(of)Tj
1.0148 0 Td
(urea)Tj
1.9785 0 Td
(into)Tj
1.8369 0 Td
(carbon)Tj
3.016 0 Td
(dioxide)Tj
3.2031 0 Td
(and)Tj
1.7292 0 Td
(ammonia)Tj
4.0535 0 Td
([)Tj
0.83 0.64 0.02 0 k
(41)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(42)Tj
0 g
(].)Tj
3.2485 0 Td
(Ammonia)Tj
-32.5245 -1.2982 Td
(generated)Tj
4.1328 0 Td
(from)Tj
2.2054 0 Td
(ureolytic)Tj
3.7417 0 Td
(activity)Tj
3.1181 0 Td
(can)Tj
1.6271 0 Td
(serve)Tj
2.2506 0 Td
(as)Tj
1.0148 0 Td
(a)Tj
0.6577 0 Td
(nitrogen)Tj
3.6453 0 Td
(source.)Tj
3.0614 0 Td
(Since)Tj
2.3584 0 Td
(urea)Tj
1.9786 0 Td
(is)Tj
0.8447 0 Td
(evenly)Tj
2.7723 0 Td
(distrib-)Tj
-33.4089 -1.2983 Td
(uted)Tj
1.9955 0 Td
(throughout)Tj
4.7792 0 Td
(the)Tj
1.4683 0 Td
(human)Tj
3.0785 0 Td
(body)Tj
2.2166 0 Td
(it)Tj
0.7824 0 Td
(is)Tj
0.8504 0 Td
(conceivable)Tj
4.8812 0 Td
(it)Tj
0.7824 0 Td
(is)Tj
0.8504 0 Td
(used)Tj
2.0579 0 Td
(as)Tj
1.0148 0 Td
(a)Tj
0.652 0 Td
(nutrient)Tj
3.5036 0 Td
(by)Tj
1.1848 0 Td
(mammalian)Tj
-30.098 -1.3039 Td
(pathogens)Tj
4.3029 0 Td
([)Tj
0.83 0.64 0.02 0 k
(43)Tj
0 g
(].)Tj
2.075 0 Td
(Beyond)Tj
3.2598 0 Td
(its)Tj
1.1452 0 Td
(nutritional)Tj
4.5354 0 Td
(role,)Tj
1.9956 0 Td
(ureolytic)Tj
3.7417 0 Td
(activity)Tj
3.1124 0 Td
(enhances)Tj
3.9118 0 Td
(the)Tj
1.4683 0 Td
(invasion)Tj
3.6113 0 Td
(of)Tj
/F14 1 Tf
1.0148 0 Td
[()]TJ
/F8 1 Tf
(.)Tj
/F14 1 Tf
1.0658 0 Td
[(\n)6()7()]TJ
-35.24 -1.2983 Td
[()9()11()-9(\r)6()16(\n )]TJ
/F8 1 Tf
3.4355 0 Td
(to)Tj
1.0205 0 Td
(the)Tj
1.474 0 Td
(central)Tj
2.965 0 Td
(nervous)Tj
3.4129 0 Td
(system)Tj
2.9367 0 Td
(by)Tj
1.1849 0 Td
(promoting)Tj
4.5183 0 Td
(the)Tj
1.4684 0 Td
(yeast)Tj
2.194 0 Td
(sequestration)Tj
5.5502 0 Td
(within)Tj
2.8119 0 Td
(the)Tj
1.4684 0 Td
(micro-)Tj
-34.4407 -1.2983 Td
(capillary)Tj
3.6113 0 Td
(beds)Tj
2.0409 0 Td
(of)Tj
1.0148 0 Td
(blood-brain)Tj
4.9946 0 Td
(barrier.)Tj
3.1918 0 Td
(The)Tj
1.7801 0 Td
(underlying)Tj
4.5978 0 Td
(mechanism)Tj
4.8472 0 Td
(is)Tj
0.8504 0 Td
(not)Tj
1.5704 0 Td
(known,)Tj
3.2315 0 Td
(but)Tj
1.5533 0 Td
(was)Tj
-33.2841 -1.3039 Td
(hypothesized)Tj
5.4594 0 Td
(that)Tj
1.7632 0 Td
(ammonia)Tj
4.0422 0 Td
(generated)Tj
4.1272 0 Td
(by)Tj
1.1678 0 Td
(urease)Tj
2.7496 0 Td
(activity)Tj
3.1125 0 Td
(was)Tj
1.6837 0 Td
(toxic)Tj
2.1713 0 Td
(to)Tj
1.0148 0 Td
(microvascular)Tj
5.8507 0 Td
(endothelial)Tj
-33.1424 -1.2982 Td
(cells)Tj
1.9218 0 Td
([)Tj
0.83 0.64 0.02 0 k
(44)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(46)Tj
0 g
(].)Tj
3.5433 0 Td
(Urease-mediated)Tj
7.0412 0 Td
(ammonia)Tj
4.0479 0 Td
(can)Tj
1.6271 0 Td
(also)Tj
1.7688 0 Td
(neutralize)Tj
4.1725 0 Td
(any)Tj
1.6555 0 Td
(acidic)Tj
2.5625 0 Td
(microenvironme)Tj
6.7577 0 Td
(nt)Tj
-35.0983 -1.2983 Td
(and)Tj
1.7291 0 Td
(thus)Tj
1.9332 0 Td
(help)Tj
1.9389 0 Td
(pathogens)Tj
4.2973 0 Td
(to)Tj
1.0261 0 Td
(survive)Tj
3.0841 0 Td
(harsh)Tj
2.4378 0 Td
(pH)Tj
1.508 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(phagolysosome.)Tj
6.5764 0 Td
(The)Tj
1.7801 0 Td
(neutralizing)Tj
5.0343 0 Td
(effect)Tj
-33.8284 -1.3039 Td
(of)Tj
/F14 1 Tf
1.0147 0 Td
[()]TJ
/F8 1 Tf
(.)Tj
/F14 1 Tf
1.1793 0 Td
[()12()3()4()11()-9()]TJ
/F8 1 Tf
('s)Tj
3.033 0 Td
(urease)Tj
2.7609 0 Td
(is)Tj
0.8504 0 Td
(well)Tj
1.8199 0 Td
(established,)Tj
4.8245 0 Td
(enabling)Tj
3.6567 0 Td
(that)Tj
1.7801 0 Td
(bacterium)Tj
4.2916 0 Td
(to)Tj
1.0262 0 Td
(colonize)Tj
3.5546 0 Td
(gastric)Tj
2.8403 0 Td
(mucosa)Tj
-32.6322 -1.2983 Td
([)Tj
0.83 0.64 0.02 0 k
(47)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(48)Tj
0 g
(].)Tj
3.2541 0 Td
(In)Tj
1.1055 0 Td
(addition)Tj
3.6 0 Td
(to)Tj
1.0261 0 Td
(its)Tj
1.1452 0 Td
(role)Tj
1.7688 0 Td
(in)Tj
1.0318 0 Td
(gastric)Tj
2.8403 0 Td
(colonization,)Tj
/F14 1 Tf
5.4142 0 Td
[()]TJ
/F8 1 Tf
(.)Tj
/F14 1 Tf
1.1848 0 Td
[()12()3()4()11()-9()]TJ
/F8 1 Tf
2.4548 0 Td
(urease)Tj
2.7609 0 Td
(regulates)Tj
3.7701 0 Td
(the)Tj
1.474 0 Td
(host-mac-)Tj
-32.8306 -1.2982 Td
(rophage)Tj
3.4639 0 Td
(interaction)Tj
4.6091 0 Td
(by)Tj
1.1792 0 Td
(retarding)Tj
3.9288 0 Td
(the)Tj
1.4683 0 Td
(opsonization)Tj
5.3971 0 Td
(of)Tj
/F14 1 Tf
1.0148 0 Td
[()]TJ
/F8 1 Tf
(.)Tj
/F14 1 Tf
1.1792 0 Td
[()12()3()4()11()-9()]TJ
/F8 1 Tf
2.4605 0 Td
([)Tj
0.83 0.64 0.02 0 k
(49)Tj
0 g
(].)Tj
2.0749 0 Td
(The)Tj
1.7859 0 Td
(enzyme)Tj
3.2995 0 Td
(can)Tj
1.627 0 Td
(also)Tj
1.7689 0 Td
(mod-)Tj
-35.2571 -1.2983 Td
(ulate)Tj
2.1486 0 Td
(phagosomal)Tj
5.04 0 Td
(pH)Tj
1.5023 0 Td
(and)Tj
1.7291 0 Td
(disrupt)Tj
3.0955 0 Td
(phagosome)Tj
4.7791 0 Td
(maturation)Tj
4.7282 0 Td
(to)Tj
1.0261 0 Td
(enhance)Tj
3.549 0 Td
(the)Tj
1.4683 0 Td
(intracellular)Tj
5.057 0 Td
(survival)Tj
-34.1232 -1.3039 Td
(of)Tj
/F14 1 Tf
1.0147 0 Td
[()]TJ
/F8 1 Tf
(.)Tj
/F14 1 Tf
1.1793 0 Td
[()12()3()4()11()-9()]TJ
/F8 1 Tf
2.4604 0 Td
(in)Tj
1.0375 0 Td
(macrophages)Tj
5.4992 0 Td
([)Tj
0.83 0.64 0.02 0 k
(50)Tj
0 g
(].)Tj
2.0806 0 Td
(Furthermore,)Tj
5.6125 0 Td
(it)Tj
0.7881 0 Td
(induces)Tj
3.2995 0 Td
(the)Tj
1.4683 0 Td
(expression)Tj
4.4617 0 Td
(of)Tj
1.0148 0 Td
(inducible)Tj
3.9628 0 Td
(NO-syn-)Tj
-33.8794 -1.2983 Td
(thesizing)Tj
3.7927 0 Td
(enzyme)Tj
3.2995 0 Td
(\(iNOS\),)Tj
3.3505 0 Td
(a)Tj
0.6577 0 Td
(M1)Tj
1.5873 0 Td
(macrophage)Tj
5.1421 0 Td
(polarization)Tj
5.0286 0 Td
(marker,)Tj
3.3619 0 Td
(in)Tj
1.0374 0 Td
(mouse)Tj
2.8573 0 Td
(macrophages)Tj
5.5049 0 Td
([)Tj
0.83 0.64 0.02 0 k
(51)Tj
0 g
(].)Tj
-35.6199 -1.2983 Td
(In)Tj
1.1055 0 Td
(contrast,)Tj
3.6906 0 Td
(in)Tj
1.0318 0 Td
(both)Tj
/F14 1 Tf
2.0637 0 Td
[()]TJ
/F8 1 Tf
(.)Tj
/F14 1 Tf
1.0658 0 Td
[(\n)6()7()11()9()11()-9(\r)6()16(\n )]TJ
/F8 1 Tf
4.8188 0 Td
(and)Tj
/F14 1 Tf
1.7292 0 Td
[()]TJ
/F8 1 Tf
(.)Tj
/F14 1 Tf
1.0715 0 Td
[()4()7( )-3()6()4( )10()12()]TJ
/F8 1 Tf
(,)Tj
4.0478 0 Td
(urease-producing)Tj
7.2623 0 Td
(strains)Tj
2.863 0 Td
(promote)Tj
3.6623 0 Td
(the)Tj
-34.4123 -1.3039 Td
(polarization)Tj
5.0286 0 Td
(of)Tj
1.0148 0 Td
(immune)Tj
3.6283 0 Td
(responses)Tj
4.0932 0 Td
(to)Tj
1.0261 0 Td
(a)Tj
0.652 0 Td
(nonprotective)Tj
5.811 0 Td
(Type)Tj
2.228 0 Td
(2)Tj
0.6917 0 Td
(\(T2\))Tj
1.9899 0 Td
(rather)Tj
2.6418 0 Td
(than)Tj
2.0296 0 Td
(a)Tj
0.6577 0 Td
(fungicidal)Tj
-31.4927 -1.2982 Td
(Type)Tj
2.228 0 Td
(1)Tj
0.6916 0 Td
(\(T1\))Tj
1.9899 0 Td
(immune)Tj
3.6227 0 Td
(response)Tj
3.736 0 Td
([)Tj
0.83 0.64 0.02 0 k
(38)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(52)Tj
0 g
(].)Tj
3.2542 0 Td
(Hence,)Tj
3.033 0 Td
(bacterial)Tj
3.6227 0 Td
(and)Tj
1.7291 0 Td
(fungal)Tj
2.7326 0 Td
(urease)Tj
2.7609 0 Td
(may)Tj
1.9276 0 Td
(have)Tj
2.0579 0 Td
(different)Tj
-33.3862 -1.2983 Td
(effects)Tj
2.7269 0 Td
(on)Tj
1.2755 0 Td
(macrophage)Tj
5.1421 0 Td
(activation,)Tj
4.3766 0 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.4684 0 Td
(role)Tj
1.7688 0 Td
(of)Tj
1.0148 0 Td
(cryptococcal)Tj
5.2497 0 Td
(urease)Tj
2.7609 0 Td
(during)Tj
2.9311 0 Td
(macrophage-)Tj
-30.4439 -1.3039 Td
(pathogen)Tj
3.9401 0 Td
(interaction,)Tj
4.8302 0 Td
(which)Tj
2.6532 0 Td
(may)Tj
1.9275 0 Td
(affect)Tj
2.3755 0 Td
(the)Tj
1.4683 0 Td
(appropriate)Tj
4.8812 0 Td
(immune)Tj
3.6227 0 Td
(response,)Tj
3.9628 0 Td
(is)Tj
0.8447 0 Td
(unexplored.)Tj
-29.31 -1.2983 Td
(In)Tj
1.1111 0 Td
(this)Tj
1.6725 0 Td
(paper,)Tj
2.7099 0 Td
(we)Tj
1.3266 0 Td
(evaluated)Tj
3.9911 0 Td
(the)Tj
1.4684 0 Td
(role)Tj
1.7688 0 Td
(of)Tj
1.0148 0 Td
(urease)Tj
2.7609 0 Td
(on)Tj
1.2756 0 Td
(intracellular)Tj
5.057 0 Td
(pathogenesis)Tj
5.3574 0 Td
(of)Tj
/F14 1 Tf
1.0148 0 Td
[()]TJ
/F8 1 Tf
(.)Tj
/F14 1 Tf
1.0658 0 Td
[(\n)6()7()11()9()11()-9(\r)6()16(\n )]TJ
/F8 1 Tf
-32.7909 -1.2983 Td
(in)Tj
1.0318 0 Td
(both)Tj
2.0636 0 Td
(amoebae)Tj
3.7643 0 Td
(and)Tj
1.7348 0 Td
(macrophages.)Tj
5.726 0 Td
(We)Tj
1.6101 0 Td
(studied)Tj
3.1521 0 Td
(the)Tj
1.474 0 Td
(effect)Tj
2.3641 0 Td
(of)Tj
1.0147 0 Td
(urease)Tj
2.761 0 Td
(on)Tj
1.2756 0 Td
(the)Tj
1.4683 0 Td
(macrophage)Tj
-29.4404 -1.2982 Td
(response)Tj
3.7247 0 Td
(to)Tj
/F14 1 Tf
1.0147 0 Td
[()]TJ
/F8 1 Tf
(.)Tj
/F14 1 Tf
1.0602 0 Td
[(\n)6()7()11()9()11()-9(\r)6()16(\n )]TJ
/F8 1 Tf
(,)Tj
5.04 0 Td
(as)Tj
1.0034 0 Td
(measured)Tj
4.1046 0 Td
(by)Tj
1.1735 0 Td
(host)Tj
1.9049 0 Td
(cell)Tj
1.5533 0 Td
(lysis)Tj
1.8992 0 Td
(and)Tj
1.7235 0 Td
(non-lytic)Tj
3.8551 0 Td
(exocytosis,)Tj
4.5071 0 Td
(cryptococcal)Tj
-32.5642 -1.3039 Td
(replication)Tj
4.524 0 Td
(inside)Tj
2.6135 0 Td
(macrophages)Tj
5.5049 0 Td
(and)Tj
1.7291 0 Td
(phagolysosomal)Tj
6.6104 0 Td
(pH.)Tj
1.7291 0 Td
(The)Tj
1.7801 0 Td
(results)Tj
2.812 0 Td
(indicate)Tj
3.4072 0 Td
(that)Tj
/F14 1 Tf
1.7802 0 Td
[()]TJ
/F8 1 Tf
(.)Tj
/F14 1 Tf
1.0658 0 Td
[(\n)6()7()11()9()11()19()]TJ
-33.5563 -1.2983 Td
[(\r)6()16(\n )]TJ
/F8 1 Tf
2.3414 0 Td
(urease)Tj
2.7609 0 Td
(affects)Tj
2.7326 0 Td
(the)Tj
1.474 0 Td
(non-lytic)Tj
3.8607 0 Td
(exocytosis)Tj
4.2917 0 Td
(and)Tj
1.7291 0 Td
(intracellular)Tj
5.057 0 Td
(replication)Tj
4.524 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(yeast)Tj
2.194 0 Td
(by)Tj
1.1792 0 Td
(modu-)Tj
-34.6278 -1.2983 Td
(lating)Tj
2.4774 0 Td
(phagolysosomal)Tj
6.6104 0 Td
(pH)Tj
1.5023 0 Td
(thus)Tj
1.9332 0 Td
(illustrating)Tj
4.5524 0 Td
(a)Tj
0.652 0 Td
(new)Tj
1.8765 0 Td
(mechanism)Tj
4.8472 0 Td
(of)Tj
1.0148 0 Td
(by)Tj
1.1793 0 Td
(which)Tj
2.6532 0 Td
(this)Tj
1.6724 0 Td
(enzyme)Tj
-30.9711 -1.3039 Td
(contributes)Tj
4.7508 0 Td
(to)Tj
1.0261 0 Td
(virulence.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 275.0173 cm
BT
/F3 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Results)Tj
/F15 1 Tf
0 -1.5023 Td
(Urease)Tj
3.0614 0 Td
(and)Tj
1.7906 0 Td
(the)Tj
1.5449 0 Td
(interaction)Tj
4.8331 0 Td
(between)Tj
/F16 1 Tf
3.6331 0 Td
[()23()3()12()18()4()5()12()5()-2( )12(\n)-2()]TJ
6.3496 0 Td
[()3()-7()6()7( )7()2()-1()12()13(\r)5(\r)]TJ
/F15 1 Tf
4.3371 0 Td
(and)Tj
/F16 1 Tf
1.7905 0 Td
[()]TJ
/F15 1 Tf
(.)Tj
/F16 1 Tf
-27.3403 -1.167 Td
[()5( )6()8()4()-12()5()12()-10()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 225.9779 cm
BT
/F8 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Many)Tj
2.5511 0 Td
(virulence)Tj
3.9061 0 Td
(factors)Tj
2.9027 0 Td
(used)Tj
2.0579 0 Td
(by)Tj
/F14 1 Tf
1.1792 0 Td
[()]TJ
/F8 1 Tf
(.)Tj
/F14 1 Tf
1.0715 0 Td
[(\n)6()7()11()9()11()-9(\r)6()16(\n )]TJ
/F8 1 Tf
4.8189 0 Td
(for)Tj
1.3833 0 Td
(survival)Tj
3.3392 0 Td
(in)Tj
1.0375 0 Td
(mammalian)Tj
5.0399 0 Td
(host)Tj
1.9162 0 Td
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