TY - JOUR
T1 - The innate immune response to Streptococcus pneumoniae in the lung depends on serotype and host response
AU - Seyoum, Beza
AU - Yano, Masahide
AU - Pirofski, Liise anne
N1 - Funding Information:
Conflict of interest statement: The authors have declared that no conflict of interest exists. Funding: This work was supported by the National Institutes of Health grants , R01-AI045459 and R01-AI044374 (to LP) and Molecular Pathogenesis Training Grant , T32-A107506 (to BS).
PY - 2011/10/19
Y1 - 2011/10/19
N2 - Bacteremic pneumonia with some pneumococcal capsular serotypes, including serotype 3 (ST3), has been associated with a higher risk of death, whereas others, such as ST8, are associated with a lower risk. To provide a molecular basis for understanding such differences, we used oligo cDNA microarrays to analyze and compare the gene expression profiles of the lungs of Balb/c mice infected intranasally with either ST3, strain A66.1, or ST8, strain ATCC 6308 (6308). Compared to uninfected controls, infection with either A66.1 or 6308 led to inoculum-dependent expression of IFN-γ inducible CXC chemokines among other pro-inflammatory genes. To investigate the role that IFN-γ inducible chemokines CXCL9, CXCL10 and CXCL11 play in A66.1- and 6308-induced pneumonia, we examined the effect of the absence of their common receptor, CXCR3, on intranasal infection in CXCR3 -/- (Balb/c) mice. Compared to wild type (WT) mice, virulence of A66.1 but not 6308 was attenuated in CXCR3 -/- mice. A66.1-infected CXCR3 -/- mice had fewer lung neutrophils and more alveolar macrophages 48h after infection and fewer blood CFU 72h after infection. Histopathological examination of lung sections revealed less inflammation among A66.1-infected CXCR3 -/- than WT mice. The reduced virulence of A66.1 in CXCR3 -/- mice suggests that inhibition of the functional activity of IFN-γ inducible chemokines modulates the host response to A66.1, in turn suggesting a novel approach to improve vaccine-mediated protection against ST3 pneumonia.
AB - Bacteremic pneumonia with some pneumococcal capsular serotypes, including serotype 3 (ST3), has been associated with a higher risk of death, whereas others, such as ST8, are associated with a lower risk. To provide a molecular basis for understanding such differences, we used oligo cDNA microarrays to analyze and compare the gene expression profiles of the lungs of Balb/c mice infected intranasally with either ST3, strain A66.1, or ST8, strain ATCC 6308 (6308). Compared to uninfected controls, infection with either A66.1 or 6308 led to inoculum-dependent expression of IFN-γ inducible CXC chemokines among other pro-inflammatory genes. To investigate the role that IFN-γ inducible chemokines CXCL9, CXCL10 and CXCL11 play in A66.1- and 6308-induced pneumonia, we examined the effect of the absence of their common receptor, CXCR3, on intranasal infection in CXCR3 -/- (Balb/c) mice. Compared to wild type (WT) mice, virulence of A66.1 but not 6308 was attenuated in CXCR3 -/- mice. A66.1-infected CXCR3 -/- mice had fewer lung neutrophils and more alveolar macrophages 48h after infection and fewer blood CFU 72h after infection. Histopathological examination of lung sections revealed less inflammation among A66.1-infected CXCR3 -/- than WT mice. The reduced virulence of A66.1 in CXCR3 -/- mice suggests that inhibition of the functional activity of IFN-γ inducible chemokines modulates the host response to A66.1, in turn suggesting a novel approach to improve vaccine-mediated protection against ST3 pneumonia.
KW - CXCR3
KW - IFN-γ inducible chemokines
KW - Inflammation
KW - Pneumococcal pathogenesis
KW - Serotype 3 pneumococcus
KW - Serotype 8 pneumococcus
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U2 - 10.1016/j.vaccine.2011.08.064
DO - 10.1016/j.vaccine.2011.08.064
M3 - Article
C2 - 21864623
AN - SCOPUS:80053654363
SN - 0264-410X
VL - 29
SP - 8002
EP - 8011
JO - Vaccine
JF - Vaccine
IS - 45
ER -