Bacillus anthracis infects hosts as a spore, germinates, and disseminates in its vegetative form. Production of anthrax lethal and edema toxins following bacterial outgrowth results in host death. Macrophages of inbred mouse strains are either sensitive or resistant to lethal toxin depending on whether they express the lethal toxin responsive or non-responsive alleles of the inflammasome sensor Nlrp1b (Nlrp1bS/S or Nlrp1bR/R, respectively). In this study, Nlrp1b was shown to affect mouse susceptibility to infection. Inbred and congenic mice harboring macrophage-sensitizing Nlrp1bS/S alleles (which allow activation of caspase-1 and IL-1β release in response to anthrax lethal toxin challenge) effectively controlled bacterial growth and dissemination when compared to mice having Nlrp1bR/R alleles (which cannot activate caspase-1 in response to toxin). Nlrp1bS-mediated resistance to infection was not dependent on the route of infection and was observed when bacteria were introduced by either subcutaneous or intravenous routes. Resistance did not occur through alterations in spore germination, as vegetative bacteria were also killed in Nlrp1bS/S mice. Resistance to infection required the actions of both caspase-1 and IL-1β as Nlrp1bS/S mice deleted of caspase-1 or the IL-1 receptor, or treated with the Il-1 receptor antagonist anakinra, were sensitized to infection. Comparison of circulating neutrophil levels and IL-1β responses in Nlrp1bS/S,Nlrp1bR/R and IL-1 receptor knockout mice implicated Nlrp1b and IL-1 signaling in control of neutrophil responses to anthrax infection. Neutrophil depletion experiments verified the importance of this cell type in resistance to B. anthracis infection. These data confirm an inverse relationship between murine macrophage sensitivity to lethal toxin and mouse susceptibility to spore infection, and establish roles for Nlrp1bS, caspase-1, and IL-1β in countering anthrax infection.
Vyšlo v časopise: Inflammasome Sensor Nlrp1b-Dependent Resistance to Anthrax Is Mediated by Caspase-1, IL-1 Signaling and Neutrophil Recruitment. PLoS Pathog 6(12): e32767. doi:10.1371/journal.ppat.1001222 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001222
1. DuesberyNS
WebbCP
LepplaSH
GordonVM
KlimpelKR
1998 Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science 280 734 737
2. VitaleG
BernardiL
NapolitaniG
MockM
MontecuccoC
2000 Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor. Biochem J 352 Pt 3 739 745
3. MoayeriM
2009 Cellular and systemic effects of anthrax lethal toxin and edema toxin. Mol Aspects Med 30 439 455
4. BoydenED
DietrichWF
2006 Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet 38 240 244
5. NewmanZL
PrintzMP
LiuS
CrownD
2010 Susceptibility to anthrax lethal toxin-induced rat death is controlled by a single chromosome 10 locus that includes rNlrp1. PLoS Pathog 6 e1000906
6. MartinonF
TschoppJ
2007 Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death Differ 14 10 22
7. FranchiL
EigenbrodT
Munoz-PlanilloR
NunezG
2009 The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol 10 241 247
8. WickliffeKE
MoayeriM
2008 Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome. Cell Microbiol 10 332 343
9. MuehlbauerSM
EveringTH
BonuccelliG
SquiresRC
AshtonAW
2007 Anthrax lethal toxin kills macrophages in a strain-specific manner by apoptosis or caspase-1-mediated necrosis. Cell Cycle 6 758 766
10. MoayeriM
MartinezNW
WigginsJ
YoungHA
2004 Mouse susceptibility to anthrax lethal toxin is influenced by genetic factors in addition to those controlling macrophage sensitivity. Infect Immun 72 4439 4447
11. MoayeriM
HainesD
2003 Bacillus anthracis lethal toxin induces TNF-á-independent hypoxia-mediated toxicity in mice. J Clin Invest 112 670 682
12. LovingCL
KhuranaT
OsorioM
LeeGM
KellyVK
2009 Role of anthrax toxins in dissemination, disease progression, and induction of protective adaptive immunity in the mouse aerosol challenge model. Infect Immun 77 255 265
13. LiuS
Miller-RandolphS
WangH
2009 Capillary morphogenesis protein-2 is the major receptor mediating lethality of anthrax toxin in vivo. Proc Natl Acad Sci U S A 106 12424 12429
14. DixonTC
FadlAA
KoehlerTM
SwansonJA
HannaPC
2000 Early Bacillus anthracis-macrophage interactions: intracellular survival and escape. Cell Microbiol 2 453 463
15. Guidi-RontaniC
LevyM
OhayonH
2001 Fate of germinated Bacillus anthracis spores in primary murine macrophages. Mol Microbiol 42 931 938
16. RossJM
1957 The pathogenesis of anthrax following administration of spores by the respiratory route. J Pathol Bacteriol 73 485 494
17. CoteCK
ReaKM
NorrisSL
Van RooijenN
WelkosSL
2004 The use of a model of in vivo macrophage depletion to study the role of macrophages during infection with Bacillus anthracis spores. Microb Pathog 37 169 175
18. CoteCK
VanRN
2006 Roles of macrophages and neutrophils in the early host response to Bacillus anthracis spores in a mouse model of infection. Infect Immun 74 469 480
19. CoteCK
DiMezzoTL
BanksDJ
FranceB
BradleyKA
2008 Early interactions between fully virulent Bacillus anthracis and macrophages that influence the balance between spore clearance and development of a lethal infection. Microbes Infect 10 613 619
20. WelkosSL
KeenerTJ
GibbsPH
1986 Differences in susceptibility of inbred mice to Bacillus anthracis. Infect Immun 51 795 800
21. WelkosSL
FriedlanderAM
1988 Pathogenesis and genetic control of resistance to the Sterne strain of Bacillus anthracis. Microb Pathog 4 53 69
22. HarvillET
LeeG
GrippeVK
MerkelTJ
2005 Complement depletion renders C57BL/6 mice sensitive to the Bacillus anthracis Sterne strain. Infect Immun 73 4420 4422
23. TerraJK
CoteCK
JenkinsAL
BozueJA
2010 Cutting edge: Resistance to Bacillus anthracis infection mediated by a lethal toxin sensitive allele of Nalp1b/Nlrp1b. J Immunol 184 17 20
24. MariathasanS
WeissDS
DixitVM
MonackDM
2005 Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis. J Exp Med 202 1043 1049
25. KafkaD
LingE
FeldmanG
BenharrochD
VoronovE
2008 Contribution of IL-1 to resistance to Streptococcus pneumoniae infection. Int Immunol 20 1139 1146
26. Lara-TejeroM
SutterwalaFS
OguraY
GrantEP
BertinJ
2006 Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis. J Exp Med 203 1407 1412
27. KangTJ
BasuS
ZhangL
ThomasKE
VogelSN
2008 Bacillus anthracis spores and lethal toxin induce IL-1beta via functionally distinct signaling pathways. Eur J Immunol 38 1574 1584
28. SoA
De SmedtT
RevazS
2007 A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther 9 R28
29. GasseP
MaryC
GuenonI
NoulinN
CharronS
2007 IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J Clin Invest 117 3786 3799
30. AbbateA
SalloumFN
VecileE
DasA
HokeNN
2008 Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction. Circulation 117 2670 2683
31. DaleyJM
ThomayAA
ConnollyMD
ReichnerJS
AlbinaJE
2008 Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice. J Leukoc Biol 83 64 70
32. TournierJN
RossiPS
Quesnel-HellmannA
BaldariCT
2009 Anthrax toxins: A weapon to systematically dismantle the host immune defenses. Mol Aspects Med 30 456 466
33. WelkosSL
TrotterRW
BeckerDM
NelsonGO
1989 Resistance to the Sterne strain of B. anthracis: phagocytic cell responses of resistant and susceptible mice. Microb Pathog 7 15 35
34. BischofTS
HahnBL
SohnlePG
2007 Characteristics of spore germination in a mouse model of cutaneous anthrax. J Infect Dis 195 888 894
35. BischofTS
2007 Experimental cutaneous Bacillus anthracis infections in hairless HRS/J mice. Int J Exp Pathol 88 75 84
36. HahnBL
BischofTS
2008 Superficial exudates of neutrophils prevent invasion of Bacillus anthracis bacilli into abraded skin of resistant mice. Int J Exp Pathol 89 180 187
37. Mayer-SchollA
HurwitzR
BrinkmannV
SchmidM
JungblutP
2005 Human neutrophils kill Bacillus anthracis. PLoS Pathog 1 e23
38. PomerantsevAP
SitaramanR
GallowayCR
KivovichV
2006 Genome engineering in Bacillus anthracis using Cre recombinase. Infect Immun 74 682 693
39. HuH
SaQ
AronsonAI
ZhouD
2006 Inactivation of Bacillus anthracis spores in murine primary macrophages. Cell Microbiol 8 1634 1642
40. VarugheseM
ChiA
TeixeiraAV
NichollsPJ
KeithJM
1998 Internalization of a Bacillus anthracis protective antigen-c-Myc fusion protein mediated by cell surface anti-c-Myc antibodies. Mol Med 4 87 95
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
