Increased mortality in lambs/kids, and increased susceptibility of West African goats, especially dwarf goats, compared to their European counterparts have been documented. Differential susceptibility of goat breeds within India have also been reported. Host genetic factors, in particular the major histocompatibility complex genes, may influence susceptibility to disease. Virus recognition can be influenced by genetic mutations in the interaction domains between virus and host receptors. In particular, non-MHC genetic variations in host TLR may cause reduced pathogen recognition and hamper innate immune activation. Studies on Maedi-Visna infection in sheep indicate that breed dependent susceptibility to the disease as well as individual susceptibility within the breed may be defined by specific polymorphisms in TLR7 and TLR8 genes. In a related morbillivirus, SNPs in TLR 3, 4, 5, 6 and associated signalling molecules like Myeloid differentiation primary response gene 88 and MD2 affected immune responses to the measles vaccine in human subjects. Single and double stranded RNA are recognized by TLR7/8 and TLR3, respectively. TLR3 is a key sensor of viral infection, as most viruses will produce dsRNA at some stage of its life cycle. TLR7 is highly expressed in immune cells like plasmacytoid dendritic cells, which produce substantial amounts of type I IFNs in response to viral RNA. In our study, the basal levels of TLR3 and TLR7 were significantly higher in the PBMCs of PPRV resistant goat breeds, Kanni and Salem Black. Engagement of both TLR3 and TLR7 with the synthetic ligands poly I:C and imiquimod respectively, led to the suppression of PPRV RNA and infectious virus yield in PBMC of goats. This indicates that TLR3 and 7 play a role in the recognition of PPRV RNA by goat PBMC, though the role of cytosolic RNA sensors like Retinoic acidinducible gene 1 and Melanoma differentiation-associated protein 5 have not been analyzed in this study and cannot be ruled out. Almost complete abrogation of viral gene expression was observed after stimulation by poly I:C. This may be because poly I:C can also be recognized by other sensors, including RIGI, MDA5 and Protein kinase R. If factors other than the receptor expression for PPRV determine clinical disease, this should be at the level of virus replication and clearance by innate and adaptive responses. The cell surface receptor for PPRV, the SLAM is expressed at lower levels in MDV3100 buffalo than goats. However, we did see virus replication in infected PBMC although at considerably reduced levels suggesting that the cells of water buffalo are permissive to PPRV infection. Therefore, we questioned whether these differences are reflected at the level of multi-cycle virus replication. PPRV replication in water buffalo PBMC was significantly lower than in goats, possibly because of enhanced type I IFN production in these species upon virus infection.