Disparate impact of oxidative host defenses determines the fate of Salmonella during systemic infection in mice.
Reactive oxygen and nitrogen species function in host defense via mechanisms that remain controversial. Pathogens might encounter varying levels of these species, but bulk measurements cannot resolve such heterogeneity. We used single-cell approaches to determine the impact of oxidative and nitrosative stresses on individual Salmonella during early infection in mouse spleen. Salmonella encounter and respond to both stresses, but the levels and impact vary widely. Neutrophils and inflammatory monocytes kill Salmonella by generating overwhelming oxidative stress through NADPH oxidase and myeloperoxidase. This controls Salmonella within inflammatory lesions but does not prevent their spread to more permissive resident red pulp macrophages, which generate only sublethal oxidative bursts. Regional host expression of inducible nitric oxide synthase exposes some Salmonella to nitrosative stress, triggering effective local Salmonella detoxification through nitric oxide denitrosylase. Thus, reactive oxygen and nitrogen species influence dramatically different outcomes of disparate Salmonella-host cell encounters, which together determine overall disease progression.
Focal Area Infection Biology, University of Basel, 4056 Basel, Switzerland.
Neil A
NA
Burton
Focal Area Infection Biology, University of Basel, 4056 Basel, Switzerland.
Nura
N
Schürmann
Focal Area Infection Biology, University of Basel, 4056 Basel, Switzerland.
Olivier
O
Casse
Focal Area Infection Biology, University of Basel, 4056 Basel, Switzerland.
Anne K
AK
Steeb
Focal Area Infection Biology, University of Basel, 4056 Basel, Switzerland.
Beatrice
B
Claudi
FACS Core Facility, University of Basel, 4056 Basel, Switzerland.
Janine
J
Zankl
Proteomics Core Facility, Biozentrum, University of Basel, 4056 Basel, Switzerland.
Alexander
A
Schmidt
Focal Area Infection Biology, University of Basel, 4056 Basel, Switzerland. Electronic address: dirk.bumann@unibas.ch.
Dirk
D
Bumann
D000818:Animals; D005260:Female; D015870:Gene Expression; D054884:Host-Pathogen Interactions; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010105:Oxygenases / Q000235:genetics / Q000378:metabolism; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst / Q000276:immunology; D012480:Salmonella Infections / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D012486:Salmonella typhimurium / Q000472:pathogenicity / Q000502:physiology*; D059010:Single-Cell Analysis; D013154:Spleen / Q000276:immunology* / Q000382:microbiology / Q000473:pathology
D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D009195:Peroxidase; D010105:Oxygenases; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019255:NADPH Oxidases