White-nose syndrome (WNS) in North American bats is caused by an invasive cutaneous infection by the psychrophilic fungus Pseudogymnoascus destructans (Pd). We compared transcriptome-wide changes in gene expression using RNA-Seq on wing skin tissue from hibernating little brown myotis (Myotis lucifugus) with WNS to bats without Pd exposure. We found that WNS caused significant changes in gene expression in hibernating bats including pathways involved in inflammation, wound healing, and metabolism. Local acute inflammatory responses were initiated by fungal invasion. Gene expression was increased for inflammatory cytokines, including interleukins (IL) IL-1β, IL-6, IL-17C, IL-20, IL-23A, IL-24, and G-CSF and chemokines, such as Ccl2 and Ccl20. This pattern of gene expression changes demonstrates that WNS is accompanied by an innate anti-fungal host response similar to that caused by cutaneous Candida albicans infections. However, despite the apparent production of appropriate chemokines, immune cells such as neutrophils and T cells do not appear to be recruited. We observed upregulation of acute inflammatory genes, including prostaglandin G/H synthase 2 (cyclooxygenase-2), that generate eicosanoids and other nociception mediators. We also observed differences in Pd gene expression that suggest host-pathogen interactions that might determine WNS progression. We identified several classes of potential virulence factors that are expressed in Pd during WNS, including secreted proteases that may mediate tissue invasion. These results demonstrate that hibernation does not prevent a local inflammatory response to Pd infection but that recruitment of leukocytes to the site of infection does not occur. The putative virulence factors may provide novel targets for treatment or prevention of WNS. These observations support a dual role for inflammation during WNS; inflammatory responses provide protection but excessive inflammation may contribute to mortality, either by affecting torpor behavior or causing damage upon emergence in the spring., Author Summary White-nose syndrome is the most devastating epizootic wildlife disease of mammals in history, having killed millions of hibernating bats in North America since 2007. We have used next-generation RNA sequencing to provide a survey of the gene expression changes that accompany this disease in the skin of bats infected with the causative fungus. We identified possible new mechanisms that may either provide protection or contribute to mortality, including inflammatory immune responses. Contrary to expectations that hibernation represents a period of dormancy, we found that gene expression pathways were responsive to the environment. We also examined which genes were expressed in the pathogen and identified several classes of genes that could contribute to the virulence of this disease. Gene expression changes in the host were associated with local inflammation despite the fact that the bats were hibernating. However, we found that hibernating bats with white-nose syndrome lack some of the responses known to defend other mammals from fungal infection. We propose that bats could be protected from white-nose syndrome if these responses could be established prior to hibernation or if treatments could block the virulence factors expressed by the pathogen.