Plasminogen Activator Pla of Yersinia pestis Utilizes Murine DEC-205 (CD205) as a Receptor to Promote Dissemination

Abstract

Yersinia pestis, a Gram-negative bacterium that causes bubonic and pneumonic plague, is able to rapidly disseminate to other parts of its mammalian hosts. Y. pestis expresses plasminogen activator (PLA) on its surface, which has been suggested to play a role in bacterial dissemination. It has been speculated that Y. pestis hijacks antigen-presenting cells, such as macrophages (MΦs) and dendritic cells, to be delivered to lymph nodes to initiate dissemination and infection. Both alveolar MΦs and pulmonary dendritic cells express a C-type lectin receptor, DEC-205 (CD205), which mediates antigen uptake and presentation. However, no ligand has been identified for DEC-205. In this study, we show that the invasion of alveolar MΦsby Y. pestis depends both in vitro and in vivo on the expression of PLA. DEC-205-expressing MΦs and transfectants, but not their negative counterparts, phagocytosed PLA-expressing Y. pestis and Escherichia coli K12 more efficiently than PLA-negative controls. The interactions between PLA-expressing bacteria and DEC-205-expressing transfectants or alveolar MΦs could be inhibited by an anti-DEC-205 antibody. Importantly, the blockage of the PLA-DEC-205 interaction reduced the dissemination of Y. pestis in mice. In conclusion, murine DEC-205 is a receptor for PLA of Y. pestis, and this host-pathogen interaction appears to play a key role in promoting bacterial dissemination. Yersinia pestis, a Gram-negative bacterium that causes bubonic and pneumonic plague, is able to rapidly disseminate to other parts of its mammalian hosts. Y. pestis expresses plasminogen activator (PLA) on its surface, which has been suggested to play a role in bacterial dissemination. It has been speculated that Y. pestis hijacks antigen-presenting cells, such as macrophages (MΦs) and dendritic cells, to be delivered to lymph nodes to initiate dissemination and infection. Both alveolar MΦs and pulmonary dendritic cells express a C-type lectin receptor, DEC-205 (CD205), which mediates antigen uptake and presentation. However, no ligand has been identified for DEC-205. In this study, we show that the invasion of alveolar MΦsby Y. pestis depends both in vitro and in vivo on the expression of PLA. DEC-205-expressing MΦs and transfectants, but not their negative counterparts, phagocytosed PLA-expressing Y. pestis and Escherichia coli K12 more efficiently than PLA-negative controls. The interactions between PLA-expressing bacteria and DEC-205-expressing transfectants or alveolar MΦs could be inhibited by an anti-DEC-205 antibody. Importantly, the blockage of the PLA-DEC-205 interaction reduced the dissemination of Y. pestis in mice. In conclusion, murine DEC-205 is a receptor for PLA of Y. pestis, and this host-pathogen interaction appears to play a key role in promoting bacterial dissemination. Yersinia pestis is the Gram-negative bacterium that causes bubonic and pneumonic plague. Y. pestis has evolved directly from Yersinia pseudotuberculosis within the last 10,000–20,000 years (1Achtman M. Zurth K. Morelli G. Torrea G. Guiyoule A. Carniel E. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 14043-14048Crossref PubMed Scopus (845) Google Scholar, 2Achtman M. Morelli G. Zhu P. Wirth T. Diehl I. Kusecek B. Vogler A.J. Wagner D.M. Allender C.J. Easterday W.R. Chenal-Francisque V. Worsham P. Thomson N.R. Parkhill J. Lindler L.E. Carniel E. Keim P. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 17837-17842Crossref PubMed Scopus (391) Google Scholar). The Yersinia genus is composed of 12 species, and 3 species of Yersinia are pathogenic to humans (3Vazquez-Torres A. Fang F.C. Curr. Opin. Microbiol. 2000; 3: 54-59Crossref PubMed Scopus (93) Google Scholar, 4Isberg R.R. Barnes P. J. Cell Sci. 2001; 114: 21-28Crossref PubMed Google Scholar). Y. pseudotuberculosis and Yersinia enterocolitica cause mild enteric diseases, whereas the hallmark of Y. pestis is its rapid dissemination in the mammalian host resulting in bubonic and pneumonic plague and high mortality. All three pathogenic Yersinia share a virulence plasmid, pCD1 (pYV), which is essential for pathogenesis (5Brubaker R.R. Rev. Infect. Dis. 1983; 5: 748-758Crossref PubMed Google Scholar, 6Portnoy D.A. Martinez R.J. Curr. Top. Microbiol. Immunol. 1985; 118: 29-51PubMed Google Scholar). This plasmid encodes a type III secretion system (7Cornelis G.R. Wolf-Watz H. Mol. Microbiol. 1997; 23: 861-867Crossref PubMed Scopus (481) Google Scholar), YadA {an adherence and virulence surface molecule, although yadA is a pseudogene in Y. pestis (8Rosqvist R. Skurnik M. Wolf-Watz H. Nature. 1988; 334: 522-524Crossref PubMed Scopus (171) Google Scholar, 9Skurnik M. Wolf-Watz H. Mol. Microbiol. 1989; 3: 517-529Crossref PubMed Scopus (137) Google Scholar)}, and a number of secreted effector proteins that inhibit bacterial phagocytosis and specific innate immune responses (10Viboud G.I. Bliska J.B. Annu. Rev. Microbiol. 2005; 59: 69-89Crossref PubMed Scopus (465) Google Scholar). Y. pestis harbors two additional plasmids, pPCP1 (9.6 kb) and pMT1 (pFra) (102 kb), which encode the plasminogen activator (PLA) 3The abbreviations used are: PLA, plasminogen activator; MΦ, macrophage; APC, antigen-presenting cell; DC, dendritic cell; LPS, lipopolysaccharide; CFU, colony-forming unit; FCS, fetal calf serum; CHO, Chinese hamster ovary; HIV-1, human immunodeficiency virus, type 1. and the F1 protein, respectively. The products of these genes are necessary for tissue invasion (11Lahteenmaki K. Virkola R. Saren A. Emody L. Korhonen T.K. Infect. PubMed Google Scholar), PubMed Scopus Google Scholar), and of the plague P. A. PubMed Scopus Google Scholar, Proc. Natl. Acad. Sci. U. 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The in show three Y. pestis alveolar and MΦs of Y. pestis by and alveolar MΦs reduced Y. pestis and as a of expression of The the E. coli MΦs an to E. coli K12 but not to expression of which not the alveolar Both and a in alveolar a in the interaction of Gram-negative bacteria alveolar MΦs and an in vivo phagocytosis which to the in vivo phagocytosis of Y. pestis by alveolar The in vivo phagocytosis of and a to the in vitro phagocytosis although the of bacteria in that the of bacteria in vivo is of the in high of bacteria in the of mice. It be that the of bacteria in in vitro invasion this we not E. coli K12 are to In the that the phagocytosis of Y. pestis by alveolar MΦs is the other than on Y. on a for Y. in that the invasion of alveolar MΦsby Y. pestis not be by of This as is a ligand for the receptor, on However, from other suggested that alveolar MΦs in not express J. S. Y. T. Infect. PubMed Scopus Google but express receptor, DEC-205 M. M. R. M. J. Immunol. 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It be that Y. pestis the pPCP1 plasmid as as the This to that the for the DEC-205 receptor be on the pPCP1 plasmid, which encodes or the genes that are to pathogenesis of Y. pestis Mol. Microbiol. 1999; PubMed Scopus Google Scholar, Mol. Microbiol. 1999; PubMed Scopus Google Scholar, Bliska J.B. Proc. Natl. Acad. Sci. U. S. A. 2005; PubMed Scopus Google Scholar). the and both and for their to Y. pseudotuberculosis used as a in Y. pestis and but not the and that pPCP1 than the is necessary for the interaction DEC-205. in this show that to cells than in the of that the of the pPCP1 plasmid inhibit other adherence of Y. pestis a for DEC-205 and a in the pPCP1 plasmid PLA is the and In from other that expression of in Yersinia the of PLA by the pPCP1 plasmid M. M. P. K. H. Virkola R. Korhonen T.K. Mol. Microbiol. 2004; PubMed Scopus Google Scholar). The in show that expression of the interaction of Y. pestis pPCP1 D.M. A. Infect. PubMed Scopus Google Scholar), E. coli K12 and E. coli K12 for their interactions and alveolar used as the negative that of the the as and and that and E. coli K12 but not the and E. coli K12 that PLA of Y. pestis is a ligand for DEC-205. In expression of PLA in and the to alveolar that PLA in the interaction of Y. pestis alveolar of and PLA-expressing Y. pestis and E. coli by DEC-205 the of the Y. we the interaction of PLA-expressing Y. pestis and E. coli and alveolar MΦs could be inhibited by anti-DEC-205 antibody. as a antibody. we used Y. pseudotuberculosis which mediates a as a that anti-DEC-205 the invasion of the and to this reduced the phagocytosis of and by alveolar MΦs the blockage not that other on alveolar MΦs be in this the of which could to specific or It be that the of used in this not the of bacteria or host cells P. S. P. P. S. S. J. J. T. J. Immunol. PubMed Scopus Google as Y. pseudotuberculosis P. Skurnik M. S. G. R. S. J. J. J. T. Infect. 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A. 2005; PubMed Scopus Google Scholar). and and Y. pestis and show that both and could be to but the is more as in the The is that the its to be to but this on the in the for reduced 1. show that both and be to for to although the are in the not that the Y. pestis in the for a However, are these Y. pestis In the that PLA a role in Y. pestis dissemination pneumonic plague. the other we speculated that the PLA-DEC-205 by expression of could the dissemination. this Y. pestis and its for their to disseminate to the of dissemination the in and B. high number of Y. pestis but not from and In bacteria in the in than It is that the in dissemination of Y. pestis be to its to DEC-205. expression of dissemination and the interaction between PLA and we that the dissemination is on the of PLA to DEC-205. is able to be other in the Y. pestis dissemination from to Y. pestis, the of pneumonic plague, is able to rapidly disseminate from the to other that PLA a role in promoting Y. pestis dissemination. It is speculated that Y. pestis hijacks to be delivered to lymph resulting in this dissemination. In this study, we that the PLA of Y. pestis is a ligand for DEC-205. that the PLA-DEC-205 interaction the dissemination of Y. The DEC-205 receptor is on in both humans and M. S. S. K. Immunol. PubMed Scopus Google Scholar, M. A. PubMed Scopus Google Scholar). The of DEC-205 receptor is to antigen L. K. M. J. PubMed Scopus Google Scholar, A. S. H. B. J. 2004; PubMed Scopus Google Scholar, S. K. PubMed Scopus Google Scholar). the DEC-205 has been used to host responses for the and from Y. pestis L. S. M. M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, B. H. Y. A. J. PubMed Scopus Google Scholar, Y. H. J. Immunol. PubMed Scopus Google Scholar). the other an to the interaction is that Y. pestis, evolved of host to the of an to disseminate in the as in this However, are and which to be to and In this study, Y. pestis for of the of the This the of the we are in the pathogenic of plague. of the of Y. pestis, this is a and its in are by and not for to a in However, the of the dissemination the In we not that of such as the that the innate immune system is these the reduced of these an of is that to to the of host-pathogen interactions Y. pestis dissemination and infection. we used to the role of specific in the dissemination of Y. pestis to from the in pneumonic plague. a been been to the dissemination these bacteria are of in we that the number of in the is reduced by a in the of from that the high expression of PLA by Y. pestis the rapid phagocytosis by alveolar resulting in bacterial or dissemination and that the in of Y. pestis in 3 and alveolar MΦs and more than the that the expression of PLA in be than in the we that Y. pestis bacteria for phagocytosed or the dissemination that a in dissemination on the of from both and are The that the dissemination is bacteria are to that we to dissemination by not but show for in this that the Y. pestis to in the MΦs as in a Bliska J.B. Proc. Natl. Acad. Sci. U. S. A. 2005; PubMed Scopus Google Scholar). The dissemination is In an of the of dissemination. on the of PubMed Scopus Google Scholar), the number of Y. pestis could in these to the infection. It is that the are more to in the dissemination is that a of the able to the be the between Y. pestis and is the of the plasmid in the its to disseminate the in this study, we to bacteria from of the not that the bacteria in the or rapidly for It is that the bacteria from not the but an as the Y. pestis which is The of this the pPCP1 plasmid, the plasmid type III secretion system and other and the D.M. A. Infect. PubMed Scopus Google Scholar). The for this to the of other virulence which of the interaction although Y. pestis not express directly cells such as cells R.R. Infect. PubMed Google Scholar). that the interaction of Y. pestis cells the of the surface in or has their to cells in the of or DEC-205. of is we used such a high of Y. pestis as an the of Y. pestis, this for to bacteria to the It is that Y. pestis is an that of Y. pestis be as as Microbiol. Rev. 1997; PubMed Google Scholar). However, to the of the bacterial the of Y. pestis is more In P. Skurnik M. S. G. R. S. J. J. J. T. Infect. PubMed Scopus Google we the and to inhibit the interactions of Y. pestis human and but of these In we both and host receptor for Y. to show a in this interaction P. Skurnik M. S. G. R. S. J. J. J. T. Infect. PubMed Scopus Google Scholar). in in this study, interaction of Y. pestis alveolar MΦs reduced by a anti-DEC-205 that DEC-205 is a receptor for Y. pestis and a specific role the phagocytosis of Y. pestis by alveolar However, this by anti-DEC-205 not that alveolar MΦs an additional for Y. Both S. Martinez M. A. P. R. PubMed Scopus Google and PubMed Scopus Google that PLA not play a role in dissemination the to and to respectively. the used in their we that of the bacteria to although the type III secretion the of bacteria to lymph in the expression of PLA, able to be although not as efficiently the are the other for promoting dissemination of Y. This on the between PLA of Y. pestis and DEC-205 of alveolar However, is that pulmonary which express both DEC-205 and than alveolar are the cells for between 2005; 23: PubMed Scopus Google Scholar, H. Immunol. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). we to for pneumonic plague. the Y. pestis its D.M. A. Infect. PubMed Scopus Google Scholar, C.J. PubMed Scopus Google to to surface and of in the the Y. pestis the pulmonary the or which to the dissemination. in vitro and in vivo that Y. pestis the PLA-DEC-205 interaction to its invasion and dissemination. However, the as to the PLA-DEC-205 interaction a role in an in vivo infection. The be to a DEC-205 be to plague or the dissemination of Y. pestis, an that we are The has been used to the receptor an to E. M. S. J. 2004; PubMed Scopus Google Scholar), is a receptor for K. R. R. A. J. PubMed Scopus Google Scholar). However, are of this for are no receptor that are more to bacterial infection. The be bacterial are more than of receptor not be to the of a bacterial a that to the of to Y. pestis J. G. R.R. S. Nature. 2004; PubMed Scopus Google Scholar, G. S. P. K. B. Nature. 2004; PubMed Google Scholar), is a receptor for Y. the DEC-205 is the receptor for Y. not on receptor in their interactions host cells, as we in or that Y. pestis human human surface and of DEC-205. this has that DEC-205 as a receptor for Y. pestis, PLA as a The in this that interactions between PLA and DEC-205 play a role in the dissemination of Y. are to the for and