NTHi-Induced Signaling
Explore and order pathway-specific siRNAs, real-time PCR assays, and expression vectors. View pathway information and literature references for your pathway.
  • Click on your proteins of interest in the pathway image or review below
  • Select your genes of interest and click "add selection"
  • When you have finished your gene selection, click "Find Products" to find assays, arrays, or create custom products
Download Image Terms of Use Download PPT
Pathway Navigator
NTHi-Induced Signaling
The Gram-negative bacterium NTHi (Nontypeable Haemophilus influenzae) is an important human respiratory pathogen in children and adults. In children, it causes OM (Otitis Media), the most common childhood infection and the leading cause of conductive hearing loss (Ref.1) whereas in adults, it exacerbates COPD (Chronic Obstructive Pulmonary Diseases), the fourth leading cause of death in the United States. A hallmark of both OM and COPD is mucus overproduction that mainly results from up-regulation of Mucin, a primary innate defensive response for mammalian airways (Ref.2).

The molecular mechanisms underlying the pathogenesis of NTHi-induced infections involve activation of NF-KappaB (Nuclear Factor-kappa B), a transcriptional activator of multiple host defense genes involved in immune and inflammatory responses. NTHi strongly activates NF-KappaB in human epithelial cells via two distinct signaling pathways, NF-KappaB translocation-dependent and -independent pathways. The NF-KappaB translocation-dependent pathway involves activation of NIK (NF-KappaB Inducing Kinase)-IKKAlpha/Beta (I-KappaB Kinases)- complex leading to I-KappaB-Alpha phosphorylation and degradation, whereas the NF-KappaB translocation-independent pathway involves activation of MKK3/6-p38MAPK (Mitogen Activated Protein Kinase) pathway. MKK6 is a common activator of p38-Alpha and p38-Beta, whereas MKK3 activates only p38-Alpha (Ref.3). Bifurcation of NTHi-induced NIK-IKK-Alpha/Beta-I-KappaB-Alpha and MKK3/6-p38MAPK signaling may occur at TAK1 (TGF-Beta Activated Kinase-1). TLR2 (Toll Like Receptor-2) is required for NTHi-induced NF-KappaB activation. In addition, several key inflammatory mediators including IL-1Beta, IL-8, and TNF-Alpha (Tumor Necrosis Factor-Alpha) are upregulated by NTHi. Furthermore, p16 protein in the outer membrane of all NTHi strains as well as in H. influenzae type b also activates NF-KappaB via similar signaling pathways.

NTHi utilizes the TGF-Beta (Transforming Growth Factor-Beta)-SMAD signaling pathway together with the TLR2-MyD88-TAK1-NIK-IKK-Beta/Gamma-I-KappaB-Alpha pathway to mediate NF-KappaB-dependent Muc2, Mucin transcription. TGF-Beta initiates signaling through the ligand-dependent activation of a heteromeric complex of TGF-BetaRII and TGF-BetaRI (Type-II and Type-I Receptors). The TGF-BetaRII kinase then phosphorylates the TGF-BetaRI in a conserved GS domain (Glycine-Serine domain), resulting in activation of the TGF-BetaRI . The activated Type-I receptor subsequently recognizes and phosphorylates the R-SMAD (Receptor-activated SMADs), including SMAD3. This causes dissociation of R-SMAD from the receptor, stimulates the assembly of a heteromeric complex between the phosphorylated R-SMAD and the Co-SMAD, SMAD4, and then induces the translocation of the SMAD complex to the nucleus, where the SMAD complex regulates the expression of target genes by direct interaction and functional cooperation with other transcription factors, such as NF-KappaB (Ref.4). The functional cooperation of NF-KappaB (p65/p50) with SMAD3/4 positively mediates NF-KappaB-dependent Muc2 transcription. Other pathways also modulate the role of NF-KappaB in H. influenzae pathogenesis. Glucocorticoids like Dex (Dexamethasone) are widely used as anti-inflammatory drugs that increase TLR2 activation by H. influenzae through the NIK/I-KappaB kinase pathway. But they repress the p38 dependent activation of NF-KappaB through activation of MKP1 (MAP Kinase Phosphatase-1), which dephosphorylates and deactivates p38 (Ref.5).

NTHi infection can aggravate underlying lung diseases such as chronic bronchitis, bronchiectasis and cystic fibrosis. Less frequently, these bacteria can also cause conditions such as septicemia, endocarditis, epiglottitis, septic arthritis and meningitis. Although tremendous effort has been put towards identifying the surface molecules of NTHi for vaccine development over the past decades, prevention of NTHi infections still remains a great challenge. Moreover, inappropriate antibiotic treatment contributes to the worldwide emergence of antibiotic-resistant strains of NTHi. Therefore, development of alternative therapeutic strategies is urgently needed for the treatment of NTHi infections based on understanding the molecular pathogenesis of NTHi infections (Ref.6).