Abstract
Heparin-binding hemagglutinin (HBHA) from mycobacteria is involved in the dissemination of infection and the activation of the host immune response. However, the interaction of Nocardia cyriacigeorgica HBHA with the host cells remains unknown. In the present study, we describe N. cyriacigeorgica HBHA interactions with epithelial cells and organ colonization. We then investigate the mechanisms by which HBHA induces the production of inflammatory cytokines in macrophages. Immunofluorescent microscopy showed that HBHA adhered to A549 cells and HeLa cells and that the C-terminal fragment, which contains a Pro-Ala-Lys–rich domain, was responsible for adhesion. The deletion of the hbha gene in N. cyriacigeorgica mutant strains impaired adhesion to A549 cells and HeLa cells. In addition, the HBHA protein activated the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways and promoted the production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-10 in macrophages. HBHA-mediated TNF-α production was dependent on the activation of the c-Jun N-terminal kinase (JNK) signal pathways, and the IL-6 and IL-10 production was dependent on the activation of extracellular regulated kinase (ERK) 1/2, MAPK p38 (p38), JNK, and nuclear NF-κB signaling pathways. Additionally, the HBHA-mediated activation of innate immunity was dependent on Toll-like receptor 4 (TLR4). Taken together, these results indicate that N. cyriacigeorgica HBHA not only adheres to epithelial cells and may be involved in organ colonization, but also plays a critical role in the modulation of innate immunity through the MAPK and NF-κB signaling pathways via TLR4.
Highlights
Nocardia are partially acid-fast, catalase-positive, and Grampositive bacteria that are widely found in soil and decompose vegetation; they are found in both fresh- and saltwater (Fatahi-Bafghi, 2018; Churgin et al, 2019)
SDS-PAGE showed that the purified protein presented as a single band, and western blotting revealed that the recombinant Heparin-binding hemagglutinin (HBHA) protein and truncated HBHA protein were each recognized by antibodies of anti-HBHA and anti-His, respectively (Figure 2)
These results indicate that N. cyriacigeorgica HBHA protein adheres to host cells and that the C-terminal domain of HBHA is critical to adhesion
Summary
Nocardia are partially acid-fast, catalase-positive, and Grampositive bacteria that are widely found in soil and decompose vegetation; they are found in both fresh- and saltwater (Fatahi-Bafghi, 2018; Churgin et al, 2019). Nocardiosis is usually an opportunistic infection and may cause life-threatening disseminated infections, especially in immunosuppressed hosts (Ambrosioni et al, 2010). There are more than 90 Nocardia species that have been recognized, and ∼33 species can cause nocardiosis in humans (Bernardin Souibgui et al, 2017; Churgin et al, 2019). Nocardia infection mainly causes brain, lung, and/or skin abscesses, and by dissemination, it can cause infection in almost all organs; the specific mechanism of dissemination remains unclear. The incidence of nocardial infections has increased, accompanying the increase in the number of immunocompromised individuals in the population, and this number has increased due to improvements in the isolation and molecular identification of Nocardia (Gomes et al, 2019)
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