Columnaris disease, caused by Flavobacterium columnare, is one of the serious bacterial diseases responsible for large scale mortalities in numerous freshwater fishes globally. This disease mainly affects the gills and skin and can cause mortality up to 100% within 24 hrs, leading to severe economic losses in the aquaculture industry. Despite the huge impact of this disease, very little is known about the host-pathogen interaction, particularly the expression of various immune genes against F. columnare infection. In order to study the expression of immune-regulatory genes in susceptible Indian major carp Catla catla, the fish were experimentally infected with F. columnare by immersion method. The infected fish exhibited typical signs of columnaris disease including lethargy, respiratory distress, swimming near the water surface and increased opercular movements. Histopathological examination of gills revealed the presence of bacterial clumps in gills, fusion of secondary filaments and sloughing of epithelial cells along with disruption of gill architecture by 24-48 h. The expression of selected immune genes, namely IL-1β, iNOS; IL-10; TGF-β; MHC-I and MHC-II was studied in gills at different time intervals following infection with F. columnare. In the gills tissue, IL-1β, iNOS and MHC-II genes showed significantly higher expression (p < 0.05) in infected catla at initial stages of infection. In addition, expression of IL-10 gene was significantly up-regulated (p < 0.05) at 6 hours post-infection (hpi) while the expression of TGF-β gene did not show any significant change (p > 0.05) throughout the experiment i.e. up to 96 hours post-infection. The expression of MHC-I gene was significantly up-regulated from 12 hpi onwards. The results indicate that immune genes of C. catla are modulated following infection with F. columnare. The knowledge generated from this study will help in understanding host-pathogen interaction in columnaris disease.