Abstract: Pasteurella multocida（Pm） infects a variety of animals and causes host septicemic and respiratory diseases. It endangers animal health and leads to serious economic losses in livestock industry. To explore the effect of the gene expression of the host in the lungs during Pm infection, Pm serotype A was selected to cha-llenge mice, and murine lungs were collected 72 hours after challenging, of which total RNA was extracted. With transcriptome sequencing, 2 443 differentially expressed genes（DEGs） were found in challenged group compared with control group, including 1 437 genes up-regulated and 1 006 genes down-regulated. The results from GO enrichment analysis of 2 443 DEGs showed that the significantly differential genes mainly were involved in B cell homeostasis, positive regulation of T cell migration, integrin complex and collagen binding; KEGG enrichment analysis of the source genes indicated that 11 immune and inflammation-related signal pathways including cytokine-cytokine receptor interaction, chemokine signaling pathway were significantly enriched; The protein-protein interaction analysis of the significantly differential genes in the 11 immune-inflammation-related signals pathways suggested that the C3, C3 ar1, C5 ar1, Cxcl10, Cxcr2 and Gng11 genes are in the center of the network, indicating that these genes play important roles during Pm infection; 10 genes of 11 immune-inflammation-related signals pathways were selected to verified by RT-qPCR, and 8 genes were consistent with the RNA-seq results on expression trends, which indicating that the transcriptome sequencing data is reliable. This study revealed the critical genes in immune response of mice during Pm infection, which offered theory evidence for exploring the molecular mechanism of host defending against Pm attacks.