Abstract
Multidrug-resistant Acinetobacter baumannii is regarded as a life-threatening pathogen mainly associated with nosocomial and community-acquired pneumonia. Here, we show that A. baumannii can bind the human carcinoembryonic antigen-related cell adhesion molecule (CEACAM) receptors CEACAM1, CEACAM5, and CEACAM6. This specific interaction enhances A. baumannii internalization in membrane-bound vacuoles, promptly decorated with Rab5, Rab7, and lipidated microtubule-associated protein light chain 3 (LC3). Dissecting intracellular signaling pathways revealed that infected pneumocytes trigger interleukin-8 (IL-8) secretion via the extracellular signal-regulated kinase (ERK)1/2 and nuclear factor-kappa B (NF-κB) signaling pathways for A. baumannii clearance. However, in CEACAM1-L-expressing cells, IL-8 secretion lasts only 24 h, possibly due to an A. baumannii-dependent effect on the CEACAM1-L intracellular domain. Conversely, the glycosylphosphatidylinositol-anchored CEACAM5 and CEACAM6 activate the c-Jun NH2-terminal kinase (JNK)1/2-Rubicon-NOX2 pathway, suggestive of LC3-associated phagocytosis. Overall, our data show for the first time novel mechanisms of adhesion to and invasion of pneumocytes by A. baumannii via CEACAM-dependent signaling pathways that eventually lead to bacterial killing. These findings suggest that CEACAM upregulation could put patients at increased risk of lower respiratory tract infection by A. baumannii IMPORTANCE This work shows for the first time that Acinetobacter baumannii binds to carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), CEACAM5, and CEACAM6. This binding significantly enhances A. baumannii internalization within alveolar host cell epithelia. Intracellular trafficking involves typical Rab5 and Rab7 vacuolar proteins as well as light chain 3 (LC3) and slowly progresses to bacterial killing by endosome acidification. CEACAM engagement by A. baumannii leads to distinct and specific downstream signaling pathways. The CEACAM1 pathway finely tunes interleukin-8 (IL-8) secretion, whereas CEACAM5 and CEACAM6 mediate LC3-associated phagocytosis. The present study provides new insights into A. baumannii-host interactions and could represent a promising therapeutic strategy to reduce pulmonary infections caused by this pathogen.
Highlights
Multidrug-resistant Acinetobacter baumannii is regarded as a life-threatening pathogen mainly associated with nosocomial and community-acquired pneumonia
To investigate if carcinoembryonic antigen-related cell adhesion molecule (CEACAM) molecules are targeted by A. baumannii cells, purified recombinant human CEACAMs were used in pulldown experiments with A. baumannii strain AB5075
Since the majority of the bacterial-carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) interactions are mediated by its N-terminal IgV-like domain, a pulldown experiment using a recombinant human CEACAM1-Fc protein lacking this domain (CEACAM1DN) was performed
Summary
Multidrug-resistant Acinetobacter baumannii is regarded as a life-threatening pathogen mainly associated with nosocomial and community-acquired pneumonia. Surface adhesins that play a role in the adhesion to human epithelial cells include the giant cell surface biofilm-associated protein (Bap), the Acinetobacter trimeric autotransporter (Ata), the filamentous hemagglutinin adhesin FhaB, the trimeric outer membrane porin OmpA, and porinD [14,15,16,17,18] The latter phosphorylcholine-containing protein was shown to be involved in A. baumannii adhesion to and internalization into membrane-bound vacuoles within epithelial cells via the platelet-activating factor receptor (PAFR) [17]. CEACAMs belong to a group of immunoglobulin (Ig)-related glycoproteins and are involved in several cellular processes, such as cell adhesion, intracellular and intercellular signaling, inflammation, and cancer progression [22] These molecules are associated with the membrane through either a hydrophobic transmembrane domain or a glycosylphosphatidylinositol (GPI) lipid moiety, while the surface-exposed N terminus is composed by a variable Ig-like domain followed by 0 to 6 constant Ig-like domains [22, 23]. We provide the first evidence of two distinct and specific CEACAM-dependent intracellular signaling pathways that, eventually, lead to bacterial killing
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
