title: Moraxella catarrhalis-produced nitric oxide has dual roles in pathogenicity and clearance of infection in bacterial-host cell co-cultures.
abstract: In humans, the free radical nitric oxide (NO) is a concentration-dependent multifunctional signaling or toxic molecule that modulates various physiological and pathological processes, and innate immunity against bacterial infections. Because the expression of bacterial genes encoding nitrite reductase (AniA) and NO reductase (NorB) is highly upregulated in biofilms in vitro, it is important to investigate whether bacterial NO-metabolism might subvert host NO signaling and play pathogenic roles during infection. The Moraxella catarrhalis AniA and NorB directly function in production and reduction of NO. Using M. catarrhalis-human bronchial epithelial cell (HBEC) co-cultures, we recently reported AniA/nitrite-dependent cytotoxic effects on HBECs, including altered protein profiles of HBECs and induced HBEC apoptosis, suggesting bacterial nitrite reduction likely dysregulates host cell gene expression. To further clarify whether nitrite reduction-derived NO or nitrite-dependent stimulation of bacterial growth was responsible for adverse effects on HBECs, we monitored bacterial nitrite reduction, levels of NO in co-cultures and resulted dynamic effects on HBEC proliferation and bacterial viability. This study demonstrated that M. catarrhalis nitrite reduction-derived NO was responsible for observed adverse effects on HBECs at mid-to-late stages of infection. More importantly, our data showed that while nitrite promoted bacterial growth and biofilm formation at early hours of infection, nitrite reduction-derived NO was toxic towards M. catarrhalis in maturing biofilms, suggesting nitrite reduction-derived NO might be a possible dualistic mechanism by which M. catarrhalis promotes diseases and spontaneous resolutions.
authors.affiliation: Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993-0002, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Mocca
authors.affiliation: Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993-0002, USA.
authors.forename: Dandan
authors.initials: D
authors.lastname: Yin
authors.affiliation: Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993-0002, USA.
authors.forename: Yamei
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993-0002, USA. Electronic address: wei02.wang@fda.hhs.gov.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
mesh_terms: D001980:Bronchi / Q000166:cytology; D018925:Chemokines / Q000276:immunology; D018920:Coculture Techniques; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000382:microbiology; D054884:Host-Pathogen Interactions; D006801:Humans; D001936:Moraxella catarrhalis / Q000201:enzymology / Q000472:pathogenicity / Q000502:physiology*; D045828:Moraxellaceae Infections / Q000201:enzymology / Q000382:microbiology; D009569:Nitric Oxide / Q000378:metabolism*; D009572:Nitrite Reductases / Q000378:metabolism*; D010084:Oxidation-Reduction
chemical_list: D018925:Chemokines; D016207:Cytokines; D009569:Nitric Oxide; D009572:Nitrite Reductases
keywords: Apoptosis; Bacterial pathogenesis; Biofilms; Infection; NO-induced cytokines and chemokines; Nitrite reduction-derived nitric oxide