Innate Immunity and Viral Infection in Asthma

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In this AADCRC program renewal, we will focus on three critical and understudied innate immune factors and how they impact viral infections in asthma: the anionic phospholipids of surfactant (palmitoyl- oleoyl-phosphatidylglycerol, POPG, and phosphatidylinositol, PI), Toll interacting protein (Tollip), and surfactant protein-A (SP-A). Because these mediators have complementary functions to modulate inflammation and immunity in asthma and infection, we propose three interrelated, synergistic, self-standing projects to investigate how these mediators orchestrate novel innate immune responses associated with viral infections in asthma. We will study three viruses with a spectrum of effects in airway disease, and determine how innate responses protect against them. Specifically, we will focus on rhinovirus C (RV-C), a known exacerbator of asthma that can cause severe disease; influenza A, a virus whose effect in asthma remains ambiguous and SARS-CoV-2, a virus that can cause severe lung disease, but for which asthma may not be a risk factor, and may in fact confer protection. We show innovative preliminary data indicating that 1) POPG, PI and SP-A attenuate RV-C infection; 2) Tollip exhibits protective effects as it is required for IL-13 to generate soluble ST2 that in turn attenuates the effects of IL-33 during influenza A infection; and 3) SP-A and type 2 cytokines confer protection in the effector and initiation phases of SARS-CoV-2 infection in asthma by inhibiting the expression and function of ACE2, the SARS-CoV-2 receptor, through effects upon transcription, receptor binding and downstream pro-inflammatory signaling. Thus, all these innate immune components appear to protect against viral infections in asthma. Our exciting preliminary data underpin our program’s overall hypothesis that POPG/PI, Tollip and SP-A function as unique immune modulators that attenuate the impact of specific viral infections (RV-C, Influenza A and SARS-CoV-2) in type-2 asthma. Therefore, supplementation of functional POPG/PI, SP-A and the IL-33 decoy receptor sST2 may be novel strategies against asthma exacerbations due to viral infections. Project 1 will critically test the activity of POPG/PI and SP- A supplementation as a novel molecular tool for disrupting infections due to RV-C, a virus known to exacerbate asthma. Project 2 will determine how Tollip protects against viral exacerbations caused by influenza A in asthma through inhibition of IL-33 signaling. Project 3 will determine how type-2 cytokines and SP-A synergize to protect against SARS-CoV-2 infection through inhibition of ACE2-mediated infection and IL-6 signaling pathways. We also include an Administrative Core and a Clinical Core, both which serve all projects equally. We build upon productive collaborations of over 20 years on innate molecular mechanisms underlying the interaction between type 2 inflammation and viral exacerbations of asthma. The strong synergy among our three projects will accelerate progress toward novel therapies by demonstrating that the innate immune components under study protect against viral infection in asthma.