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Atypical disease after Bordetella pertussis respiratory infection of mice with targeted disruptions of interferon-gamma receptor or immunoglobulin mu chain genes.

Mahon BP, Sheahan BJ, Griffin F, Murphy G, Mills KH - J. Exp. Med. (1997)

Bottom Line: Viable virulent bacteria were detected in the blood and livers of diseased animals.An examination of the course of infection in the lung of IFN-gamma receptor-deficient, IL-4-deficient and wild-type mice demonstrated that lack of functional IFN-gamma or IL-4, cytokines that are considered to play major roles in regulating the development of Th1 and Th2 cells, respectively, did not affect the kinetics of bacterial elimination from the lung.In contrast, B cell-deficient mice developed a persistent infection and failed to clear the bacteria after aerosol inoculation.

View Article: PubMed Central - PubMed

Affiliation: Infection and Immunity Group, Department of Biology, National University of Ireland, Maynooth, County Kildare, Ireland.

ABSTRACT
Using a murine respiratory challenge model we have previously demonstrated a role for Th1 cells in natural immunity against Bordetella pertussis, but could not rule out a role for antibody. Here we have demonstrated that B. pertussis respiratory infection of mice with targeted disruptions of the genes for the IFN-gamma receptor resulted in an atypical disseminated disease which was lethal in a proportion of animals, and was characterized by pyogranulomatous inflammation and postnecrotic scarring in the livers, mesenteric lymph nodes and kidneys. Viable virulent bacteria were detected in the blood and livers of diseased animals. An examination of the course of infection in the lung of IFN-gamma receptor-deficient, IL-4-deficient and wild-type mice demonstrated that lack of functional IFN-gamma or IL-4, cytokines that are considered to play major roles in regulating the development of Th1 and Th2 cells, respectively, did not affect the kinetics of bacterial elimination from the lung. In contrast, B cell-deficient mice developed a persistent infection and failed to clear the bacteria after aerosol inoculation. These findings demonstrate an absolute requirement for B cells or their products in the resolution of a primary infection with B. pertussis, but also define a critical role for IFN-gamma in containing bacteria to the mucosal site of infection.

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Cell mediated immune responses induced after B.  pertussis infection of normal and  gene disrupted mice. Proliferation (A), IL-2 (B), IFN-γ (C),  and IL-5 (D) secretion by spleen  cells from gene disrupted (IFN-γR−/−, IL-4−/−, and Ig−/−) and  wild-type (129Sv/Ev and  C57BL/6) mice examined 43 d  after challenge. Spleen cells (2 ×  106/ml) were incubated with  heat-killed whole B. pertussis, 1  × 106 cells/ml (open bar), inactivated PT 5.0 μg/ml (solid bar),  FHA (hatched bar) 5.0 μg/ml, or  pertactin 5.0 μg/ml (horizontal  shading). Results are the mean  responses for 4 mice per group  assayed individually in triplicate.  Proliferative responses are expressed as CPM (±SE) after subtraction of background responses to medium alone, which  ranged from 5,000–10,000 cpm.
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Figure 5: Cell mediated immune responses induced after B. pertussis infection of normal and gene disrupted mice. Proliferation (A), IL-2 (B), IFN-γ (C), and IL-5 (D) secretion by spleen cells from gene disrupted (IFN-γR−/−, IL-4−/−, and Ig−/−) and wild-type (129Sv/Ev and C57BL/6) mice examined 43 d after challenge. Spleen cells (2 × 106/ml) were incubated with heat-killed whole B. pertussis, 1 × 106 cells/ml (open bar), inactivated PT 5.0 μg/ml (solid bar), FHA (hatched bar) 5.0 μg/ml, or pertactin 5.0 μg/ml (horizontal shading). Results are the mean responses for 4 mice per group assayed individually in triplicate. Proliferative responses are expressed as CPM (±SE) after subtraction of background responses to medium alone, which ranged from 5,000–10,000 cpm.

Mentions: The development of systemic cell-mediated immune responses in B. pertussis infected animals is thought to be central to clearance of the bacteria from the lungs (9–11). Positive spleen cell proliferative responses to heat killed B. pertussis could be detected in gene knockout and wild-type mice at day 14 after aerosol challenge (data not shown). Although relatively high background responses were observed with medium alone, this has previously been reported during B. pertussis infection of mice and children (21, 22) and may reflect activation of cells in vivo. The proliferative response to the putative protective antigens showed some variation; responses to PT were strongest in IFN-γR−/− mice and were detectable in this group from day 14, but were detectable in all animals by day 43 (Fig. 5 A). Unlike the C57BL/6 wild-type mice, responses to FHA could not be detected in IL-4−/− mice until 24 d after challenge. Responses to pertactin could not be detected from any mice before day 24. The B. pertussis-specific proliferative responses of Ig−/− mice were compromised compared with the wild-type C57BL/6 strain. Proliferative responses to B. pertussis and component antigens were detected on day 43 (Fig. 5 A), but this had declined by day 100 and positive proliferative responses could only be detected in Ig−/− mice at time points beyond 100 d against whole bacterial preparations at high concentrations. Responses to the putative protective antigens PT, FHA and pertactin could not be restored by the addition of MHC-matched APC to the cultures (data not shown).


Atypical disease after Bordetella pertussis respiratory infection of mice with targeted disruptions of interferon-gamma receptor or immunoglobulin mu chain genes.

Mahon BP, Sheahan BJ, Griffin F, Murphy G, Mills KH - J. Exp. Med. (1997)

Cell mediated immune responses induced after B.  pertussis infection of normal and  gene disrupted mice. Proliferation (A), IL-2 (B), IFN-γ (C),  and IL-5 (D) secretion by spleen  cells from gene disrupted (IFN-γR−/−, IL-4−/−, and Ig−/−) and  wild-type (129Sv/Ev and  C57BL/6) mice examined 43 d  after challenge. Spleen cells (2 ×  106/ml) were incubated with  heat-killed whole B. pertussis, 1  × 106 cells/ml (open bar), inactivated PT 5.0 μg/ml (solid bar),  FHA (hatched bar) 5.0 μg/ml, or  pertactin 5.0 μg/ml (horizontal  shading). Results are the mean  responses for 4 mice per group  assayed individually in triplicate.  Proliferative responses are expressed as CPM (±SE) after subtraction of background responses to medium alone, which  ranged from 5,000–10,000 cpm.
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Related In: Results  -  Collection

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Figure 5: Cell mediated immune responses induced after B. pertussis infection of normal and gene disrupted mice. Proliferation (A), IL-2 (B), IFN-γ (C), and IL-5 (D) secretion by spleen cells from gene disrupted (IFN-γR−/−, IL-4−/−, and Ig−/−) and wild-type (129Sv/Ev and C57BL/6) mice examined 43 d after challenge. Spleen cells (2 × 106/ml) were incubated with heat-killed whole B. pertussis, 1 × 106 cells/ml (open bar), inactivated PT 5.0 μg/ml (solid bar), FHA (hatched bar) 5.0 μg/ml, or pertactin 5.0 μg/ml (horizontal shading). Results are the mean responses for 4 mice per group assayed individually in triplicate. Proliferative responses are expressed as CPM (±SE) after subtraction of background responses to medium alone, which ranged from 5,000–10,000 cpm.
Mentions: The development of systemic cell-mediated immune responses in B. pertussis infected animals is thought to be central to clearance of the bacteria from the lungs (9–11). Positive spleen cell proliferative responses to heat killed B. pertussis could be detected in gene knockout and wild-type mice at day 14 after aerosol challenge (data not shown). Although relatively high background responses were observed with medium alone, this has previously been reported during B. pertussis infection of mice and children (21, 22) and may reflect activation of cells in vivo. The proliferative response to the putative protective antigens showed some variation; responses to PT were strongest in IFN-γR−/− mice and were detectable in this group from day 14, but were detectable in all animals by day 43 (Fig. 5 A). Unlike the C57BL/6 wild-type mice, responses to FHA could not be detected in IL-4−/− mice until 24 d after challenge. Responses to pertactin could not be detected from any mice before day 24. The B. pertussis-specific proliferative responses of Ig−/− mice were compromised compared with the wild-type C57BL/6 strain. Proliferative responses to B. pertussis and component antigens were detected on day 43 (Fig. 5 A), but this had declined by day 100 and positive proliferative responses could only be detected in Ig−/− mice at time points beyond 100 d against whole bacterial preparations at high concentrations. Responses to the putative protective antigens PT, FHA and pertactin could not be restored by the addition of MHC-matched APC to the cultures (data not shown).

Bottom Line: Viable virulent bacteria were detected in the blood and livers of diseased animals.An examination of the course of infection in the lung of IFN-gamma receptor-deficient, IL-4-deficient and wild-type mice demonstrated that lack of functional IFN-gamma or IL-4, cytokines that are considered to play major roles in regulating the development of Th1 and Th2 cells, respectively, did not affect the kinetics of bacterial elimination from the lung.In contrast, B cell-deficient mice developed a persistent infection and failed to clear the bacteria after aerosol inoculation.

View Article: PubMed Central - PubMed

Affiliation: Infection and Immunity Group, Department of Biology, National University of Ireland, Maynooth, County Kildare, Ireland.

ABSTRACT
Using a murine respiratory challenge model we have previously demonstrated a role for Th1 cells in natural immunity against Bordetella pertussis, but could not rule out a role for antibody. Here we have demonstrated that B. pertussis respiratory infection of mice with targeted disruptions of the genes for the IFN-gamma receptor resulted in an atypical disseminated disease which was lethal in a proportion of animals, and was characterized by pyogranulomatous inflammation and postnecrotic scarring in the livers, mesenteric lymph nodes and kidneys. Viable virulent bacteria were detected in the blood and livers of diseased animals. An examination of the course of infection in the lung of IFN-gamma receptor-deficient, IL-4-deficient and wild-type mice demonstrated that lack of functional IFN-gamma or IL-4, cytokines that are considered to play major roles in regulating the development of Th1 and Th2 cells, respectively, did not affect the kinetics of bacterial elimination from the lung. In contrast, B cell-deficient mice developed a persistent infection and failed to clear the bacteria after aerosol inoculation. These findings demonstrate an absolute requirement for B cells or their products in the resolution of a primary infection with B. pertussis, but also define a critical role for IFN-gamma in containing bacteria to the mucosal site of infection.

Show MeSH
Related in: MedlinePlus