• Pellino-1 regulates immune responses to Haemophilus influenzae in models of inflammatory lung disease.

      Hughes, Bethany; Burton, Charlotte; Reese, Abigail; Jabeen, Maisha; Wright, Carl; Khoshaein, Nika; Marsh, Elizabeth; Peachell, Peter; Sun, Shao-Cong; Dockrell, David; et al. (Frontiers Media, 2019-07-31)
      Nontypeable Haemophilus influenzae (NTHi) is a frequent cause of lower respiratory tract infection in people with chronic obstructive pulmonary disease (COPD). Pellino proteins are a family of E3 ubiquitin ligases that are critical regulators of TLR signalling and inflammation. The aim of this study was to identify a role for Pellino-1 in airway defence against NTHi in the context of COPD. Pellino-1 is rapidly upregulated by LPS and NTHi in monocyte-derived macrophages (MDMs) isolated from individuals with COPD and healthy control subjects, in a TLR4 dependent manner. C57BL/6 Peli1-/- and wild-type (WT) mice were subjected to acute (single LPS challenge) or chronic (repeated LPS and elastase challenge) airway inflammation followed by NTHi infection. Both WT and Peli1-/- mice develop airway inflammation in acute and chronic airway inflammation models. Peli1-/- animals recruit significantly more neutrophils to the airway following NTHi infection which is associated with an increase in the neutrophil chemokine, KC, in bronchoalveolar lavage fluid as well as enhanced clearance of NTHi from the lung. These data suggest that therapeutic inhibition of Pellino-1 may augment immune responses in the airway and enhance bacterial clearance in individuals with COPD.
    • Pellino-1 regulates the responses of the airway to viral infection

      Marsh, Elizabeth K; Prestwich, Elizabeth C; Marriott, Helen M; Williams, Lynne; Hart, Amber R; Muir, Claire F; Parker, Lisa C; Jonker, Marnix R; Heijink, Irene H; Timens, Wim; et al. (Frontiers, 2020-08-31)
      Exposure to respiratory pathogens is a leading cause of exacerbations of airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Pellino-1 is an E3 ubiquitin ligase known to regulate virally-induced inflammation. We wished to determine the role of Pellino-1 in the host response to respiratory viruses in health and disease. Pellino-1 expression was examined in bronchial sections from patients with GOLD stage 2 COPD and healthy controls. Primary bronchial epithelial cells (PBECs), in which Pellino-1 expression had been knocked down, were extracellularly challenged with the TLR3 agonist poly(I:C). C57BL/6 Peli1-/- mice and wild type littermates were subjected to intranasal infection with clinically-relevant respiratory viruses; rhinovirus (RV1B) and influenza A. We find that Pellino-1 is expressed in the airways of normal subjects and those with COPD, and that Pellino-1 regulates TLR3 signalling and responses to airways viruses. In particular we observed that knockout of Pellino‐1 in the murine lung resulted in increased production of proinflammatory cytokines IL‐6 and TNFα upon viral infection, accompanied by enhanced recruitment of immune cells to the airways, without any change in viral replication. Pellino-1 therefore regulates inflammatory airway responses without altering replication of respiratory viruses.