Quantitative and Longitudinal Assessment of Systemic Innate Immunity in Health and Disease Using a 2D Gene Model

Abstract

Dysregulation of innate immunity is deeply involved in infectious and autoimmune diseases. For a better understanding of pathogenesis and improved management of these diseases, it is of vital importance to implement convenient monitoring of systemic innate immunity. Built upon our previous works on the host transcriptional response to infection in peripheral blood, we proposed a 2D gene model for the simultaneous assessment of two major components of systemic innate immunity, including VirSig as the signature of the host response to viral infection and BacSig as the signature of the host response to bacterial infection. The revelation of dysregulation in innate immunity by this 2D gene model was demonstrated with a wide variety of transcriptome datasets. In acute infection, distinctive patterns of VirSig and BacSig activation were observed in viral and bacterial infection. In comparison, both signatures were restricted to a defined range in the vast majority of healthy adults, regardless of age. In addition, BacSig showed significant elevation during pregnancy and an upward trend during development. In tuberculosis (TB), elevation of BacSig and VirSig was observed in a significant portion of active TB patients, and abnormal BacSig was also associated with a longer treatment course. In cystic fibrosis (CF), abnormal BacSig was observed in a subset of patients, and no overall change in BacSig abnormality was observed after the drug treatment. In systemic sclerosis-associated interstitial lung disease (SSc-ILD), significant elevation of VirSig and BacSig was observed in some patients, and treatment with a drug led to the further deviation of BacSig from the control level. In systemic lupus erythematosus (SLE), positivity for the anti-Ro autoantibody was associated with significant elevation of VirSig in SLE patients, and the additive effect of VirSig/BacSig activation was also observed in SLE patients during pregnancy. Overall, these data demonstrated that the 2D gene model can be used to assess systemic innate immunity in health and disease, with the potential clinical applications including patient stratification, prescription of antibiotics, understanding of pathogenesis, and longitudinal monitoring of treatment response.