Russell-Lodrigue, Kasi Elizabeth (2006-12). An inhalation model of acute Q fever in guinea pigs. Doctoral Dissertation. Thesis uri icon

abstract

  • Coxiella burnetii is an intracellular pathogen that can cause both acute and chronic disease (Q fever) in humans and infects many animals with varying clinical illness and persistence. A guinea pig aerosol-challenge model of acute Q fever was developed using infection with C. burnetii across a 5-log range of challenge doses. Clinical signs included fever, weight loss, respiratory difficulty, and death, with degree and duration of response corresponding to dose of organism delivered. Histopathologic evaluation revealed coalescing panleukocytic bronchointerstitial pneumonia 7 days after a high-dose challenge, resolving to multifocal lymphohistiocytic interstitial pneumonia by 28 days. Clinical and pathologic changes noted in these guinea pigs were comparable to those seen in human acute Q fever, making this an accurate and valuable animal model. This model was used to compare the relative virulence of eight isolates from four different genotypic groups: I (RSA493, RSA334, and RSA270), IV (Q177 and Q173), V (Q212 and Q217), and VI (5J108-111). Guinea pigs infected with group I acute-diseaseassociated isolates had severe respiratory disease, while no to moderate clinical illness was observed in animals given group IV or V chronic-disease-associated isolates. 5J108- 111 appeared avirulent. These data suggest that C. burnetii isolates have a range of disease potentials and support a distinction in strain virulence between established genotypic groups, though isolates within the same genomic group cause similar pathologic responses. Heterologous protection was confirmed by cross vaccination and challenge with RSA493 and Q217. A marked non-specific suppression of lymphoproliferation was noted at 14 and 28 days post infection with RSA493; similar suppression was seen after infection with Q173 and Q212 but not 5J108-111. Proinflammatory cytokines IFN-? and TNF-? were produced during early C. burnetii infection, at which time anti-inflammatory cytokines TGF-? and IL-10 were repressed. A vaccine made from phase I C. burnetii was found to be completely protective against lethal infection in the guinea pig model, while vaccination with killed phase II organisms conferred only partial protection, preventing death and reducing but not precluding fever and respiratory illness. Protective vaccination significantly stimulated cell-mediated immunity and elicited increases in IFN-?, TNF-?, and IL-12p40 mRNA levels.
  • Coxiella burnetii is an intracellular pathogen that can cause both acute and
    chronic disease (Q fever) in humans and infects many animals with varying clinical
    illness and persistence. A guinea pig aerosol-challenge model of acute Q fever was
    developed using infection with C. burnetii across a 5-log range of challenge doses.
    Clinical signs included fever, weight loss, respiratory difficulty, and death, with degree
    and duration of response corresponding to dose of organism delivered. Histopathologic
    evaluation revealed coalescing panleukocytic bronchointerstitial pneumonia 7 days after
    a high-dose challenge, resolving to multifocal lymphohistiocytic interstitial pneumonia
    by 28 days. Clinical and pathologic changes noted in these guinea pigs were comparable
    to those seen in human acute Q fever, making this an accurate and valuable animal
    model. This model was used to compare the relative virulence of eight isolates from four
    different genotypic groups: I (RSA493, RSA334, and RSA270), IV (Q177 and Q173), V
    (Q212 and Q217), and VI (5J108-111). Guinea pigs infected with group I acute-diseaseassociated
    isolates had severe respiratory disease, while no to moderate clinical illness
    was observed in animals given group IV or V chronic-disease-associated isolates. 5J108-
    111 appeared avirulent. These data suggest that C. burnetii isolates have a range of
    disease potentials and support a distinction in strain virulence between established genotypic groups, though isolates within the same genomic group cause similar
    pathologic responses. Heterologous protection was confirmed by cross vaccination and
    challenge with RSA493 and Q217. A marked non-specific suppression of
    lymphoproliferation was noted at 14 and 28 days post infection with RSA493; similar
    suppression was seen after infection with Q173 and Q212 but not 5J108-111. Proinflammatory
    cytokines IFN-? and TNF-? were produced during early C. burnetii
    infection, at which time anti-inflammatory cytokines TGF-? and IL-10 were repressed.
    A vaccine made from phase I C. burnetii was found to be completely protective against
    lethal infection in the guinea pig model, while vaccination with killed phase II organisms
    conferred only partial protection, preventing death and reducing but not precluding fever
    and respiratory illness. Protective vaccination significantly stimulated cell-mediated
    immunity and elicited increases in IFN-?, TNF-?, and IL-12p40 mRNA levels.

publication date

  • December 2006