The innate immune response to Streptococcus pneumoniae in the lung depends on serotype and host response

► To gain insight into differences in the serotype-specific host response to pneumococcal in the lungs, we compared the effect of intranasal infection with a serotype 3 and a serotype 8 strain of pneumococcus on gene expression in the lungs of mice. ► Both strains induced expression of interferon-gamma-inducible genes in an inoculum dependent manner. ► In a model in which the lung bacterial burden was similar and death occurred by 72 h after infection, serotype 3-infected mice exhibited a more exuberant inflammatory response and higher levels of interferon-gamma-inducible gene expression than serotype 8-infected mice. ► The virulence of serotype 3, but not serotype 8 was reduced in CXCR3-deficient mice. ► Serotype 3-infected CXCR3-deficient mice recruited more macrophages to their lungs and had a less exuberant lung inflammatory response than wild type mice.