Regulation of Nontypeable Haemophilus influenzae-induced Host Innate Immunity in Lung Epithelium
Date of Award
Doctor of Philosophy (PhD)
The host's innate immune response begins with the identification of molecules known as pathogen-associated molecular patterns by a series of germline-encoded pattern-recognition receptors. Retinoic acid-inducible gene I (RIG-I) is one such innate immune receptor that detects viral RNA in the cytosol of cells and is crucial to mount an effective antiviral immune response in the course of viral infections. RIG-I with the adaptor protein mitochondrial antiviral signaling protein (MAVS) leads to the activation of the transcription factors including interferon-regulatory factor 3 (IRF3), IRF7 and nuclear factor-κB (NF-κB), which induce type I and III interferon (IFN), and proinflammatory cytokines. Many studies have demonstrated the crucial role of RIG-I in viral infections such as influenza A virus (IAV) and respiratory syncytial virus (RSV) infections. However, as airway viral infection is frequently followed by bacterial co-infections, the role of RIG-I and how it is regulated in airway epithelium inflammation in mixed viral and bacterial infection remains undefined. Despite the well-known role of viruses in bacterial co-infections, the impact of bacterial infections on viral co-infections remains largely unknown. Therefore, understanding the mechanism of airway bacterial pathogen Nontypeable Haemophilus influenzae (NTHi)-induced RIG-I will help to understand the complex inflammatory signaling pathway and further contribute to the development of new therapies.
In the present study, we showed that NTHi induced RIG-I upregulation in airway epithelial cells. We also demonstrated that NTHi induced RIG-I upregulation by activation of TNF receptor associated factor 6 (TRAF6)-inhibitor of nuclear factor-κB kinase subunit β (IKKβ)-p65 pathway. Interestingly, interleukin-1 receptor-associated kinase M (IRAK-M) negatively regulated NTHi-induced up-regulation of RIG-I via inhibiting the IKKβ-p65 pathway and inflammation. We also confirmed that IKKβ activation is sufficient for RIG-I up-regulation. We showed that p65 phosphorylation at S276 and S536 residues is likely critical for RIG-I up-regulation. We also investigated the role of histone deacetylases (HDACs) as a positive regulator for NTHi-induced RIG-I up-regulation. Along with NTHi-induced RIG-I upregulation, we also confirmed the functional significance of RIG-I by confirming the CXCL10 expression mediated via RIG-I. Thus, our study provides new insights into the regulation of NTHi-induced RIG-I upregulation, which may contribute to the development of a new therapeutic strategy for controlling inflammation in mixed airway infections.
Singh, Hardeep, "Regulation of Nontypeable Haemophilus influenzae-induced Host Innate Immunity in Lung Epithelium." Dissertation, Georgia State University, 2023.
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