ライフサイエンスコーパス: Y. pestis

1 Y. pestis actively inhibits the innate immune system to

2 Y. pestis Ail interacts with the regulatory factors Vn a

3 Y. pestis biofilm formation has been studied in the rat

4 Y. pestis CU pathways y0348-0352 and y1858-1862 were fou

5 Y. pestis has two well-characterized CU pathways: the ca

6 Y. pestis lacking Ivy had attenuated virulence, unless a

7 Y. pestis phoP-negative mutants achieved normal infectio

8 Y. pestis recently evolved from the gastrointestinal pat

9 Y. pestis strains containing deletions in CU pathways y0

10 Y. pestis type III secretion system effectors YopJ and Y

11 Y. pestis-infected Mefv(M680I/M680I) FMF knock-in mice e

12 A phylogenic tree including 36 Y. pestis strains highlighted an association between the

13 a library comprised of approximately 31,500 Y. pestis KIM6+ transposon insertion mutants (input pool

14 nd that plasmid-expressed ExsA complements a Y. pestis lcrF mutant for T3SS gene expression.

15 taasd triple mutations was used to deliver a Y. pestis fusion protein, YopE amino acid 1 to 138-LcrV

16 Death genomes shows the diversification of a Y. pestis lineage into multiple genetically distinct cla

17 Recently, a Y. pestis pgm strain was isolated from a researcher with

18 In addition, Y. pestis was identified directly from positive blood cu

19 in the usher genes for six of the additional Y. pestis CU pathways.

20 r findings demonstrate that self-adjuvanting Y. pestis OMVs provide a novel plague vaccine candidate

21 dependent caspase-1 activation pathway after Y. pestis challenge.

22 trolling IL-18 and IL-1beta production after Y. pestis infection, and NLRP12-deficient mice were more

23 masome activation, and host resistance after Y. pestis infection.

24 arlier work reported that antibodies against Y. pestis LcrV cannot block type III injection by Yersin

25 denced by high serum antibody levels against Y. pestis F1 antigen.

26 lly, it afforded complete protection against Y. pestis pulmonary infection.

27 ence or mutation provides protection against Y. pestis.

28 onal or monoclonal antibodies raised against Y. pestis KIM D27 LcrV (LcrV(D27)) bind LcrV from Y. ent

29 ytokines important to host responses against Y. pestis and many other infectious agents.

30 platform for intranasal vaccination against Y. pestis and other infectious pathogens.

31 proteins based on the roles of their aligned Y. pestis and S. enterica partners and showed that up to

32 All Y. pestis strains, including those phylogenetically clos

33 nning this period and reconstruct 34 ancient Y. pestis genomes.

34 nsus binding sites in both P. aeruginosa and Y. pestis T3SS promoters prevent activation by ExsA and

35 etection of F. tularensis, B. anthracis, and Y. pestis directly from patient blood samples was develo

36 mutants of Y. pseudotuberculosis IP32953 and Y. pestis KIM6+.

37 conserved between Y. pseudotuberculosis and Y. pestis differs in both timing and dependence on Hfq,

38 suggests that both Y. pseudotuberculosis and Y. pestis produce an oligosaccharide core with a single

39 sceptibility by 50% to 75% for B. anthracis, Y. pestis, and B. pseudomallei compared to conventional

40 progressive stages of the disease with anti-Y. pestis antibodies alone or in combination with the co

41 As Y. pestis further evolved, modern strains acquired a sin

42 previously identified the causative agent as Y. pestis, little is known about the bacterium's spread,

43 ng genomic and historical data, we assembled Y. pestis genomes from nine individuals covering four Eu

44 Finally, we find that at Y. pestis concentrations reflective of early-stage septi

45 In contrast, attenuated Y. pestis lacking the conserved pigmentation locus could

46 After vaccinating with live attenuated Y. pestis and challenging intranasally with virulent pla

47 e immunization with the EV76 live attenuated Y. pestis strain rapidly induced the expression of hemop

48 The development of live, attenuated Y. pestis vaccines may be facilitated by detoxification

49 in the ear with wild-type (WT) or attenuated Y. pestis lacking the pYV virulence plasmid (pYV(-)).

50 DeltamsbB double mutant severely attenuated Y. pestis CO92 to evoke pneumonic plague in a mouse mode

51 -/-) mice with a subunit vaccine that blocks Y. pestis type III secretion generated protection agains

52 nonical drug target for infections caused by Y. pestis and possibly for those caused by other blood-b

53 The rapid killing of macrophages induced by Y. pestis, dependent upon type III secretion system effe

54 fic antibodies blocked type III injection by Y. pestis expressing lcrV(W22703) or lcrV(WA-314) and pr

55 of mice that are cleaved and/or processed by Y. pestis in a Pla-dependent manner.

56 y responses are believed to be suppressed by Y. pestis virulence factors in order to prevent clearanc

57 iety on the surface of many mammalian cells, Y. pestis appears to prefer interacting with certain typ

58 as shown with recombinant Escherichia coli, Y. pestis, or purified passenger domains.

59 hich could be extremely useful in confirming Y. pestis persistence in the ground.

60 his detrimental effect under proper control, Y. pestis expresses the caf operon (encoding the F1 caps

61 nogen activator protease (Pla) is a critical Y. pestis virulence factor that is important for early b

62 Deletion of Pla results in a decreased Y. pestis bacterial burden in the lung and failure to pr

63 Deletion of ivy decreased Y. pestis' ability to counter lysozyme and polymorphonuc

64 infection with either wild-type or Deltapla Y. pestis, Prdx6-deficient mice exhibit no differences i

65 mpared to that after infection with Deltapla Y. pestis, suggesting that Pla cleaves Prdx6 in the pulm

66 PhiA1122::luxAB rapidly detects Y. pestis in pure culture and human serum by transducing

67 rom yapJ in its contribution to disseminated Y. pestis infection.

68 idence for the presence of multiple distinct Y. pestis strains in Europe.

69 eract with YopD within targeted cells during Y. pestis infection, suggesting that YopK's regulatory m

70 contributes to type I IFN expression during Y. pestis infection and suggest that the TLR7-driven typ

71 interferon (IFN) signaling is induced during Y. pestis infection and contributes to neutrophil deplet

72 A fast and efficient Y. pestis dissemination in SEG mice may be critical for

73 estroy immune cells in humans, thus enabling Y. pestis to reproduce in the bloodstream and be transmi

74 inflammatory responses and enables enhanced Y. pestis outgrowth in the lungs.

75 Here, we present six new European Y. pestis genomes spanning the Late Neolithic to the Bro

76 identified has not been found in any extant Y. pestis foci sampled to date, and has its ancestry in

77 ession limits initial growth but facilitates Y. pestis access to a protected replicative niche.

78 Thus, by degrading FasL, Y. pestis manipulates host cell death pathways to facili

79 Here we present five Y. pestis genomes from one of the last European outbreak

80 is not only dispensable but deleterious for Y. pestis virulence.

81 ional regulator YfbA, which is essential for Y. pestis colonization and biofilm formation in cat flea

82 ilable in <4 h for B. anthracis and <6 h for Y. pestis and B. pseudomallei One exception was B. pseud

83 To identify genes that are important for Y. pestis survival in macrophages, a library comprised o

84 rter displayed 100% (n = 59) inclusivity for Y. pestis and consistent intraspecific signal transducti

85 a long-read nanopore sequencer (MinION) for Y. pestis (6.5 h) and B. anthracis (8.5 h) and sequenced

86 CFU/ml for B. anthracis, and 4.5 CFU/ml for Y. pestis The sensitivity was 100% at the LOD for all th

87 o the noninflammatory environment needed for Y. pestis colonization and proliferation.

88 K and PKC inhibitors were selective only for Y. pestis infection.

89 ria, Britain, Germany, France, and Spain for Y. pestis DNA and reconstructed eight genomes.

90 minogen-activating protease (pla) genes from Y. pestis CO92.

91 ies and oxidative stress genes that may help Y. pestis survive at the host temperature.

92 criptional profiling experiments to identify Y. pestis quorum sensing regulated functions.

93 In Y. pestis CO92, the autotransporter genes yapK and yapJ

94 xpression of lcrV(W22703) or lcrV(WA-314) in Y. pestis did not allow these strains to escape LcrV-med

95 ructure, blocking effector transport even in Y. pestis yscF variants that are otherwise calcium blind

96 a role for the Yaps as virulence factors in Y. pestis.

97 Deletion mutants of ilp were generated in Y. pestis strains KIM5(pCD1(+)) Pgm(-) (pigmentation neg

98 of yersiniosis, as does the inactivation in Y. pestis of a conserved, Yersinia-specific sRNA in a mo

99 IM6 to identify surface proteins involved in Y. pestis host cell invasion and bacterial virulence.

100 f the caf operon are minimally manifested in Y. pestis.

101 of rfaH in Y. pseudotuberculosis but not in Y. pestis.

102 We also show that cleavage of YapE occurs in Y. pestis but not in the enteric Yersinia species, and r

103 ting that a noncanonical mechanism occurs in Y. pestis-infected macrophages.

104 gene in a strain-specific manner and only in Y. pestis and Y. pseudotuberculosis.

105 ffecting the expression of the feo operon in Y. pestis.

106 er confirmed when they were overexpressed in Y. pestis KIM6+.

107 late motility, the role of quorum sensing in Y. pestis has been unclear.

108 ssess the functional role of AI-2 sensing in Y. pestis, microarray studies were conducted by comparin

109 e first global analysis of AI-2 signaling in Y. pestis and identifies potential roles for the system

110 Studies in Y. pestis and Y. pseudotuberculosis have shown that YopM

111 hatase, LpxE, from Francisella tularensis in Y. pestis yields predominantly 1-dephosphorylated lipid

112 m a variety of pathogenic bacteria including Y. pestis, H. influenzae, and Proteus that cause plague,

113 potential agents of bioterrorism, including Y. pestis.

114 lence in many bacterial pathogens, including Y. pestis, any change in autotransporter content should

115 Pathogenic Yersinia, including Y. pestis, the agent of plague in humans, and Y. pseudot

116 f bacteria in the footpad revealed increased Y. pestis-neutrophil interactions and increased neutroph

117 erived from the recognition of intracellular Y. pestis by host Toll-like receptor 7 (TLR7).

118 re robust titers of antibodies against LcrV, Y. pestis whole-cell lysate (YPL), and F1 antigen and mo

119 Immunization against a concomitant lethal Y. pestis respiratory challenge was correlated with temp

120 the same intradermal site with purified LPS, Y. pestis did not prevent recruitment of neutrophils.

121 of a functional ureD was sufficient to make Y. pestis orally toxic to fleas.

122 inst pneumonic plague challenge with 250 MLD Y. pestis CO92, immunization with recombinant F1 did not

123 R10 single-nucleotide polymorphisms modulate Y. pestis-induced cytokine responses.

124 The YPTB3286-like gene of most Y. pestis strains appears to be inactivated, perhaps in

125 g T cell-mediated defense against Pla-mutant Y. pestis Moreover, the efficacy of T cell-mediated prot

126 m, but not mouse serum, to kill ail-negative Y. pestis in vitro.

127 -/-) mice were not protected by neutralizing Y. pestis antibodies, yet bacterial growth in the lungs

128 stores the virulence defects of nonpigmented Y. pestis.

129 o include homologous sequences from numerous Y. pestis and Y. pseudotuberculosis strains, we determin

130 The ability of Y. pestis to create this early noninflammatory environme

131 stic basis of the evolutionary adaptation of Y. pestis to flea-borne transmission.

132 These findings reveal adaptations of Y. pestis to the dermis and how these adaptations can de

133 ains, suggesting an evolutionary adaption of Y. pestis to specific local animal hosts or reservoirs.

134 tem that oversynthesized the LcrV antigen of Y. pestis, raised the amounts of LcrV enclosed in OMVs b

135 may contribute to the severe attenuation of Y. pestis lacking this RNA chaperone in animal models of

136 ian lethal doses (LD50) (2.4 x 10(4) CFU) of Y. pestis KIM6+(pCD1Ap) than chi10057(pYA3332) (40% surv

137 ed infection kinetics and early clearance of Y. pestis.

138 Here, we demonstrate that omptin cleavage of Y. pestis YapE is required to mediate bacterial aggregat

139 ucosamine to the lipooligosaccharide core of Y. pestis.

140 We conclude that, throughout the course of Y. pestis infection, OmpR-EnvZ is required to counter to

141 binding and delivery of Yops (cytotoxins of Y. pestis), a novel interaction, distinct from other bac

142 ver, we report the first direct detection of Y. pestis in soil, which could be extremely useful in co

143 lture), sensitive, and specific detection of Y. pestis in such complex samples.

144 tightly controlled virulence determinant of Y. pestis.

145 y adaptation that followed the divergence of Y. pestis from the closely related food- and waterborne

146 cquisition of pPCP1 during the divergence of Y. pestis from Y. pseudotuberculosis, and are the first

147 (AGMs) after challenge with a lethal dose of Y. pestis delivered as an aerosol, in 4 independent stud

148 tant steps in the evolution and emergence of Y. pestis as a flea-borne pathogen.

149 The emergence of Y. pestis fits evolutionary theories that emphasize ecol

150 Five cases demonstrated evidence of Y. pestis in fetal or neonatal tissues.

151 obial regimen, and 2) laboratory evidence of Y. pestis infection or an epidemiologic link to patients

152 link to patients with laboratory evidence of Y. pestis.

153 ts show that a key event in the evolution of Y. pestis from the ancestral Yersinia pseudotuberculosis

154 ors, ureD mutation early in the evolution of Y. pestis was likely subject to strong positive selectio

155 dentified Ilp as a novel virulence factor of Y. pestis.

156 Our results suggest that the fate of Y. pestis infection of the lung is decided extremely ear

157 Thus, an important feature of Y. pestis infection is reduced activation and organizati

158 age formation and acquisition and fitness of Y. pestis during flea gut infection, consistent with pos

159 nd F130, are required for the interaction of Y. pestis Ail with Vn, factor H and C4BP.

160 Thus, the interactions of Y. pestis with its flea vector that lead to colonization

161 ed that multiple and independent lineages of Y. pestis branched and expanded across Eurasia during th

162 ers of IgG response to whole-cell lysates of Y. pestis (YpL) and subunit LcrV similar to those seen w

163 Using established mouse models of Y. pestis infection, we demonstrated that despite the hi

164 agenic approach, we created 5,088 mutants of Y. pestis strain CO92 and screened them in a mouse model

165 P-PhoQ system, OmpR-EnvZ was the only one of Y. pestis' 23 other 2CSs required for production of bubo

166 gocytes in vitro and in vivo Opsonization of Y. pestis with polyclonal antiserum modestly increased p

167 ole for pneumonic plague during outbreaks of Y. pestis infections.

168 ifies three of the additional CU pathways of Y. pestis as mediating interactions with host cells that

169 e lcrV gene on the pCD1 virulence plasmid of Y. pestis KIM D27 with either lcrV(W22703) or lcrV(WA-31

170 gative selection screen using a vast pool of Y. pestis mutants revealed no selection against any know

171 culosis, the relatively recent progenitor of Y. pestis, shows no similar trans-complementation effect

172 r capacity to modulate binding properties of Y. pestis in its hosts, in conjunction with other adhesi

173 participate in broadening the host range of Y. pestis.

174 mpounded fears of the intentional release of Y. pestis as a biological weapon.

175 The discovery of molecular signatures of Y. pestis in prehistoric Eurasian individuals and two ge

176 The formation of fibrin at sites of Y. pestis infection supports innate host defense against

177 a possible scenario for the early spread of Y. pestis: the pathogen may have entered Europe from Cen

178 o septicemic infection by the KIM5 strain of Y. pestis but not to infection by the CO92 Deltapgm stra

179 ks in detecting capsular-positive strains of Y. pestis in bubonic and pneumonic plague.

180 the most ancestral, deeply rooted strains of Y. pestis to cause pneumonic plague, indicating that Y.

181 ins in serum is critical for the survival of Y. pestis during the septicemic stage of plague infectio

182 genes known to be important for survival of Y. pestis in macrophages, including phoPQ and members of

183 wecB and wecC), is important for survival of Y. pestis in macrophages.

184 ntiport is indispensable for the survival of Y. pestis in the bloodstreams of infected animals and th

185 le immune environment leading to survival of Y. pestis within the eukaryotic host.

186 ting a comparable evolutionary trajectory of Y. pestis during both events.

187 suggests that maternal-fetal transmission of Y. pestis is possible, particularly in the absence of an

188 accharide function, reduced the virulence of Y. pestis CO92 in mouse models of bubonic and pneumonic

189 tion alone had no effect on the virulence of Y. pestis in either bubonic or pneumonic plague models.

190 ded no significant reduction in virulence of Y. pestis in mice when it was administered i.n. but actu

191 of LpxE does not attenuate the virulence of Y. pestis.

192 factor in evolution of the high virulence of Y. pestis.

193 we examine the effects of Ab opsonization on Y. pestis interactions with phagocytes in vitro and in v

194 sonizing Ab had a dramatic effect in vivo on Y. pestis-neutrophil interactions in the dermis and dLN

195 through tight regulation of the caf operon, Y. pestis precisely balances its capsular anti-phagocyti

196 showed increased association of Ab-opsonized Y. pestis with neutrophils in the dermis in a mouse mode

197 R2 agonist), E. coli LPS (a TLR4 agonist) or Y. pestis infection, while the PI3K and PKC inhibitors w

198 nfected with either F. tularensis SCHU S4 or Y. pestis CO92.

199 osis; however, it is not known at what point Y. pestis gained the ability to induce a fulminant pneum

200 od vector prior to transmission may preadapt Y. pestis to resist the initial encounter with the mamma

201 that cell surface expression of Ail produces Y. pestis virulence phenotypes in E. coli, including res

202 f the LPS membrane, and collectively promote Y. pestis survival in human serum, antibiotic resistance

203 17-kDa outer membrane protein that protects Y. pestis against complement-mediated lysis, on bubonic

204 receptor CXC receptor 2 (CXCR2) to pulmonary Y. pestis infection.

205 biphasic inflammatory response to pulmonary Y. pestis infection.

206 in vivo; the role of A2AP during respiratory Y. pestis infection is not known either.

207 edundant roles for yapJ and yapK in systemic Y. pestis infection.

208 mponents, and provide a handle for targeting Y. pestis pathogenesis.

209 in response to Y. pestis infection, and that Y. pestis entry into macrophages may involve the partici

210 Thus, we conclude that Y. pestis YopJ and YopM can both exert a tight control o

211 These findings demonstrate that Y. pestis Ail uses multiple extracellular loops to inter

212 The discovery that Y. pestis thwarts T cell defense by promoting fibrinolys

213 Previous work established that Y. pestis uses the T3SS to inhibit neutrophil respirator

214 Importantly, we find that Y. pestis containing combined deletions of YopJ and YopM

215 in Yersinia pestis virulence and found that Y. pestis strains lacking the major Na(+)/H(+) antiporte

216 These findings indicate that Y. pestis was capable of causing pneumonic plague before

217 s to cause pneumonic plague, indicating that Y. pestis was primed to infect the lungs at a very early

218 We propose that Y. pestis utilizes Hfq to link c-di-GMP levels to enviro

219 In this study, we report that Y. pestis YopE is a dominant Ag recognized by CD8 T cell

220 Here, we show that Y. pestis also inhibits release of granules in a T3SS-de

221 Here, we show that Y. pestis does not appreciably cleave A2AP in a Pla-depe

222 Here, we show that Y. pestis infects and replicates as a biofilm in the for

223 o genomes from Southern Siberia suggest that Y. pestis caused some form of disease in humans prior to

224 The Y. pestis ail mutant was attenuated for virulence in bot

225 The Y. pestis Ail protein is an important bubonic plague vir

226 The Y. pestis derivative strain lacking the nhaA and nhaB ge

227 The Y. pestis genome contains additional CU pathways that ar

228 The Y. pestis KIM5 Deltailp strain had reduced adhesion to a

229 The Y. pestis outer membrane Pla protease is essential for t

230 a polytomy similar to others seen across the Y. pestis phylogeny, associated with the Second and Thir

231 protects neutrophils from destruction by the Y. pestis type III secretion system.

232 hree relevant protein markers encoded by the Y. pestis-specific plasmids pFra (murine toxin) and pPla

233 Under static growth conditions, the Y. pestis feo::lacZ fusion was repressed by iron in a Fu

234 ate that omptin cleavage is specific for the Y. pestis and Y. pseudotuberculosis YapE orthologues but

235 orm a single putatively extinct clade in the Y. pestis phylogeny.

236 Expression of the Y. pestis F1 capsule was not required for the developmen

237 o significant effect on transcription of the Y. pestis feo promoter.

238 r nhaB in trans restored the survival of the Y. pestis nhaA nhaB double deletion mutant in blood.

239 ocking infection depends on induction of the Y. pestis PhoP-PhoQ two-component regulatory system in t

240 Through deep sequencing analysis of the Y. pestis sRNA-ome, we found 63 previously unidentified

241 how that LcrV, the needle cap protein of the Y. pestis type III secretion system, binds to the N-form

242 led, including novel multimeric forms of the Y. pestis virulence plasmid, pPCP1, MinION reads were er

243 We examined binding of the Y. pestis WT and usher deletion strains to A549 human lu

244 This study focuses on the Y. pestis KIM yapV gene and its product, recognized as a

245 activator protease), which is encoded on the Y. pestis-specific plasmid pPCP1.

246 inia pestis This study demonstrated that the Y. pestis plasminogen activator Pla, a protease that pro

247 -dependent addition of aminoarabinose to the Y. pestis lipid A, because an aminoarabinose-deficient m

248 e investigated the role and function of this Y. pestis system in fleas.

249 Thus, Y. pestis-orchestrated LN remodeling promoted its dissem

250 t on the importance of neutrophils in AMI to Y. pestis and may provide a new correlate of protection

251 for this antibody-mediated immunity (AMI) to Y. pestis remain poorly understood.

252 One mechanism contributing to Y. pestis virulence is the presence of a type-three secr

253 1 day prior to lethal pulmonary exposure to Y. pestis strain KIM D27 significantly improves survival

254 arify the contributions of these proteins to Y. pestis pathogenesis.

255 ytokine response, and a higher resistance to Y. pestis-induced apoptosis.

256 populations confer heightened resistance to Y. pestis.

257 ulus for NF-kappaB activation in response to Y. pestis infection, and that Y. pestis entry into macro

258 ghtened IL-1beta specifically in response to Y. pestis.

259 This response was not specific to Y. pestis and involved a reduced sensitivity to M2 polar

260 dification of YapE appears to be specific to Y. pestis, was acquired along with the acquisition of pP

261 signaling led to increased susceptibility to Y. pestis, producing tetra-acylated lipid A, and an atte

262 nd that B10.T(6R) mice become susceptible to Y. pestis infection by the age of 5 months.

263 pseudotuberculosis, while yapJ is unique to Y. pestis.

264 r testing antimicrobial agents used to treat Y. pestis, except for chloramphenicol and trimethoprim-s

265 Additionally, LpxE synthesis in wild-type Y. pestis KIM6+(pCD1Ap) led to slight attenuation by s.c

266 tion, we found that infection with wild-type Y. pestis reduces the abundance of extracellular Prdx6 i

267 rly, lungs of mice challenged with wild-type Y. pestis show reduced levels of FasL and activated casp

268 Wild-type Y. pestis, but not a Pla mutant (Deltapla), degrades Fas

269 ing bacterial spread is key to understanding Y. pestis and the immune responses it encounters during

270 als the existence of previously undocumented Y. pestis diversity during the sixth to eighth centuries

271 Untreated Y. pestis infection during pregnancy is associated with

272 f T cell-mediated protection against various Y. pestis strains displayed an inverse relationship with

273 chanisms that are effective against virulent Y. pestis, raising new insight into the activation of ne

274 cell-mediated defense against fully virulent Y. pestis Introducing a single point mutation into the a

275 ubcutaneously infected with a fully virulent Y. pestis strain and treated at progressive stages of th

276 ite of Pla suffices to render fully virulent Y. pestis susceptible to primed T cells.

277 ltamsbB double mutant of the highly virulent Y. pestis CO92 strain.

278 o quantitate the internalization of virulent Y. pestis CO92 by macrophages and the subsequent activat

279 e with 5 x 10(3) CFU (50 LD(50)) of virulent Y. pestis This protection was significantly superior to

280 ter subcutaneous infection with the virulent Y. pestis CO92.

281 In vivo, Y. pestis lacking OmpR-EnvZ did not induce an early immu

282 icity to the flea vectors of plague, whereas Y. pestis does not.

283 late (c-di-GMP), but the mechanisms by which Y. pestis regulates c-di-GMP synthesis and turnover are

284 et al. (2014) explore the mechanism by which Y. pestis spreads and thus leads to this striking lympha

285 d-and water-borne enteric species from which Y. pestis diverged less than 6,400 y ago, exhibits signi

286 e of Yersinia pseudotuberculosis, from which Y. pestis diverged only within the last 20000 years.

287 gest a step-wise evolutionary model in which Y. pestis emerged as a flea-borne clone, with each genet

288 a complex, fluctuating environment in which Y. pestis senses nutrient depletion via OmpR-EnvZ.

289 ost recent 19(th) century pandemic, in which Y. pestis spread worldwide [5] and became endemic in sev

290 Following intravenous challenge with Y. pestis KIM5 Deltailp, mice had a delayed time to deat

291 otection against subcutaneous challenge with Y. pestis strain CO92 even though it fails to protect mi

292 tive against lethal pulmonary challenge with Y. pestis.

293 developed lethal plague when challenged with Y. pestis pgm strains.

294 e with host sensing of YscF, consistent with Y. pestis pathogenesis.

295 hermore, following intranasal infection with Y. pestis, A2AP-deficient mice exhibit no difference in

296 apoptotic death pathway after infection with Y. pestis, influenced by Toll-like receptor 4-TIR-domain

297 defense in mice challenged intranasally with Y. pestis.

298 Intranasal challenge in mice with Y. pestis CO92 Deltailp had a 55-fold increase in the 50

299 which require help from fibrin to withstand Y. pestis encounters and effectively clear bacteria.

300 lenge of Myd88(-/-) mice with wild-type (WT) Y. pestis results in significant loss of pro- and anti-i