Lymph node colonization dynamics after oral Salmonella Typhimurium infection in mice.
An understanding of how pathogens colonize their hosts is crucial for the rational design of vaccines or therapy. While the molecular factors facilitating the invasion and systemic infection by pathogens are a central focus of research in microbiology, the population biological aspects of colonization are still poorly understood. Here, we investigated the early colonization dynamics of Salmonella enterica subspecies 1 serovar Typhimurium (S. Tm) in the streptomycin mouse model for diarrhea. We focused on the first step on the way to systemic infection -- the colonization of the cecal lymph node (cLN) from the gut -- and studied roles of inflammation, dendritic cells and innate immune effectors in the colonization process. To this end, we inoculated mice with mixtures of seven wild type isogenic tagged strains (WITS) of S. Tm. The experimental data were analyzed with a newly developed mathematical model describing the stochastic immigration, replication and clearance of bacteria in the cLN. We estimated that in the beginning of infection only 300 bacterial cells arrive in the cLN per day. We further found that inflammation decreases the net replication rate in the cLN by 23%. In ccr7(-/-) mice, in which dendritic cell movement is impaired, the bacterial migration rate was reduced 10-fold. In contrast, cybb(-/-) mice that cannot generate toxic reactive oxygen species displayed a 4-fold higher migration rate from gut to cLN than wild type mice. Thus, combining infections with mixed inocula of barcoded strains and mathematical analysis represents a powerful method for disentangling immigration into the cLN from replication in this compartment. The estimated parameters provide an important baseline to assess and predict the efficacy of interventions.
Institute of Microbiology, ETH Zurich, Zurich, Switzerland.
Patrick
P
Kaiser
Emma
E
Slack
Andrew J
AJ
Grant
Wolf-Dietrich
WD
Hardt
Roland R
RR
Regoes
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D018988:Bacterial Translocation; D002432:Cecum; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism; D012478:Salmonella Food Poisoning / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity / Q000502:physiology; D013047:Specific Pathogen-Free Organisms; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
D001426:Bacterial Proteins; C515371:Ccr7 protein, mouse; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D054400:Receptors, CCR7; D037521:Virulence Factors; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases