The Impact of Colistin Resistance on the Activation of Innate Immunity by Lipopolysaccharide Modification

• Published in: Infection and immunity Vol. 91; no. 2; p. e0001223
• Main Authors: Avendaño-Ortiz, José, Ponce-Alonso, Manuel, Llanos-González, Emilio, Barragán-Prada, Hugo, Barbero-Herranz, Raquel, Lozano-Rodríguez, Roberto, Márquez-Garrido, Francesc J, Hernández-Pérez, José María, Morosini, María-Isabel, Cantón, Rafael, Del Campo, Rosa, López-Collazo, Eduardo
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 16-02-2023
• Subjects: Anti-Bacterial Agents - pharmacology; Antimicrobial Chemotherapy; Bacterial Infections; Bacterial Proteins - genetics; Colistin - pharmacology; Cytokines; Drug Resistance, Bacterial - genetics; Humans; Immunity, Innate; Klebsiella Infections - microbiology; Klebsiella pneumoniae; Lipopolysaccharides - pharmacology; Microbial Sensitivity Tests; monocytes; phagocytosis; antibiotic resistance; inflammation; LPS modification; colistin; immune checkpoints
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/iai.00012-23

Colistin resistance is acquired by different lipopolysaccharide (LPS) modifications. We proposed to evaluate the of effect
colistin resistance acquisition on the innate immune response. We used a pair of ST11 clone Klebsiella pneumoniae strains: an OXA-48, CTX-M-15 K. pneumoniae strain susceptible to colistin (CS-Kp) isolated from a urinary infection and its colistin-resistant variant (CR-Kp) from the same patient after prolonged treatment with colistin. No mutation of previously described genes for colistin resistance (
,
,
,
, and
) was found in the CR-Kp genome; however, LPS modifications were characterized by negative-ion matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry. The strains were cocultured with human monocytes to determine their survival after phagocytosis and induction to apoptosis. Also, monocytes were stimulated with bacterial LPS to study cytokine and immune checkpoint production. The addition of 4-amino-4-deoxy-l-arabinose (Ara4N) to lipid A of CR-Kp accounted for the colistin resistance. CR-Kp survived significantly longer inside human monocytes after being phagocytosed than did the CS-Kp strain. In addition, LPS from CR-Kp induced both higher apoptosis in monocytes and higher levels of cytokine and immune checkpoint production than LPS from CS-Kp. Our data reveal a variable impact of colistin resistance on the innate immune system, depending on the responsible mechanism. Adding Ara4N to LPS in K. pneumoniae increases bacterial survival after phagocytosis and elicits a higher inflammatory response than its colistin-susceptible counterpart.