title: Gingipains: Critical Factors in the Development of Aspiration Pneumonia Caused by Porphyromonas gingivalis.
abstract: Aspiration pneumonia is a life-threatening infectious disease often caused by oral anaerobic and periodontal pathogens such as Porphyromonas gingivalis. This organism produces proteolytic enzymes, known as gingipains, which manipulate innate immune responses and promote chronic inflammation. Here, we challenged mice with P. gingivalis W83 and examined the role of gingipains in bronchopneumonia, lung abscess formation, and inflammatory responses. Although gingipains were not required for P. gingivalis colonization and survival in the lungs, they were essential for manifestation of clinical symptoms and infection-related mortality. Pathologies caused by wild-type (WT) P. gingivalis W83, including hemorrhage, necrosis, and neutrophil infiltration, were absent from lungs infected with gingipain-null isogenic strains or WT bacteria preincubated with gingipain-specific inhibitors. Damage to lung tissue correlated with systemic inflammatory responses, as manifested by elevated levels of TNF, IL-6, IL-17, and C-reactive protein. These effects were unequivocally dependent on gingipain activity. Gingipain activity was also implicated in the observed increase in IL-17 in lung tissues. Furthermore, gingipains increased platelet counts in the blood and activated platelets in the lungs. Arginine-specific gingipains made a greater contribution to P. gingivalis-related morbidity and mortality than lysine-specific gingipains. Thus, inhibition of gingipain may be a useful adjunct treatment for P. gingivalis-mediated aspiration pneumonia.
authors.affiliation: Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Benedyk
authors.forename: Piotr Mateusz
authors.initials: PM
authors.lastname: Mydel
authors.forename: Nicolas
authors.initials: N
authors.lastname: Delaleu
authors.forename: Karolina
authors.initials: K
authors.lastname: Płaza
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Gawron
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Milewska
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Maresz
authors.forename: Joanna
authors.initials: J
authors.lastname: Koziel
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Pyrc
authors.forename: Jan
authors.initials: J
authors.lastname: Potempa
mesh_terms: D018829:Adhesins, Bacterial / Q000235:genetics / Q000276:immunology*; D000818:Animals; D016866:Bacteroidaceae Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D001792:Blood Platelets / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D005260:Female; D000080867:Gingipain Cysteine Endopeptidases; D006470:Hemorrhage / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D015539:Platelet Activation / Q000276:immunology; D010976:Platelet Count; D011015:Pneumonia, Aspiration / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016966:Porphyromonas gingivalis / Q000235:genetics / Q000276:immunology*
chemical_list: D018829:Adhesins, Bacterial; D016207:Cytokines; D000080867:Gingipain Cysteine Endopeptidases; D003546:Cysteine Endopeptidases