title: Invasion of endothelial cells and arthritogenic potential of endocarditis-associated Corynebacterium diphtheriae.
abstract: Although infection by Corynebacterium diphtheriae is a model of extracellular mucosal pathogenesis, different clones have been also associated with invasive infections such as sepsis, endocarditis, septic arthritis and osteomyelitis. The mechanisms that promote C. diphtheriae infection and haematogenic dissemination need further investigation. In this study we evaluated the association and invasion mechanisms with human umbilical vein endothelial cells (HUVECs) and experimental arthritis in mice of endocarditis-associated strains and control non-invasive strains. C. diphtheriae strains were able to adhere to and invade HUVECs at different levels. The endocarditis-associated strains displayed an aggregative adherence pattern and a higher number of internalized viable cells in HUVECs. Transmission electron microscopy (TEM) analysis revealed intracellular bacteria free in the cytoplasm and/or contained in a host-membrane-confined compartment as single micro-organisms. Data showed bacterial internalization dependent on microfilament and microtubule stability and involvement of protein phosphorylation in the HUVEC signalling pathway. A high number of affected joints and high arthritis index in addition to the histopathological features indicated a strain-dependent ability of C. diphtheriae to cause severe polyarthritis. A correlation between the arthritis index and increased systemic levels of IL-6 and TNF-α was observed for endocarditis-associated strains. In conclusion, higher incidence of potential mechanisms by which C. diphtheriae may access the bloodstream through the endothelial barrier and stimulate the production of pro-inflammatory cytokines such as IL-6 and TNF-α, in addition to the ability to affect the joints and induce arthritis through haematogenic spread are thought to be related to the pathogenesis of endocarditis-associated strains.
authors.affiliation: Department of Medical Microbiology, Institute of Microbiology, Rio de Janeiro Federal University (IMPPG/UFRJ), Rio de Janeiro, RJ, Brazil.|Laboratory of Diphtheria and Corynebacteria of Clinical Relevance (LDCIC), Faculty of Medical Sciences, Rio de Janeiro State University (UERJ), Rio de Janeiro, RJ, Brazil.
authors.forename: Renata Stavracakis
authors.initials: RS
authors.lastname: Peixoto
authors.affiliation: Department of Medical Microbiology, Institute of Microbiology, Rio de Janeiro Federal University (IMPPG/UFRJ), Rio de Janeiro, RJ, Brazil.|Laboratory of Diphtheria and Corynebacteria of Clinical Relevance (LDCIC), Faculty of Medical Sciences, Rio de Janeiro State University (UERJ), Rio de Janeiro, RJ, Brazil.
authors.forename: Gabriela Andrade
authors.initials: GA
authors.lastname: Pereira
authors.affiliation: Laboratory of Diphtheria and Corynebacteria of Clinical Relevance (LDCIC), Faculty of Medical Sciences, Rio de Janeiro State University (UERJ), Rio de Janeiro, RJ, Brazil.
authors.forename: Louisy
authors.initials: L
authors.lastname: Sanches Dos Santos
authors.affiliation: Laboratory of Diphtheria and Corynebacteria of Clinical Relevance (LDCIC), Faculty of Medical Sciences, Rio de Janeiro State University (UERJ), Rio de Janeiro, RJ, Brazil.
authors.forename: Cláudio Marcos
authors.initials: CM
authors.lastname: Rocha-de-Souza
authors.affiliation: Faculty of Pharmacy, Federal Institute of Education, Science and Technology of Rio de Janeiro (IFRJ), Rio de Janeiro, RJ, Brazil.
authors.forename: Débora Leandro Rama
authors.initials: DLR
authors.lastname: Gomes
authors.affiliation: Department of Medical Microbiology, Institute of Microbiology, Rio de Janeiro Federal University (IMPPG/UFRJ), Rio de Janeiro, RJ, Brazil.|Laboratory of Diphtheria and Corynebacteria of Clinical Relevance (LDCIC), Faculty of Medical Sciences, Rio de Janeiro State University (UERJ), Rio de Janeiro, RJ, Brazil.
authors.forename: Cintia
authors.initials: C
authors.lastname: Silva Dos Santos
authors.affiliation: National Institute for Quality Control in Health (INCQS), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, RJ, Brazil.
authors.forename: Lucia Maria Correa
authors.initials: LMC
authors.lastname: Werneck
authors.affiliation: National Institute for Quality Control in Health (INCQS), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, RJ, Brazil.
authors.forename: Alexandre Alves de Souza de Oliveira
authors.initials: AASO
authors.lastname: Dias
authors.affiliation: Laboratory of Diphtheria and Corynebacteria of Clinical Relevance (LDCIC), Faculty of Medical Sciences, Rio de Janeiro State University (UERJ), Rio de Janeiro, RJ, Brazil.
authors.forename: Raphael
authors.initials: R
authors.lastname: Hirata
authors.affiliation: Biology Institute Roberto Alcântara Gomes, Rio de Janeiro State University (UERJ), Rio de Janeiro, RJ, Brazil.
authors.forename: Prescilla Emy
authors.initials: PE
authors.lastname: Nagao
authors.affiliation: Laboratory of Diphtheria and Corynebacteria of Clinical Relevance (LDCIC), Faculty of Medical Sciences, Rio de Janeiro State University (UERJ), Rio de Janeiro, RJ, Brazil.
authors.forename: Ana Luíza
authors.initials: AL
authors.lastname: Mattos-Guaraldi
mesh_terms: D000818:Animals; D001168:Arthritis / Q000382:microbiology; D001422:Bacterial Adhesion; D002460:Cell Line; D003353:Corynebacterium diphtheriae / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis; D004696:Endocarditis / Q000378:metabolism / Q000382:microbiology*; D042783:Endothelial Cells / Q000378:metabolism / Q000382:microbiology*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D051379:Mice
chemical_list: D016207:Cytokines