Lipid A modification of colistin-resistant Klebsiella pneumoniae does not alter innate immune response in a mouse model of pneumonia

Author:

Bhushan Gitanjali1ORCID,Castano Victor1,Wong Fok Lung Tania1,Chandler Courtney2,McConville Thomas H.3,Ernst Robert K.2ORCID,Prince Alice S.1,Ahn Danielle1ORCID

Affiliation:

1. Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA

2. Department of Microbial Pathogenesis, University of Maryland, School of Dentistry, Baltimore, Maryland, USA

3. Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA

Abstract

ABSTRACT Polymyxin resistance in carbapenem-resistant Klebsiella pneumoniae bacteria is associated with high morbidity and mortality in vulnerable populations throughout the world. Ineffective antimicrobial activity by these last resort therapeutics can occur by transfer of mcr-1 , a plasmid-mediated resistance gene, causing modification of the lipid A portion of lipopolysaccharide (LPS) and disruption of the interactions between polymyxins and lipid A. Whether this modification alters the innate host immune response or carries a high fitness cost in the bacteria is not well established. To investigate this, we studied infection with K. pneumoniae (KP) ATCC 13883 harboring either the mcr-1 plasmid (p mcr-1 ) or the vector control (pBCSK) ATCC 13883. Bacterial fitness characteristics of mcr-1 acquisition were evaluated. Differentiated human monocytes (THP-1s) were stimulated with KP bacterial strains or purified LPS from both parent isolates and isolates harboring mcr-1 . Cell culture supernatants were analyzed for cytokine production. A bacterial pneumonia model in WT C57/BL6J mice was used to monitor immune cell recruitment, cytokine induction, and bacterial clearance in the bronchoalveolar lavage fluid (BALF). Isolates harboring mcr-1 had increased colistin MIC compared to the parent isolates but did not alter bacterial fitness. Few differences in cytokines were observed with purified LPS from mcr-1 expressing bacteria in vitro . However, in a mouse pneumonia model, no bacterial clearance defect was observed between p mcr-1 -harboring KP and parent isolates. Consistently, no differences in cytokine production or immune cell recruitment in the BALF were observed, suggesting that other mechanisms outweigh the effect of these lipid A mutations in LPS.

Funder

HHS | National Institutes of Health

Publisher

American Society for Microbiology

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