Identification of Nogo-B as a novel regulator of Toll-like receptor activation in virus-induced inflammation

An effective immune response is critical for host protection against viruses. However, diseases caused by viral infections are caused not only by tissue damage as a direct result of virus replication, but also as a consequence of inflammatory immune responses mounted in response to infection. Thus, the immune response induced by viruses must be carefully balanced to enable efficient control of pathogen replication without inducing over-exuberant immune response that can damage the host it should be protecting. In cases of severe disease, however, this does not occur and substantial and, at times, irreversible damage can occur in vital organs such as the lungs and brain. Understanding what goes wrong in these scenarios and identifying the mechanisms and processes within cells that drive these responses will inform the development of drugs and other therapeutic strategies to treat viral diseases.

Cytokines are the hormones of the immune system that are secreted by cells and can induce transmission of signals in other cells. Although certain cytokines help protect from viral infections, they can also participate in tissue damage if expressed at inappropriate levels and/or times. Cytokines are produced by immune cells following stimulation of certain receptors that recognise certain patterns within microbes to be foreign. One such family of receptors is the Toll-like receptors (TLRs). TLRs are critical for induction of cytokines that protect the host from viral infections, but overt activation can also lead to over-production of cytokines and subsequent disease. The mechanisms that regulate the activation of TLRs and thus the balance of 'good' and 'bad' responses to viruses is poorly understood.

We identified that a protein called Nogo-B is a potent mediator of virus-induced inflammation and that it functions by modulating the activation of TLRs. Excitingly, when we depleted Nogo-B, we found that the production cytokine responses required to control virus replication were maintained whereas inflammatory responses were greatly reduced. When we deleted Nogo-B from mice, this led to a dramatic reduction in virus-induced disease during infection without affecting the ability of the host to control the virus. These data suggest that 1) understanding the mechanisms that regulate TLR activation through studying the biology of Nogo-B may lead to new ways to target virus-induced inflammation and 2) targeting Nogo-B in its own right may represent an exciting therapeutic strategy for the treatment of virus-induced inflammation.

In this proposal, we will study what impact Nogo-B has on TLR activation and identify the mechanisms through which it does this. We will also investigate whether ablation of the function of Nogo-B during different viral infections can influence how the immune system responds to viruses in the body and whether this can reduce inflammation and tissue damage that is triggered by the virus with impacting host control of infection.

Overall, these studies will inform the development of strategies to safely treat the inflammatory consequences of current and, potentially, future infectious threats.

Inflammation is a critical component of viral diseases. Whilst pattern recognition receptors like Toll like receptors (TLRs) are critical for antiviral host protection, the inflammatory cytokines that they induce also promote tissue pathologies. The mechanisms that regulate TLR activation are poorly understood. We identified that a novel regulator of TLR activation, Neurite outgrowth inhibitor-B (Nogo-B), preferentially promotes virus-induced inflammatory responses without impacting virus-induced IFN induction and control of viral infection in vivo. These data suggest that targeting Nogo-B and/or the pathways it regulates during viral infection could preferentially target inflammatory responses that are induced by viruses without impacting host control of virus replication.

In this proposal, we will use murine and human stem cell-derived cellular models to identify what impact Nogo-B has on TLR-induced signaling and subsequent cytokine production in cells relevant for antiviral immunity and tissue inflammation. We will use a combination of imaging, biochemical and cellular immunology approaches to determine what impact Nogo-B has on TLR activation upon innate immune recognition of evolutionary distinct viruses, identify how Nogo-B modulates TLR activation and identify the cellular processes that Nogo-b regulates within cells. Finally, we will use murine models of viral infection to understand how Nogo-B regulation of innate immune activation shapes virus-induced immunity and inflammation-induced pathology within organs of the body. Overall, these studies will reveal regulatory mechanisms and/or intracellular processes that could be targeted to safely treat virus-induced inflammation without impacting host control of virus replication.