A Plasminogen-Activating Protease Specifically Controls the Development of Primary Pneumonic Plague

Abstract

Primary pneumonic plague is transmitted easily, progresses rapidly, and causes high mortality, but the mechanisms by which Yersinia pestis overwhelms the lungs are largely unknown. We show that the plasminogen activator Pla is essential for Y. pestis to cause primary pneumonic plague but is less important for dissemination during pneumonic plague than during bubonic plague. Experiments manipulating its temporal expression showed that Pla allows Y. pestis to replicate rapidly in the airways, causing a lethal fulminant pneumonia; if unexpressed, inflammation is aborted, and lung repair is activated. Inhibition of Pla expression prolonged the survival of animals with the disease, offering a therapeutic option to extend the period during which antibiotics are effective.

Plasminogen activator/plasmin system in arthritis and inflammation: Friend or foe?

“…Just to add to the complexity, it is interesting and perhaps surprising, given the literature on the contribution to bacterial virulence of plasminogen activation to plasmin by bacterial enzymes, possibly via fibrin dissolution (see, for example, refs. [18][19][20], that Plg Ϫ/Ϫ mice were found to be more susceptible to S aureus-induced arthritis than the wild-type controls. When human plasminogen was given intravenously to the Plg Ϫ/Ϫ mice, bacterial clearance was enhanced, and the amount of necrotic tissue in the joint cavity was reduced.…”

“…It might have been expected that there would have been less severe infection in the Plg Ϫ/Ϫ mice (18)(19)(20) and therefore perhaps less arthritis. Whether the intraarticular route of administration rather than the normal route of a systemic infection contributes to these intriguing findings is unknown, as is whether the protective effects of plasmin(ogen) are direct or indirect.…”

In vivo gene silencing identifies the Mycobacterium tuberculosis proteasome as essential for the bacteria to persist in mice

“…Tet-ON systems have been applied to infection models for pathogens such as Staphylococcus aureus and Yersinia pestis 25,26 but have not heretofore allowed analysis of Mtb mutants during mouse infections. Moreover, application of revTetR-dependent Tet-OFF systems to the in vivo analysis of a bacterial pathogen has not been reported.…”

Capsular Antigen Fraction 1 and Pla Modulate the Susceptibility of Yersinia pestis to Pulmonary Antimicrobial Peptides Such as Cathelicidin

“…Pla is essential for bubonic plague (but not for septicemic plague) after flea-mediated transmission (53,57,68). Pla is also essential for the development of (but not dissemination of) primary pneumonic plague (36). Plague lethality is generally assumed to be due to sepsis.…”

“…The pla gene was deleted from strain DSY9 to obtain strain DSY85 by using a lambda red recombination system (15). Briefly, the primer sequences were described previously (36), and the primers were used to prepare an amplified PCR product for the replacement of the pla gene with a kanamycin cassette. Strain DSY9 carrying the lambda red plasmid pSIM9 (16) was grown to log phase at 26°C, the red recombinase genes were induced for 15 min at 42°C, and the bacteria were transformed by electroporation with the gel-purified amplicons.…”