Aerosols Transmit Prions to Immunocompetent and Immunodeficient Mice
Prions, the agents causing transmissible spongiform encephalopathies, colonize the brain of hosts after oral, parenteral, intralingual, or even transdermal uptake. However, prions are not generally considered to be airborne. Here we report that inbred and crossbred wild-type mice, as well as tga20 transgenic mice overexpressing PrPC, efficiently develop scrapie upon exposure to aerosolized prions. NSE-PrP transgenic mice, which express PrPC selectively in neurons, were also susceptible to airborne prions. Aerogenic infection occurred also in mice lacking B- and T-lymphocytes, NK-cells, follicular dendritic cells or complement components. Brains of diseased mice contained PrPSc and transmitted scrapie when inoculated into further mice. We conclude that aerogenic exposure to prions is very efficacious and can lead to direct invasion of neural pathways without an obligatory replicative phase in lymphoid organs. This previously unappreciated risk for airborne prion transmission may warrant re-thinking on prion biosafety guidelines in research and diagnostic laboratories.
Vyšlo v časopise:
Aerosols Transmit Prions to Immunocompetent and Immunodeficient Mice. PLoS Pathog 7(1): e32767. doi:10.1371/journal.ppat.1001257
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1001257
Souhrn
Prions, the agents causing transmissible spongiform encephalopathies, colonize the brain of hosts after oral, parenteral, intralingual, or even transdermal uptake. However, prions are not generally considered to be airborne. Here we report that inbred and crossbred wild-type mice, as well as tga20 transgenic mice overexpressing PrPC, efficiently develop scrapie upon exposure to aerosolized prions. NSE-PrP transgenic mice, which express PrPC selectively in neurons, were also susceptible to airborne prions. Aerogenic infection occurred also in mice lacking B- and T-lymphocytes, NK-cells, follicular dendritic cells or complement components. Brains of diseased mice contained PrPSc and transmitted scrapie when inoculated into further mice. We conclude that aerogenic exposure to prions is very efficacious and can lead to direct invasion of neural pathways without an obligatory replicative phase in lymphoid organs. This previously unappreciated risk for airborne prion transmission may warrant re-thinking on prion biosafety guidelines in research and diagnostic laboratories.
Zdroje
1. PrusinerSB
1998 Prions. Proc Natl Acad Sci U S A 95 13363 13383
2. WillRG
1999 Prion related disorders. J R Coll Physicians Lond 33 311 315
3. CuilleJ
ChellePL
1939 Experimental transmission of trembling to the goat. C R Seances Acad Sci 208 1058 1160
4. WeissmannC
EnariM
KlohnPC
RossiD
FlechsigE
2002 Transmission of prions. J Infect Dis 186 Suppl 2 S157 165
5. HillAF
DesbruslaisM
JoinerS
SidleKC
GowlandI
1997 The same prion strain causes vCJD and BSE. Nature 389 448 450 526
6. MaignienT
LasmezasCI
BeringueV
DormontD
DeslysJP
1999 Pathogenesis of the oral route of infection of mice with scrapie and bovine spongiform encephalopathy agents. J Gen Virol 80 Pt 11 3035 3042
7. HeppnerFL
ChristAD
KleinMA
PrinzM
FriedM
2001 Transepithelial prion transport by M cells. Nat Med 7 976 977
8. HerzogC
SalesN
EtchegarayN
CharbonnierA
FreireS
2004 Tissue distribution of bovine spongiform encephalopathy agent in primates after intravenous or oral infection. Lancet 363 422 428
9. ZhangJ
ChenL
ZhangBY
HanJ
XiaoXL
2004 Comparison study on clinical and neuropathological characteristics of hamsters inoculated with scrapie strain 263K in different challenging pathways. Biomed Environ Sci 17 65 78
10. AguzziA
PolymenidouM
2004 Mammalian prion biology: one century of evolving concepts. Cell 116 313 327
11. BessenRA
MartinkaS
KellyJ
GonzalezD
2009 Role of the lymphoreticular system in prion neuroinvasion from the oral and nasal mucosa. J Virol 83 6435 6445
12. SbriccoliM
CardoneF
ValanzanoA
LuM
GrazianoS
2009 Neuroinvasion of the 263K scrapie strain after intranasal administration occurs through olfactory-unrelated pathways. Acta Neuropathol 117 175 184
13. MathiasonCK
PowersJG
DahmesSJ
OsbornDA
MillerKV
2006 Infectious prions in the saliva and blood of deer with chronic wasting disease. Science 314 133 136
14. SeegerH
HeikenwalderM
ZellerN
KranichJ
SchwarzP
2005 Coincident scrapie infection and nephritis lead to urinary prion excretion. Science 310 324 326
15. VascellariM
NonnoR
MutinelliF
BigolaroM
Di BariMA
2007 PrPSc in Salivary Glands of Scrapie-Affected Sheep. J Virol 81 4872 4876
16. TamguneyG
MillerMW
WolfeLL
SirochmanTM
GliddenDV
2009 Asymptomatic deer excrete infectious prions in faeces. Nature 461 529 532
17. LacrouxC
SimonS
BenestadSL
MailletS
MatheyJ
2008 Prions in milk from ewes incubating natural scrapie. PLoS Pathog 4 e1000238
18. DickinsonAG
StampJT
RenwickCC
1974 Maternal and lateral transmission of scrapie in sheep. J Comp Pathol 84 19 25
19. FosterJ
McKenzieC
ParnhamD
DrummondD
ChongA
2006 Lateral transmission of natural scrapie to scrapie-free New Zealand sheep placed in an endemically infected UK flock. Vet Rec 159 633 634
20. FosterJ
McKenzieC
ParnhamD
DrummondD
GoldmannW
2006 Derivation of a scrapie-free sheep flock from the progeny of a flock affected by scrapie. Vet Rec 159 42 45
21. MillerMW
WilliamsES
2003 Prion disease: horizontal prion transmission in mule deer. Nature 425 35 36
22. RyderS
DexterG
BellworthyS
TongueS
2004 Demonstration of lateral transmission of scrapie between sheep kept under natural conditions using lymphoid tissue biopsy. Res Vet Sci 76 211 217
23. AguzziA
HeikenwalderM
2006 Pathogenesis of prion diseases: current status and future outlook. Nat Rev Microbiol 4 765 775
24. HadlowWJ
KennedyRC
RaceRE
1982 Natural infection of Suffolk sheep with scrapie virus. J Infect Dis 146 657 664
25. MillerMW
WilliamsES
HobbsNT
WolfeLL
2004 Environmental sources of prion transmission in mule deer. Emerg Infect Dis 10 1003 1006
26. BartzJC
KincaidAE
BessenRA
2003 Rapid prion neuroinvasion following tongue infection. J Virol 77 583 591
27. ZanussoG
FerrariS
CardoneF
ZampieriP
GelatiM
2003 Detection of pathologic prion protein in the olfactory epithelium in sporadic Creutzfeldt-Jakob disease. N Engl J Med 348 711 719
28. TabatonM
MonacoS
CordoneMP
ColucciM
GiacconeG
2004 Prion deposition in olfactory biopsy of sporadic Creutzfeldt-Jakob disease. Ann Neurol 55 294 296
29. KincaidAE
BartzJC
2007 The nasal cavity is a route for prion infection in hamsters. J Virol 81 4482 4491
30. DeJoiaC
MoreauxB
O'ConnellK
BessenRA
2006 Prion infection of oral and nasal mucosa. J Virol 80 4546 4556
31. DotyRL
2008 The olfactory vector hypothesis of neurodegenerative disease: is it viable? Ann Neurol 63 7 15
32. CoronaC
PorcarioC
MartucciF
IuliniB
ManeaB
2009 Olfactory system involvement in natural scrapie disease. J Virol 83 3657 3667
33. HamirAN
KunkleRA
RichtJA
MillerJM
GreenleeJJ
2008 Experimental transmission of US scrapie agent by nasal, peritoneal, and conjunctival routes to genetically susceptible sheep. Vet Pathol 45 7 11
34. ParkCH
IshinakaM
TakadaA
KidaH
KimuraT
2002 The invasion routes of neurovirulent A/Hong Kong/483/97 (H5N1) influenza virus into the central nervous system after respiratory infection in mice. Arch Virol 147 1425 1436
35. ShawIC
1995 BSE and farmworkers [letter]. Lancet 346 1365
36. SawcerSJ
YuillGM
EsmondeTF
EstibeiroP
IronsideJW
1993 Creutzfeldt-Jakob disease in an individual occupationally exposed to BSE. Lancet 341 642
37. ReuberM
Al-DinAS
BaborieA
ChakrabartyA
2001 New variant Creutzfeldt-Jakob disease presenting with loss of taste and smell. J Neurol Neurosurg Psychiatry 71 412 413
38. GlatzelM
HeppnerFL
AlbersKM
AguzziA
2001 Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron 31 25 34
39. PrinzM
HeikenwalderM
JuntT
SchwarzP
GlatzelM
2003 Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. Nature 425 957 962
40. HeikenwalderM
ZellerN
SeegerH
PrinzM
KlohnPC
2005 Chronic lymphocytic inflammation specifies the organ tropism of prions. Science 307 1107 1110
41. HeikenwalderM
KurrerMO
MargalithI
KranichJ
ZellerN
2008 Lymphotoxin-dependent prion replication in inflammatory stromal cells of granulomas. Immunity 29 998 1008
42. MabbottNA
YoungJ
McConnellI
BruceME
2003 Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphotoxin pathway dramatically reduces scrapie susceptibility. J Virol 77 6845 6854
43. MabbottNA
BruceME
BottoM
WalportMJ
PepysMB
2001 Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie. Nat Med 7 485 487
44. MabbottNA
MackayF
MinnsF
BruceME
2000 Temporary inactivation of follicular dendritic cells delays neuroinvasion of scrapie. Nat Med 6 719 720
45. DenkersND
SeeligDM
TellingGC
HooverEA
2010 Aerosol and nasal transmission of chronic wasting disease in cervidized mice. J Gen Virol 91 1651 1658
46. FischerM
RülickeT
RaeberA
SailerA
MoserM
1996 Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO J 15 1255 1264
47. RadovanovicI
BraunN
GigerOT
MertzK
MieleG
2005 Truncated prion protein and Doppel are myelinotoxic in the absence of oligodendrocytic PrPC. J Neurosci 25 4879 4888
48. SigurdsonCJ
NilssonKP
HornemannS
HeikenwalderM
MancoG
2009 De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis. Proc Natl Acad Sci U S A 106 304 309
49. SigurdsonCJ
NilssonKP
HornemannS
MancoG
PolymenidouM
2007 Prion strain discrimination using luminescent conjugated polymers. Nat Methods 4 1023 1030
50. RadovanovicI
BraunN
GigerOT
MertzK
MieleG
2005 Truncated Prion Protein and Doppel Are Myelinotoxic in the Absence of Oligodendrocytic PrPC. J Neurosci 25 4879 4888
51. MontrasioF
FriggR
GlatzelM
KleinMA
MackayF
2000 Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science 288 1257 1259
52. MackayF
BrowningJL
1998 Turning off follicular dendritic cells. Nature 395 26 27
53. HuberC
ThielenC
SeegerH
SchwarzP
MontrasioF
2005 Lymphotoxin-beta receptor-dependent genes in lymph node and follicular dendritic cell transcriptomes. J Immunol 174 5526 5536
54. HeikenwalderM
FederauC
BoehmerL
SchwarzP
WagnerM
2007 Germinal center B cells are dispensable in prion transport and neuroinvasion. J Neuroimmunol 192 113 123
55. ZabelMD
HeikenwalderM
PrinzM
ArrighiI
SchwarzP
2007 Stromal complement receptor CD21/35 facilitates lymphoid prion colonization and pathogenesis. J Immunol 179 6144 6152
56. KleinMA
KaeserPS
SchwarzP
WeydH
XenariosI
2001 Complement facilitates early prion pathogenesis. Nat Med 7 488 492
57. WadsworthJDF
JoinerS
HillAF
CampbellTA
DesbruslaisM
LuthertPJ
CollingeJ
2001 Tissue distribution of protease resistant prion protein in variant CJD using a highly sensitive immuno-blotting assay. Lancet 358 171 180
58. SafarJ
WilleH
ItriV
GrothD
SerbanH
1998 Eight prion strains have PrP(Sc) molecules with different conformations. Nat Med 4 1157 1165
59. AgrawalA
SinghSK
SinghVP
MurphyE
ParikhI
2008 Partitioning of nasal and pulmonary resistance changes during noninvasive plethysmography in mice. J Appl Physiol 105 1975 1979
60. BatesJH
IrvinCG
2003 Measuring lung function in mice: the phenotyping uncertainty principle. J Appl Physiol 94 1297 1306
61. AguzziA
HeikenwalderM
MieleG
2004 Progress and problems in the biology, diagnostics, and therapeutics of prion diseases. J Clin Invest 114 153 160
62. DiringerH
1995 Proposed link between transmissible spongiform encephalopathies of man and animals. Lancet 346 1208 1210
63. BlättlerT
BrandnerS
RaeberAJ
KleinMA
VoigtländerT
1997 PrP-expressing tissue required for transfer of scrapie infectivity from spleen to brain. Nature 389 69 73
64. SigurdsonCJ
WilliamsES
MillerMW
SprakerTR
O'RourkeKI
1999 Oral transmission and early lymphoid tropism of chronic wasting disease PrPres in mule deer fawns (Odocoileus hemionus). J Gen Virol 80 2757 2764
65. HiltonDA
FathersE
EdwardsP
IronsideJW
ZajicekJ
1998 Prion immunoreactivity in appendix before clinical onset of variant Creutzfeldt-Jakob disease Lancet 352 703 704
66. MabbottNA
MacPhersonGG
2006 Prions and their lethal journey to the brain. Nat Rev Microbiol 4 201 211
67. HillAF
ZeidlerM
IronsideJ
CollingeJ
1997 Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy. Lancet 349 99
68. MouldDL
DawsonAM
RennieJC
1970 Very early replication of scrapie in lymphocytic tissue. Nature 228 779 780
69. BeekesM
McBridePA
2000 Early accumulation of pathological PrP in the enteric nervous system and gut-associated lymphoid tissue of hamsters orally infected with scrapie. Neurosci Lett 278 181 184
70. KleinMA
FriggR
RaeberAJ
FlechsigE
HegyiI
1998 PrP expression in B lymphocytes is not required for prion neuroinvasion. Nat Med 4 1429 1433
71. KleinMA
FriggR
FlechsigE
RaeberAJ
KalinkeU
1997 A crucial role for B cells in neuroinvasive scrapie. Nature 390 687 690
72. PrinzM
MontrasioF
KleinMA
SchwarzP
PrillerJ
2002 Lymph nodal prion replication and neuroinvasion in mice devoid of follicular dendritic cells. Proc Natl Acad Sci U S A 99 919 924
73. TaraboulosA
JendroskaK
SerbanD
YangSL
DeArmondSJ
1992 Regional mapping of prion proteins in brain. Proc Natl Acad Sci U S A 89 7620 7624
74. RaabOG
YehHC
NewtonGJ
PhalenRF
VelasquezDJ
1975 Deposition of inhaled monodisperse aerosols in small rodents. Inhaled Part 4 Pt 1 3 21
75. LauAL
YamAY
MichelitschMM
WangX
GaoC
2007 Characterization of prion protein (PrP)-derived peptides that discriminate full-length PrPSc from PrPC. Proc Natl Acad Sci U S A 104 28 11551 6
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