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Caspase-3 mediates the pathogenic effect of Yersinia pestis YopM in liver of C57BL/6 mice and contributes to YopM's function in spleen.

Ye Z, Gorman AA, Uittenbogaard AM, Myers-Morales T, Kaplan AM, Cohen DA, Straley SC - PLoS ONE (2014)

Bottom Line: The bacteria were found associated with myeloid cells in foci of inflammation and in liver sinusoids.By 2 d post-infection, YopM had no effect on distribution of these cells, but by 3 d cellular decomposition had outstripped acute inflammation in foci due to parent Y. pestis, while foci due to the ΔyopM-1 strain still contained many inflammatory cells.This result identified caspase-3 as a co-factor or effector in YopM's action and supports the hypothesis that in liver YopM's main pathogenic effect is mediated by caspase-3 to cause apoptosis of PMNs.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY, United States of America.

ABSTRACT
The virulence protein YopM of the plague bacterium Yersinia pestis has different dominant effects in liver and spleen. Previous studies focused on spleen, where YopM inhibits accumulation of inflammatory dendritic cells. In the present study we focused on liver, where PMN function may be directly undermined by YopM without changes in inflammatory cell numbers in the initial days of infection, and foci of inflammation are easily identified. Mice were infected with parent and ΔyopM-1 Y. pestis KIM5, and effects of YopM were assessed by immunohistochemistry and determinations of bacterial viable numbers in organs. The bacteria were found associated with myeloid cells in foci of inflammation and in liver sinusoids. A new in-vivo phenotype of YopM was revealed: death of inflammatory cells, evidenced by TUNEL staining beginning at d 1 of infection. Based on distributions of Ly6G(+), F4/80(+), and iNOS(+) cells within foci, the cells that were killed could have included both PMNs and macrophages. By 2 d post-infection, YopM had no effect on distribution of these cells, but by 3 d cellular decomposition had outstripped acute inflammation in foci due to parent Y. pestis, while foci due to the ΔyopM-1 strain still contained many inflammatory cells. The destruction depended on the presence of both PMNs in the mice and YopM in the bacteria. In mice that lacked the apoptosis mediator caspase-3 the infection dynamics were novel: the parent Y. pestis was limited in growth comparably to the ΔyopM-1 strain in liver, and in spleen a partial growth limitation for parent Y. pestis was seen. This result identified caspase-3 as a co-factor or effector in YopM's action and supports the hypothesis that in liver YopM's main pathogenic effect is mediated by caspase-3 to cause apoptosis of PMNs.

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YopM did not affect the distributions of inflammatory cells.Liver sections from the mice of Figure 3 were stained for inducible nitric oxide synthase (iNOS; panels A and B), the KC/MO marker F4/80 (panels C), or the PMN marker Ly6G (panels D). Antigen detection used DAB staining (black or brown) in sections from livers infected by parent Y. pestis (left panels) and the ΔYopM-1 strain (right panels). The arrows in panels C point to inflammatory foci. The bars represent 100 µm (panels A, C, D) or 10 µm (panels B).
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pone-0110956-g005: YopM did not affect the distributions of inflammatory cells.Liver sections from the mice of Figure 3 were stained for inducible nitric oxide synthase (iNOS; panels A and B), the KC/MO marker F4/80 (panels C), or the PMN marker Ly6G (panels D). Antigen detection used DAB staining (black or brown) in sections from livers infected by parent Y. pestis (left panels) and the ΔYopM-1 strain (right panels). The arrows in panels C point to inflammatory foci. The bars represent 100 µm (panels A, C, D) or 10 µm (panels B).

Mentions: Within the foci, clusters of bacteria were associated with groups of inflammatory cells (Fig. 3C). In the sinusoids, bacteria were associated with PMNs (Fig. 3D) and mononuclear cells (KCs/MOs/DCs; Fig. 3C, E and F) and not with endothelial cells or hepatocytes. Similar observations were made at d 2 p.i. in mice infected with a lower dose as in Figures 4 and 5 (data not shown).


Caspase-3 mediates the pathogenic effect of Yersinia pestis YopM in liver of C57BL/6 mice and contributes to YopM's function in spleen.

Ye Z, Gorman AA, Uittenbogaard AM, Myers-Morales T, Kaplan AM, Cohen DA, Straley SC - PLoS ONE (2014)

YopM did not affect the distributions of inflammatory cells.Liver sections from the mice of Figure 3 were stained for inducible nitric oxide synthase (iNOS; panels A and B), the KC/MO marker F4/80 (panels C), or the PMN marker Ly6G (panels D). Antigen detection used DAB staining (black or brown) in sections from livers infected by parent Y. pestis (left panels) and the ΔYopM-1 strain (right panels). The arrows in panels C point to inflammatory foci. The bars represent 100 µm (panels A, C, D) or 10 µm (panels B).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4220956&req=5

pone-0110956-g005: YopM did not affect the distributions of inflammatory cells.Liver sections from the mice of Figure 3 were stained for inducible nitric oxide synthase (iNOS; panels A and B), the KC/MO marker F4/80 (panels C), or the PMN marker Ly6G (panels D). Antigen detection used DAB staining (black or brown) in sections from livers infected by parent Y. pestis (left panels) and the ΔYopM-1 strain (right panels). The arrows in panels C point to inflammatory foci. The bars represent 100 µm (panels A, C, D) or 10 µm (panels B).
Mentions: Within the foci, clusters of bacteria were associated with groups of inflammatory cells (Fig. 3C). In the sinusoids, bacteria were associated with PMNs (Fig. 3D) and mononuclear cells (KCs/MOs/DCs; Fig. 3C, E and F) and not with endothelial cells or hepatocytes. Similar observations were made at d 2 p.i. in mice infected with a lower dose as in Figures 4 and 5 (data not shown).

Bottom Line: The bacteria were found associated with myeloid cells in foci of inflammation and in liver sinusoids.By 2 d post-infection, YopM had no effect on distribution of these cells, but by 3 d cellular decomposition had outstripped acute inflammation in foci due to parent Y. pestis, while foci due to the ΔyopM-1 strain still contained many inflammatory cells.This result identified caspase-3 as a co-factor or effector in YopM's action and supports the hypothesis that in liver YopM's main pathogenic effect is mediated by caspase-3 to cause apoptosis of PMNs.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY, United States of America.

ABSTRACT
The virulence protein YopM of the plague bacterium Yersinia pestis has different dominant effects in liver and spleen. Previous studies focused on spleen, where YopM inhibits accumulation of inflammatory dendritic cells. In the present study we focused on liver, where PMN function may be directly undermined by YopM without changes in inflammatory cell numbers in the initial days of infection, and foci of inflammation are easily identified. Mice were infected with parent and ΔyopM-1 Y. pestis KIM5, and effects of YopM were assessed by immunohistochemistry and determinations of bacterial viable numbers in organs. The bacteria were found associated with myeloid cells in foci of inflammation and in liver sinusoids. A new in-vivo phenotype of YopM was revealed: death of inflammatory cells, evidenced by TUNEL staining beginning at d 1 of infection. Based on distributions of Ly6G(+), F4/80(+), and iNOS(+) cells within foci, the cells that were killed could have included both PMNs and macrophages. By 2 d post-infection, YopM had no effect on distribution of these cells, but by 3 d cellular decomposition had outstripped acute inflammation in foci due to parent Y. pestis, while foci due to the ΔyopM-1 strain still contained many inflammatory cells. The destruction depended on the presence of both PMNs in the mice and YopM in the bacteria. In mice that lacked the apoptosis mediator caspase-3 the infection dynamics were novel: the parent Y. pestis was limited in growth comparably to the ΔyopM-1 strain in liver, and in spleen a partial growth limitation for parent Y. pestis was seen. This result identified caspase-3 as a co-factor or effector in YopM's action and supports the hypothesis that in liver YopM's main pathogenic effect is mediated by caspase-3 to cause apoptosis of PMNs.

Show MeSH
Related in: MedlinePlus