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Early emergence of Yersinia pestis as a severe respiratory pathogen.

Zimbler DL, Schroeder JA, Eddy JL, Lathem WW - Nat Commun (2015)

Bottom Line: Y. pestis recently evolved from the gastrointestinal pathogen Y. pseudotuberculosis; however, it is not known at what point Y. pestis gained the ability to induce a fulminant pneumonia.As Y. pestis further evolved, modern strains acquired a single amino-acid modification within Pla that optimizes protease activity.While this modification is unnecessary to cause pneumonic plague, the substitution is instead needed to efficiently induce the invasive infection associated with bubonic plague.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.

ABSTRACT
Yersinia pestis causes the fatal respiratory disease pneumonic plague. Y. pestis recently evolved from the gastrointestinal pathogen Y. pseudotuberculosis; however, it is not known at what point Y. pestis gained the ability to induce a fulminant pneumonia. Here we show that the acquisition of a single gene encoding the protease Pla was sufficient for the most ancestral, deeply rooted strains of Y. pestis to cause pneumonic plague, indicating that Y. pestis was primed to infect the lungs at a very early stage in its evolution. As Y. pestis further evolved, modern strains acquired a single amino-acid modification within Pla that optimizes protease activity. While this modification is unnecessary to cause pneumonic plague, the substitution is instead needed to efficiently induce the invasive infection associated with bubonic plague. These findings indicate that Y. pestis was capable of causing pneumonic plague before it evolved to optimally cause invasive infections in mammals.

No MeSH data available.


Related in: MedlinePlus

Pestoides F resembles Δpla Y. pestis during intranasal infections.(a) Survival of mice (n=20) infected i.n. with Y. pestis CO92, CO92 Δpla or Pestoides F. (b) Bacterial burden within the lungs and spleens of mice (n=10) infected i.n. with the indicated Y. pestis strains, as described in Fig. 1. By 72 h, mice begin to succumb to the CO92 infection (indicated by “X” on the x axis). (c) Pathology of mouse lung sections stained with H&E at 48 h post inoculation with PBS (mock), Pestoides F, CO92 Δpla or CO92 Y. pestis. Representative images of inflammatory lesions are shown (arrows; n=3). Scale bar, 200 μm. (d) Enumeration of total immune cells present in BAL fluid 48 h post inoculation with PBS (mock), Pestoides F, CO92 Δpla or CO92 Y. pestis (n=10). (e) Abundance of the indicated inflammatory cytokines present in BAL fluid at 48 h post inoculation. Data are combined from two independent experiments and error bars represent the s.e.m. (*P≤0.05, **P≤0.01, NS, not significant by Log-Rank test (survival), Mann–Whitney U-test (c.f.u.)). H&E, haematoxylin/eosin.
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f2: Pestoides F resembles Δpla Y. pestis during intranasal infections.(a) Survival of mice (n=20) infected i.n. with Y. pestis CO92, CO92 Δpla or Pestoides F. (b) Bacterial burden within the lungs and spleens of mice (n=10) infected i.n. with the indicated Y. pestis strains, as described in Fig. 1. By 72 h, mice begin to succumb to the CO92 infection (indicated by “X” on the x axis). (c) Pathology of mouse lung sections stained with H&E at 48 h post inoculation with PBS (mock), Pestoides F, CO92 Δpla or CO92 Y. pestis. Representative images of inflammatory lesions are shown (arrows; n=3). Scale bar, 200 μm. (d) Enumeration of total immune cells present in BAL fluid 48 h post inoculation with PBS (mock), Pestoides F, CO92 Δpla or CO92 Y. pestis (n=10). (e) Abundance of the indicated inflammatory cytokines present in BAL fluid at 48 h post inoculation. Data are combined from two independent experiments and error bars represent the s.e.m. (*P≤0.05, **P≤0.01, NS, not significant by Log-Rank test (survival), Mann–Whitney U-test (c.f.u.)). H&E, haematoxylin/eosin.

Mentions: As Pestoides F is considered to be one of the most ancestral existing isolates of Y. pestis635 after it emerged from Y. pseudotuberculosis but before the acquisition of pPCP1, we further examined the interaction of this strain with the respiratory environment and in comparison with a mutant of CO92 lacking pla. To confirm that Pestoides F does not display functional activity generally attributed to Pla, we validated that Pestoides F is unable to activate Plg, similarly to an isogenic Δpla mutant of CO92 Y. pestis (Supplementary Fig. 1b,c). We then infected mice via the i.n. route and followed survival over time; while all mice infected with the wild-type CO92 strain rapidly succumbed to the infection by day 4 post infection, the Pestoides F-infected mice showed a survival curve similar to that of Δpla CO92 and were significantly delayed in time to death compared with CO92 (Fig. 2a). To further assess the kinetics of infection of Pestoides F compared with CO92, we enumerated the colony-forming unit (c.f.u.) in the lungs and spleens at various times post infection and found that neither the Δpla CO92 mutant nor the ancestral Pestoides F isolate are unable to replicate to high levels in the pulmonary compartment as compared with modern CO92 (Fig. 2b). Interestingly, by 48 h Pestoides F is able to modestly but significantly outgrow by ∼10–100-fold in the lungs compared with mice infected with the Δpla CO92 mutant, although similar numbers of bacteria are detected in spleens of Pestoides F and Δpla CO92-infected mice at all time points examined (Fig. 2b).


Early emergence of Yersinia pestis as a severe respiratory pathogen.

Zimbler DL, Schroeder JA, Eddy JL, Lathem WW - Nat Commun (2015)

Pestoides F resembles Δpla Y. pestis during intranasal infections.(a) Survival of mice (n=20) infected i.n. with Y. pestis CO92, CO92 Δpla or Pestoides F. (b) Bacterial burden within the lungs and spleens of mice (n=10) infected i.n. with the indicated Y. pestis strains, as described in Fig. 1. By 72 h, mice begin to succumb to the CO92 infection (indicated by “X” on the x axis). (c) Pathology of mouse lung sections stained with H&E at 48 h post inoculation with PBS (mock), Pestoides F, CO92 Δpla or CO92 Y. pestis. Representative images of inflammatory lesions are shown (arrows; n=3). Scale bar, 200 μm. (d) Enumeration of total immune cells present in BAL fluid 48 h post inoculation with PBS (mock), Pestoides F, CO92 Δpla or CO92 Y. pestis (n=10). (e) Abundance of the indicated inflammatory cytokines present in BAL fluid at 48 h post inoculation. Data are combined from two independent experiments and error bars represent the s.e.m. (*P≤0.05, **P≤0.01, NS, not significant by Log-Rank test (survival), Mann–Whitney U-test (c.f.u.)). H&E, haematoxylin/eosin.
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f2: Pestoides F resembles Δpla Y. pestis during intranasal infections.(a) Survival of mice (n=20) infected i.n. with Y. pestis CO92, CO92 Δpla or Pestoides F. (b) Bacterial burden within the lungs and spleens of mice (n=10) infected i.n. with the indicated Y. pestis strains, as described in Fig. 1. By 72 h, mice begin to succumb to the CO92 infection (indicated by “X” on the x axis). (c) Pathology of mouse lung sections stained with H&E at 48 h post inoculation with PBS (mock), Pestoides F, CO92 Δpla or CO92 Y. pestis. Representative images of inflammatory lesions are shown (arrows; n=3). Scale bar, 200 μm. (d) Enumeration of total immune cells present in BAL fluid 48 h post inoculation with PBS (mock), Pestoides F, CO92 Δpla or CO92 Y. pestis (n=10). (e) Abundance of the indicated inflammatory cytokines present in BAL fluid at 48 h post inoculation. Data are combined from two independent experiments and error bars represent the s.e.m. (*P≤0.05, **P≤0.01, NS, not significant by Log-Rank test (survival), Mann–Whitney U-test (c.f.u.)). H&E, haematoxylin/eosin.
Mentions: As Pestoides F is considered to be one of the most ancestral existing isolates of Y. pestis635 after it emerged from Y. pseudotuberculosis but before the acquisition of pPCP1, we further examined the interaction of this strain with the respiratory environment and in comparison with a mutant of CO92 lacking pla. To confirm that Pestoides F does not display functional activity generally attributed to Pla, we validated that Pestoides F is unable to activate Plg, similarly to an isogenic Δpla mutant of CO92 Y. pestis (Supplementary Fig. 1b,c). We then infected mice via the i.n. route and followed survival over time; while all mice infected with the wild-type CO92 strain rapidly succumbed to the infection by day 4 post infection, the Pestoides F-infected mice showed a survival curve similar to that of Δpla CO92 and were significantly delayed in time to death compared with CO92 (Fig. 2a). To further assess the kinetics of infection of Pestoides F compared with CO92, we enumerated the colony-forming unit (c.f.u.) in the lungs and spleens at various times post infection and found that neither the Δpla CO92 mutant nor the ancestral Pestoides F isolate are unable to replicate to high levels in the pulmonary compartment as compared with modern CO92 (Fig. 2b). Interestingly, by 48 h Pestoides F is able to modestly but significantly outgrow by ∼10–100-fold in the lungs compared with mice infected with the Δpla CO92 mutant, although similar numbers of bacteria are detected in spleens of Pestoides F and Δpla CO92-infected mice at all time points examined (Fig. 2b).

Bottom Line: Y. pestis recently evolved from the gastrointestinal pathogen Y. pseudotuberculosis; however, it is not known at what point Y. pestis gained the ability to induce a fulminant pneumonia.As Y. pestis further evolved, modern strains acquired a single amino-acid modification within Pla that optimizes protease activity.While this modification is unnecessary to cause pneumonic plague, the substitution is instead needed to efficiently induce the invasive infection associated with bubonic plague.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.

ABSTRACT
Yersinia pestis causes the fatal respiratory disease pneumonic plague. Y. pestis recently evolved from the gastrointestinal pathogen Y. pseudotuberculosis; however, it is not known at what point Y. pestis gained the ability to induce a fulminant pneumonia. Here we show that the acquisition of a single gene encoding the protease Pla was sufficient for the most ancestral, deeply rooted strains of Y. pestis to cause pneumonic plague, indicating that Y. pestis was primed to infect the lungs at a very early stage in its evolution. As Y. pestis further evolved, modern strains acquired a single amino-acid modification within Pla that optimizes protease activity. While this modification is unnecessary to cause pneumonic plague, the substitution is instead needed to efficiently induce the invasive infection associated with bubonic plague. These findings indicate that Y. pestis was capable of causing pneumonic plague before it evolved to optimally cause invasive infections in mammals.

No MeSH data available.


Related in: MedlinePlus