Abstract
ABSTRACTSeven non-toxigenic C. diphtheriae strains and one toxigenic strain were analyzed with regard to their interaction with murine macrophages (BMM) and human THP-1 macrophage-like cells. Proliferation assays with BMM and THP-1 revealed similar intracellular CFUs for C. diphtheriae strains independent of the host cell. Strain ISS4060 showed highest intracellular CFUs, while the toxigenic DSM43989 was almost not detectable. This result was confirmed by TLR 9 reporter assays, showing a low signal for DSM43989, indicating that the bacteria are not endocytosed. In contrast, the non-pathogenic C. glutamicum showed almost no intracellular CFUs independent of the host cell, but was recognized by TLR9, indicating that the bacteria were degraded immediately after endocytosis. In terms of G-CSF and IL-6 production, no significant differences between BMM and THP-1 were observed. G-CSF production was considerably higher than IL-6 for all C. diphtheriae strains and the C. glutamicum did not induce high cytokine secretion in general. Furthermore, all corynebacteria investigated in this study were able to induce NFκB signaling but only viable C. diphtheriae strains were able to cause host cell damage, whereas C. glutamicum did not. The absence of Mincle resulted in reduced G-CSF production, while no influence on the uptake of the bacteria was observed. In contrast, when MyD88 was absent, both the uptake of the bacteria and cytokine production were blocked. Consequently, phagocytosis only occurs when the TLR/MyD88 pathway is functional, which was also supported by showing that all corynebacteria used in this study interact with human TLR2.
Highlights
Corynebacterium diphtheriae is the classical etiological agent of diphtheria and the type species of the genus Corynebacterium [1,2]
For the other investigated strains, the colony forming units (CFU) after 2 h ranged between 0.5% and 1.5% of the inoculum in bone marrow-derived macrophages (BMM), which is representatively shown for strain ISS3319
The Toll-like receptor 2 (TLR2)/Myd88 pathway is required for phagocytosis of C. diphtheriae and leads to NFκB-signaling as well as upregulation of the C-type lectin receptor Mincle
Summary
Corynebacterium diphtheriae is the classical etiological agent of diphtheria and the type species of the genus Corynebacterium [1,2]. The transmission of C. diphtheriae from person to person occurs by close physical contact or respiratory droplets [3]. Vaccination against classical respiratory diphtheria is available with toxoid vaccine that is directed against the toxin. Toxigenic and non-toxigenic C. diphtheriae strains are increasingly associated with invasive infections, such as endocarditis, osteomyelitis, splenic abscesses, meningitis, and septic arthritis [5,6,7]. Recent characterization of a non-toxigenic C. diphtheriae strain isolated from a cancer patient with osteomyelitis indicates that C. diphtheriae can colonize epithelia but can infect deeper parts of the body [8]
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