The major sensors of flaviviruses, retinoic acid-inducible gene 1 protein (RlG-1), melanoma differentiation antigen 5 (MDA5;also known as 1F1H1) and LGP2 (also known as DHX58), are expressed basally in nearly all cell types in the body and are induced to increased levels during viral infection and in response to type I IFNs The downstream adaptor protein, mitochondrial antiviral signaling (MAVS) is also broadly expressed. This makes it difficult to define exactly in which cells and when these sensor pathways are critical for innate immunity or immunopathology. In spite of the advances of using conditionally knocked in (Kl) mice, floxed mice for innate immune signaling components either have not been gene rated or have not been used widely. This Core will help investigators by developing and providing investigators with Kl mice in which key viral sensors (RIG-1, MDA5, LPG2), signaling elements (MAVS, IFNR, IL28RA, 1L-1R) or cytokines (BAFF, IL-IBeta) have been selectively knocked out in innate immune cells such as dendritic cells (DC) or macrophages or in B cells, CD4 T cells or neurons. The Core will also develop a set of novel reporter mice so that innate immune cytokines like IFNB, 1L-1B and BAFF can be readily detected after viral infections. This Core is likely to significantly impact the field of innate immunity and viral immunology by providing these novel mouse resources.

Public Health Relevance

The major sensors of flaviviruses are the RNA sensor proteins within the retinoic acid-inducible gene 1 protein (RIG-I) family that signal through a downstream adaptor protein called MAVS to induce antiviral immune responses and cytokines like type 1 interferons (IFNs) and 1L-1B. These sensors and MAVS are expressed in many cell types in the body and are induced to change their expression during viral infection. The antiviral cytokines also affect a number of different cells. This makes it difficult to define exactly in which

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-ZL-I (J1))
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University of Washington
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