title: Natural History of Francisella tularensis in Aerosol-Challenged BALB/c Mice.
abstract: The objective of this study was to evaluate the natural history and pathogenesis of Francisella tularensis in a murine model of inhalational tularemia with the SchuS4 strain. Before the efficacy of antimicrobials could be assessed in this model, further model development was required to determine the optimal time to start therapy. This study helped define the time course of infection after aerosol challenge by quantifying the presence of bacteria in lung, blood, and spleen at multiple harvest points. In this study, mice were infected via a targeted inhaled dose of 100 50% lethal doses (LD50s) (LD50 = 300 CFU) of F. tularensis by whole-body aerosol. At 1, 24, 36, 48, 60, 72, 75, 78, 81, 84, 87, and 90 h postchallenge, groups of 15 animals were sacrificed and blood, lung, and splenic tissue samples were harvested, homogenized, plated, and incubated to evaluate the bacterial load in those tissues. It was determined that of the 3 sample types harvested, splenic tissue provided the most consistent bacterial counts, which steadily increased with the progressing infection. Further, it was determined that lung samples from all (15/15) animals were positive for infection at 75 h postaerosolization and that 14/15 animals had positive splenic tissue counts. Bacterial levels in blood were not predictive of treatment initiation. For future therapeutic evaluation studies in this model using F. tularensis (SchuS4), it was determined that therapy should be initiated at 75 h postchallenge and validated by spleen involvement.
authors.affiliation: Institute for Therapeutic Innovation, University of Florida, Lake Nona, Florida, USA Henry.Heine@medicine.ufl.edu.
authors.forename: Henry S
authors.initials: HS
authors.lastname: Heine
authors.affiliation: Institute for Therapeutic Innovation, University of Florida, Lake Nona, Florida, USA.
authors.forename: Lara
authors.initials: L
authors.lastname: Chuvala
authors.affiliation: Institute for Therapeutic Innovation, University of Florida, Lake Nona, Florida, USA.
authors.forename: Renaldo
authors.initials: R
authors.lastname: Riggins
authors.affiliation: Achaogen, Inc., South San Francisco, California, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Cirz
authors.affiliation: Achaogen, Inc., South San Francisco, California, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Cass
authors.affiliation: Institute for Therapeutic Innovation, University of Florida, Lake Nona, Florida, USA.
authors.forename: Arnold
authors.initials: A
authors.lastname: Louie
authors.affiliation: Institute for Therapeutic Innovation, University of Florida, Lake Nona, Florida, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: Drusano
mesh_terms: D000336:Aerosols; D000818:Animals; D016470:Bacteremia / Q000382:microbiology*; D058491:Bacterial Load; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005604:Francisella tularensis / Q000472:pathogenicity*; D008168:Lung / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008962:Models, Theoretical; D013154:Spleen / Q000382:microbiology*; D014406:Tularemia / Q000473:pathology*
chemical_list: D000336:Aerosols
references.citation: Am J Med. 1984 Dec;77(6):1091-4
references.pmid: 6507460
references.citation: J Infect Dis. 2014 Oct 15;210(8):1319-24
references.pmid: 24760199
references.citation: Can Med Assoc J. 1979 Jul 7;121(1):57-61
references.pmid: 38002
references.citation: Antimicrob Agents Chemother. 2010 Oct;54(10):4368-72
references.pmid: 20516275
references.citation: Infect Immun. 2008 Dec;76(12):5488-99
references.pmid: 18852245
references.citation: PLoS One. 2012;7(9):e45310
references.pmid: 23028924
references.citation: Am J Physiol. 1947 Jul 1;150(1):70-7
references.pmid: 20252828
references.citation: Antimicrob Agents Chemother. 1998 Mar;42(3):675-81
references.pmid: 9517950
references.citation: Antimicrob Agents Chemother. 2007 Apr;51(4):1373-9
references.pmid: 17296745
references.citation: Open Microbiol J. 2010 Jun 03;4:34-46
references.pmid: 21127743
references.citation: Infect Immun. 2006 Sep;74(9):5114-25
references.pmid: 16926403
references.citation: J Pharmacol Toxicol Methods. 2004 Jan-Feb;49(1):39-55
references.pmid: 14670693
references.citation: Antimicrob Agents Chemother. 2013 May;57(5):2010-5
references.pmid: 23403418
references.citation: J Antimicrob Chemother. 1989 May;23(5):681-9
references.pmid: 2759920
references.citation: PLoS Negl Trop Dis. 2011;5(2):e959
references.pmid: 21347450
references.citation: Antimicrob Agents Chemother. 2011 Jun;55(6):2693-5
references.pmid: 21422203