**5.5 Lung diseases and protein misfolding**

UPR activation is induced by several pathogens associated with respiratory diseases, including cystic fibrosis, asthma, and COPD. Toll-like receptor (TLR) activation and bacterial infection can trigger UPR. TLR2 and TLR4, specifically activate IRE1 to promote the release of inflammatory mediators. Respiratory pathogens can also interfere with UPR. Intracellular pathogens, such as bacteria, replicate in ER-associated compartments and selectively block IRE1 pathway activation [61]. Secreted bacterial toxins can modulate the UPR. For example, pyocyanin from *Pseudomonas aeruginosa* induces a similar response in the alveoli evidenced by XBP1 splicing and BiP induction. *Aspergillus fumigatus* is a fungal pathogen that interacts with airway protection in a variety of ways to cause broncho-pulmonary aspergillosis. We found that the expression of BiP was increased in lung tissue. Administration of *A. fumigatus* to rats induced pulmonary UPR and airway hyper-responsiveness. Although the mechanisms are not fully elucidated, they include the generation of mitochondrial reactive oxygen species (ROS) and impaired PDI function leading to ER stress. Many viruses cause ER stress, including RSV, influenza A virus (IAV), Coxsackie virus A16, SARSCoV1, and SARSCoV2 (COVID-19). The mechanism of virus-induced ER stress may involve abundant translation of viral proteins that inhibit their ability to fold. It has been reported that IAV induces inflammation and apoptosis in primary human bronchial epithelial cells by activating IRE1 with little or no activation of PERK or ATF6. Picornaviruses, such as rhinoviruses, can benefit from IRE1 activation because they can promote autophagy, and picornaviruses use autophagosomes as RNA replication sites. In contrast, RSV was reported to induce noncanonical UPR activation with IRE1 and ATF6 activation but not PERK, whereas IRE1 inhibits RSV replication, suggesting that inhibition of this UPR arm may be detrimental to RSV infection [62].
