| A successful immune response to an invading pathogen relies on recognition of the microbe, recruitment and trafficking of relevant immune cells, and proper activation and execution of their effector functions. A vast array of receptor-ligand interactions controls these events and over millennia of co-evolution, many microorganisms have acquired methods of perturbing these vital binding events in host cells. Accordingly, it is possible to use immunomodulatory molecules from a given microbe as "bait" to identify host-encoded proteins that are important to the immune defense against that organism.;Using a structurally-constrained hidden Markov model, we identified orthopoxvirus MHC class I-like protein (OMCP) as a molecule potentially involved in immune evasion. OMCP binds with high affinity to the activating receptor NKG2D expressed on NK cells and subsets of T cells and macrophages. In killing assays, soluble OMCP prevents the interaction of NKG2D with its cellular ligands, leading to inhibition of killing, suggesting that OMCP is a competitive antagonist of NKG2D. In addition to NKG2D, we identified the immunoregulatory protein FcRL5 as a receptor for OMCP on murine splenic marginal zone and peritoneal B-1a cells. FcRL5 engagement by OMCP does not alter intracellular calcium levels or affect its cell surface expression, which indicates that OMCP may act by blocking the interaction of FcRL5 with its natural ligand(s), which are unknown at this time.;Taken together, these results identify a virally-encoded immunomodulator with specificity for two host cell receptors, neither of which were previously known to participate in anti-orthopoxvirus immunity. Our study supports the idea that using microbial-encoded immune modifiers as "bait" is a useful strategy to identify signaling pathways important to pathogen survival and thus to host defense. |
