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Innate Immunity and Viral Infection in Asthma

Sponsored by National Institute of Allergy and Infectious Disease

$4.3M Funding
5 People

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In this AADCRC program renewal we will focus on three critical and understudied innate immune factorsand how they impact viral infections in asthma: the anionic phospholipids of surfactant (palmitoyl-oleoyl-phosphatidylglycerol POPG and phosphatidylinositol PI) Toll interacting protein (Tollip) andsurfactant protein-A (SP-A). Because these mediators have complementary functions to modulateinflammation and immunity in asthma and infection we propose three interrelated synergistic self-standingprojects to investigate how these mediators orchestrate novel innate immune responses associated with viralinfections in asthma. We will study three viruses with a spectrum of effects in airway disease anddetermine how innate responses protect against them. Specifically we will focus on rhinovirus C (RV-C) aknown exacerbator of asthma that can cause severe disease; influenza A a virus whose effect in asthma remainsambiguous and SARS-CoV-2 a virus that can cause severe lung disease but for which asthma may not be arisk factor and may in fact confer protection. We show innovative preliminary data indicating that 1) POPG PIand SP-A attenuate RV-C infection; 2) Tollip exhibits protective effects as it is required for IL-13 to generatesoluble ST2 that in turn attenuates the effects of IL-33 during influenza A infection; and 3) SP-A and type 2cytokines confer protection in the effector and initiation phases of SARS-CoV-2 infection in asthma by inhibitingthe expression and function of ACE2 the SARS-CoV-2 receptor through effects upon transcription receptorbinding and downstream pro-inflammatory signaling. Thus all these innate immune components appear toprotect against viral infections in asthma. Our exciting preliminary data underpin our programs overallhypothesis that POPG/PI Tollip and SP-A function as unique immune modulators that attenuate theimpact of specific viral infections (RV-C Influenza A and SARS-CoV-2) in type-2 asthma. Thereforesupplementation of functional POPG/PI SP-A and the IL-33 decoy receptor sST2 may be novel strategiesagainst 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 exacerbateasthma. Project 2 will determine how Tollip protects against viral exacerbations caused by influenza A in asthmathrough inhibition of IL-33 signaling. Project 3 will determine how type-2 cytokines and SP-A synergize to protectagainst SARS-CoV-2 infection through inhibition of ACE2-mediated infection and IL-6 signaling pathways. Wealso include an Administrative Core and a Clinical Core both which serve all projects equally. We build uponproductive collaborations of over 20 years on innate molecular mechanisms underlying the interaction betweentype 2 inflammation and viral exacerbations of asthma. The strong synergy among our three projects willaccelerate progress toward novel therapies by demonstrating that the innate immune components understudy protect against viral infection in asthma.