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Border Patrol Gone Awry: Lung NKT Cell Activation by Francisella tularensis Exacerbates Tularemia-Like Disease.

Hill TM, Gilchuk P, Cicek BB, Osina MA, Boyd KL, Durrant DM, Metzger DW, Khanna KM, Joyce S - PLoS Pathog. (2015)

Bottom Line: Here we show for the first time that respiratory infection with Francisella tularensis live vaccine strain resulted in rapid accumulation of NKT cells within the lung interstitium.Consistent with these results, NKT cell-deficient mice showed reduced inflammatory cytokine and chemokine response yet they survived the infection better than their wild type counterparts.Strikingly, NKT cell-deficient mice had increased lymphocytic infiltration in the lungs that organized into tertiary lymphoid structures resembling induced bronchus-associated lymphoid tissue (iBALT) at the peak of infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.

ABSTRACT
The respiratory mucosa is a major site for pathogen invasion and, hence, a site requiring constant immune surveillance. The type I, semi-invariant natural killer T (NKT) cells are enriched within the lung vasculature. Despite optimal positioning, the role of NKT cells in respiratory infectious diseases remains poorly understood. Hence, we assessed their function in a murine model of pulmonary tularemia--because tularemia is a sepsis-like proinflammatory disease and NKT cells are known to control the cellular and humoral responses underlying sepsis. Here we show for the first time that respiratory infection with Francisella tularensis live vaccine strain resulted in rapid accumulation of NKT cells within the lung interstitium. Activated NKT cells produced interferon-γ and promoted both local and systemic proinflammatory responses. Consistent with these results, NKT cell-deficient mice showed reduced inflammatory cytokine and chemokine response yet they survived the infection better than their wild type counterparts. Strikingly, NKT cell-deficient mice had increased lymphocytic infiltration in the lungs that organized into tertiary lymphoid structures resembling induced bronchus-associated lymphoid tissue (iBALT) at the peak of infection. Thus, NKT cell activation by F. tularensis infection hampers iBALT formation and promotes a systemic proinflammatory response, which exacerbates severe pulmonary tularemia-like disease in mice.

No MeSH data available.


Related in: MedlinePlus

CD1d-/- mice have reduced splenic LVS burden but no difference in the liver.(A) Blood, liver, and spleen burden were determined as in Fig 4. Data are combined from 3 separate experiments. Bars are mean+SD of 6–10 mice/group/time point. Data were analyzed as indicated in Materials and Methods. **p<0.01. (B) H&E stained FFPE liver (top) and spleen (bottom) sections d9 p.i., 200X magnification. Data are representative of 3 mice/group. Arrows indicate granulomas.
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ppat.1004975.g005: CD1d-/- mice have reduced splenic LVS burden but no difference in the liver.(A) Blood, liver, and spleen burden were determined as in Fig 4. Data are combined from 3 separate experiments. Bars are mean+SD of 6–10 mice/group/time point. Data were analyzed as indicated in Materials and Methods. **p<0.01. (B) H&E stained FFPE liver (top) and spleen (bottom) sections d9 p.i., 200X magnification. Data are representative of 3 mice/group. Arrows indicate granulomas.

Mentions: After i.n. infection, F. tularensis rapidly disseminates to the periphery [44]. The kinetics and extent of dissemination are suggested as determinants of disease severity [45–48]. Hence, we measured burden in blood, liver, and spleen. LVS was only transiently detectable in the blood, where levels peaked at d3 p.i., but there were no differences in bacteremia between groups (Fig 5A). Liver burden was similar in both groups, but CD1d-/- mice had significantly lower splenic burden d3–7 p.i. (Fig 5A). Further analysis showed that only lung burden—but not liver or spleen—correlated with weight loss at d7 p.i. (S4 Fig). Consistent with these findings, histopathological analysis failed to identify any striking differences in either liver or spleen pathology after intranasal inoculation (Fig 5B). The extent of hepatic granuloma formation did not differ between groups (Fig 5B). Contrary to previous reports in BALB/c mice [49,50], splenic architecture was mostly intact with some evidence of apoptosis and extramedullary hematopoiesis that did not seem to differ between groups (Fig 5B).


Border Patrol Gone Awry: Lung NKT Cell Activation by Francisella tularensis Exacerbates Tularemia-Like Disease.

Hill TM, Gilchuk P, Cicek BB, Osina MA, Boyd KL, Durrant DM, Metzger DW, Khanna KM, Joyce S - PLoS Pathog. (2015)

CD1d-/- mice have reduced splenic LVS burden but no difference in the liver.(A) Blood, liver, and spleen burden were determined as in Fig 4. Data are combined from 3 separate experiments. Bars are mean+SD of 6–10 mice/group/time point. Data were analyzed as indicated in Materials and Methods. **p<0.01. (B) H&E stained FFPE liver (top) and spleen (bottom) sections d9 p.i., 200X magnification. Data are representative of 3 mice/group. Arrows indicate granulomas.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4465904&req=5

ppat.1004975.g005: CD1d-/- mice have reduced splenic LVS burden but no difference in the liver.(A) Blood, liver, and spleen burden were determined as in Fig 4. Data are combined from 3 separate experiments. Bars are mean+SD of 6–10 mice/group/time point. Data were analyzed as indicated in Materials and Methods. **p<0.01. (B) H&E stained FFPE liver (top) and spleen (bottom) sections d9 p.i., 200X magnification. Data are representative of 3 mice/group. Arrows indicate granulomas.
Mentions: After i.n. infection, F. tularensis rapidly disseminates to the periphery [44]. The kinetics and extent of dissemination are suggested as determinants of disease severity [45–48]. Hence, we measured burden in blood, liver, and spleen. LVS was only transiently detectable in the blood, where levels peaked at d3 p.i., but there were no differences in bacteremia between groups (Fig 5A). Liver burden was similar in both groups, but CD1d-/- mice had significantly lower splenic burden d3–7 p.i. (Fig 5A). Further analysis showed that only lung burden—but not liver or spleen—correlated with weight loss at d7 p.i. (S4 Fig). Consistent with these findings, histopathological analysis failed to identify any striking differences in either liver or spleen pathology after intranasal inoculation (Fig 5B). The extent of hepatic granuloma formation did not differ between groups (Fig 5B). Contrary to previous reports in BALB/c mice [49,50], splenic architecture was mostly intact with some evidence of apoptosis and extramedullary hematopoiesis that did not seem to differ between groups (Fig 5B).

Bottom Line: Here we show for the first time that respiratory infection with Francisella tularensis live vaccine strain resulted in rapid accumulation of NKT cells within the lung interstitium.Consistent with these results, NKT cell-deficient mice showed reduced inflammatory cytokine and chemokine response yet they survived the infection better than their wild type counterparts.Strikingly, NKT cell-deficient mice had increased lymphocytic infiltration in the lungs that organized into tertiary lymphoid structures resembling induced bronchus-associated lymphoid tissue (iBALT) at the peak of infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.

ABSTRACT
The respiratory mucosa is a major site for pathogen invasion and, hence, a site requiring constant immune surveillance. The type I, semi-invariant natural killer T (NKT) cells are enriched within the lung vasculature. Despite optimal positioning, the role of NKT cells in respiratory infectious diseases remains poorly understood. Hence, we assessed their function in a murine model of pulmonary tularemia--because tularemia is a sepsis-like proinflammatory disease and NKT cells are known to control the cellular and humoral responses underlying sepsis. Here we show for the first time that respiratory infection with Francisella tularensis live vaccine strain resulted in rapid accumulation of NKT cells within the lung interstitium. Activated NKT cells produced interferon-γ and promoted both local and systemic proinflammatory responses. Consistent with these results, NKT cell-deficient mice showed reduced inflammatory cytokine and chemokine response yet they survived the infection better than their wild type counterparts. Strikingly, NKT cell-deficient mice had increased lymphocytic infiltration in the lungs that organized into tertiary lymphoid structures resembling induced bronchus-associated lymphoid tissue (iBALT) at the peak of infection. Thus, NKT cell activation by F. tularensis infection hampers iBALT formation and promotes a systemic proinflammatory response, which exacerbates severe pulmonary tularemia-like disease in mice.

No MeSH data available.


Related in: MedlinePlus