bThe high morbidity and mortality in pigeons caused by pigeon paramyxovirus type 1 (PPMV-1) highlights the need for new insights into the host immune response and novel treatment approaches. Host defense peptides (HDPs) are key components of the innate immune system. In this study, three novel avian -defensins (AvBDs 2, 7, and 10) were characterized in pigeons and shown to possess direct antiviral activity against PPMV-1 in vitro. In addition, we evaluated the mRNA expression of these AvBDs and other immune-related genes in tissues of 2-month-old infected pigeons at 3 and 7 days postinfection. We observed that the expression of AvBD2 in the cecal tonsil, lungs, and proventriculus, as well as the expression of AvBD10 in the spleen, lungs, proventriculus, and kidneys, was upregulated in infected pigeons. Similarly, the expression of both Toll-like receptor 3 (TLR3) and TLR7 was increased in the spleen, trachea, and proventriculus, while TLR15 expression was increased only in the lungs of infected pigeons. In addition, inducible nitric oxide synthase (iNOS) expression was upregulated in the spleen, the bursa of Fabricius, the trachea, and the proventriculus of infected pigeons. Furthermore, we observed a high correlation between the expression of AvBD2 and the expression of either TLR7 or TLR15, as well as between AvBD10 expression and either TLR3 or TLR7 expression in respective tissues. The results suggest that PPMV-1 infection can induce innate host responses characterized by the activation of TLRs, particularly TLR3 and TLR7, AvBDs (2 and 10), and iNOS in pigeons.T he paramyxoviruses are a subfamily of the Paramyxoviridae family (order Mononegavirales) of enveloped, nonsegmented negative-strand RNA viruses (NNSV), which also includes the Pneumovirus subfamily. Based largely on antigenic cross-reactivity and neuramidase activity, paramyxoviruses currently are classified into seven genera: Rubulavirus, Avulavirus, Henipavirus, Morbillivirus, Respirovirus, Ferlavirus, and Aquaparamyxovirus (1). Members of the paramyxovirus family show diverse tissue tropism and infect a variety of species in a fashion that does not appear to be specific to genus classification.Newcastle disease virus (NDV), a member of the genus Avulavirus in the family Paramyxovirus, is the causative agent of Newcastle disease (ND), a highly contagious disease that may result in high morbidity and mortality in poultry (2). Pigeon paramyxovirus type 1 (PPMV-1) viruses are variant strains of NDV associated with infections of pigeons, and they have a worldwide distribution. Several ND outbreaks in chickens have been attributed to PPMV-1, which makes it a real threat to the poultry industry (3-5).Despite control measures, including heightened biosecurity and intensive vaccination, ND is still a serious problem in the poultry industry around the world. Despite extensive research characterizing the pathogenesis of different isolates and pathotypes, limited data about the host response to NDV have been reported. NDV infection in vitro results in nitri...