TY - JOUR
T1 - Lethal pulmonary infection with Francisella novicida is associated with severe sepsis
AU - Sharma, Jyotika
AU - Li, Qun
AU - Mishra, Bibhuti B.
AU - Pena, Christopher
AU - Teale, Judy M.
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2009/9/1
Y1 - 2009/9/1
N2 - The bacterial or host determinants of lethality associated with respiratory Francisella infections are currently unknown. No exo- or endotoxins that contribute to the severity of this disease have been identified. However, a deregulated host immune response upon infection is characterized by an initial 36- to 48-h delay followed by a rapid and excessive inflammatory response prior to death at 72-120 h. Here, we extend these findings by comparing host immune responses between sublethal and lethal respiratory infections of mice with an attenuated transposon mutant (Mut) of F. novicida (F.n.) strain U112 (sublethal) versus the wild-type (WT) strain (lethal). Infection with WT bacteria, but not the Mut, was characterized by sustained bacteremia and systemic dissemination of the pathogen with temporal increases in bacterial burdens in liver and spleen. Severe pathology with large foci of infiltrates associated with extensive tissue damage was evident in WT-infected lungs, and Mut-infected mice displayed much reduced pathology with intact lung architecture. Similar to other experimental models of severe sepsis, WT- but not the Mutinfected mice exhibited a robust increase in numbers of Gr1+ and CD11b+ cells, while displaying a significant depletion of αβ T cells. Further, a dramatic up-regulation of multiple cytokines and chemokines was observed only in lethal WT infection. In addition, an earlier and larger increased expression of S100A9, a known mediator of sepsis, was observed in WT-infected mice. Taken together, these results show that a hyperinflammatory host immune response, culminating in severe sepsis, is responsible for the lethal outcome of respiratory tularemia.
AB - The bacterial or host determinants of lethality associated with respiratory Francisella infections are currently unknown. No exo- or endotoxins that contribute to the severity of this disease have been identified. However, a deregulated host immune response upon infection is characterized by an initial 36- to 48-h delay followed by a rapid and excessive inflammatory response prior to death at 72-120 h. Here, we extend these findings by comparing host immune responses between sublethal and lethal respiratory infections of mice with an attenuated transposon mutant (Mut) of F. novicida (F.n.) strain U112 (sublethal) versus the wild-type (WT) strain (lethal). Infection with WT bacteria, but not the Mut, was characterized by sustained bacteremia and systemic dissemination of the pathogen with temporal increases in bacterial burdens in liver and spleen. Severe pathology with large foci of infiltrates associated with extensive tissue damage was evident in WT-infected lungs, and Mut-infected mice displayed much reduced pathology with intact lung architecture. Similar to other experimental models of severe sepsis, WT- but not the Mutinfected mice exhibited a robust increase in numbers of Gr1+ and CD11b+ cells, while displaying a significant depletion of αβ T cells. Further, a dramatic up-regulation of multiple cytokines and chemokines was observed only in lethal WT infection. In addition, an earlier and larger increased expression of S100A9, a known mediator of sepsis, was observed in WT-infected mice. Taken together, these results show that a hyperinflammatory host immune response, culminating in severe sepsis, is responsible for the lethal outcome of respiratory tularemia.
KW - 58 kDa mutant
KW - Bacteremia
KW - Hypercytokinemia
KW - Tularemia
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U2 - 10.1189/jlb.1208728
DO - 10.1189/jlb.1208728
M3 - Article
C2 - 19401387
AN - SCOPUS:70149085644
SN - 0741-5400
VL - 86
SP - 491
EP - 504
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
IS - 3
ER -