Enzymatic modification of lipid A by ArnT protects Bordetella bronchiseptica against cationic peptides and is required for transmission.
Pathogen transmission cycles require many steps: initial colonization, growth and persistence, shedding, and transmission to new hosts. Alterations in the membrane components of the bacteria, including lipid A, the membrane anchor of lipopolysaccharide, could affect any of these steps via its structural role protecting bacteria from host innate immune defenses, including antimicrobial peptides and signaling through Toll-like receptor 4 (TLR4). To date, lipid A has been shown to affect only the within-host dynamics of infection, not the between-host dynamics of transmission. Here, we investigate the effects of lipid A modification in a mouse infection and transmission model. Disruption of the Bordetella bronchiseptica locus (BB4268) revealed that ArnT is required for addition of glucosamine (GlcN) to B. bronchiseptica lipid A. ArnT modification of lipid A did not change its TLR4 agonist activity in J774 cells, but deleting arnT decreased resistance to killing by cationic antimicrobial peptides, such as polymyxin B and β-defensins. In the standard infection model, mutation of arnT did not affect B. bronchiseptica colonization, growth, persistence throughout the respiratory tract, recruitment of neutrophils to the nasal cavity, or shedding of the pathogen. However, the number of bacteria necessary to colonize a host (50% infective dose [ID50]) was 5-fold higher for the arnT mutant. Furthermore, the arnT mutant was defective in transmission between hosts. These results reveal novel functions of the ArnT lipid A modification and highlight the sensitivity of low-dose infections and transmission experiments for illuminating aspects of infectious diseases between hosts. Factors such as ArnT can have important effects on the burden of disease and are potential targets for interventions that can interrupt transmission.
Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA.
Olivier
O
Rolin
Sarah J
SJ
Muse
Chetan
C
Safi
Shokrollah
S
Elahi
Volker
V
Gerdts
Lauren E
LE
Hittle
Robert K
RK
Ernst
Eric T
ET
Harvill
Andrew
A
Preston
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D001885:Bordetella Infections / Q000382:microbiology* / Q000635:transmission*; D016950:Bordetella bronchiseptica / Q000201:enzymology* / Q000276:immunology*; D004195:Disease Models, Animal; D005944:Glucosamine / Q000378:metabolism; D006602:Hexosyltransferases / Q000378:metabolism*; D008050:Lipid A / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D050296:Microbial Viability / Q000187:drug effects
D023181:Antimicrobial Cationic Peptides; D008050:Lipid A; D006602:Hexosyltransferases; D005944:Glucosamine