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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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Related in: MedlinePlus

Pathological findings in IFN-γR−/− mice after  respiratory infection with B. pertussis. Mice were challenged  with 2 × 1010 CFU/ml giving 6  × 104 CFU/lung 2 h later. (A)  Liver: aggregates of neutrophils  and macrophages with reactive  changes in adjoining hepatocytes.  (B) Mesentery: macrophages and  neutrophils surround a central  area of necrosis (necrotic pyogranuloma). (C) Brain: neutrophils, macrophages and fibrin deposits in the leptomeninges. (D)  Lung: granular basophilic debris  (arrows) in the alveolar spaces with  macrophage and neutrophil infiltration primarily in alveolar walls.  (A–D, hematoxylin and eosin [H  & E] staining) (E) Lung: B. pertussis  antigen in the lumen of alveoli  and a bronchiole (arrow). Anti–B.  pertussis, haematoxylin counterstain. (F) Mesentry: intracytoplasmic deposits of B. pertussis antigen in macrophages in an area of  pyogranulomatous inflammation.  Anti–B. pertussis, haematoxylin  counterstain. Results are representative of 15 mice from two  challenge experiments. Similar  pathological lesions were observed  in tissue from all mice examined,  except for the brain, where lesions  were visible in only 3 out of 7 mice  examined. Original magnifications: (A, C–F) ×400; (B) ×200.
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Figure 2: Pathological findings in IFN-γR−/− mice after respiratory infection with B. pertussis. Mice were challenged with 2 × 1010 CFU/ml giving 6 × 104 CFU/lung 2 h later. (A) Liver: aggregates of neutrophils and macrophages with reactive changes in adjoining hepatocytes. (B) Mesentery: macrophages and neutrophils surround a central area of necrosis (necrotic pyogranuloma). (C) Brain: neutrophils, macrophages and fibrin deposits in the leptomeninges. (D) Lung: granular basophilic debris (arrows) in the alveolar spaces with macrophage and neutrophil infiltration primarily in alveolar walls. (A–D, hematoxylin and eosin [H & E] staining) (E) Lung: B. pertussis antigen in the lumen of alveoli and a bronchiole (arrow). Anti–B. pertussis, haematoxylin counterstain. (F) Mesentry: intracytoplasmic deposits of B. pertussis antigen in macrophages in an area of pyogranulomatous inflammation. Anti–B. pertussis, haematoxylin counterstain. Results are representative of 15 mice from two challenge experiments. Similar pathological lesions were observed in tissue from all mice examined, except for the brain, where lesions were visible in only 3 out of 7 mice examined. Original magnifications: (A, C–F) ×400; (B) ×200.

Mentions: Examination of 60 B. pertussis–infected IFN-γR−/− mice killed between 7–100 d after challenge (6 experiments), revealed evidence of gross pathological changes outside the lungs in 80% of animals. The most common examination features were multiple pale, firm nodules up to 10 mm in diameter projecting above the capsular surface of the liver. Similar nodular lesions were visible in the kidneys, spleens, and mesentery, but these were smaller than those in the livers. In two separate experiments histopathological examination was performed on 15 B. pertussis infected IFN-γR−/− 24 d after challenge and atypical liver pathology was observed in 100% of animals. The histological appearance of the lesions was of pyogranulomatous inflammation and postnecrotic scarring. Aggregates of neutrophils and macrophages adjoined the areas of necrosis and infiltrates of lymphocytes and plasma cells (Fig. 2, a and b). Fibroblastic proliferation and collagenization were prominent particularly in the livers. Localized infiltrates of neutrophils, macrophages and lymphoid cells observed in the brains of a minority of surviving IFN-γR−/− mice were largely confined to the leptomeninges (Fig. 2 c and 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)

Pathological findings in IFN-γR−/− mice after  respiratory infection with B. pertussis. Mice were challenged  with 2 × 1010 CFU/ml giving 6  × 104 CFU/lung 2 h later. (A)  Liver: aggregates of neutrophils  and macrophages with reactive  changes in adjoining hepatocytes.  (B) Mesentery: macrophages and  neutrophils surround a central  area of necrosis (necrotic pyogranuloma). (C) Brain: neutrophils, macrophages and fibrin deposits in the leptomeninges. (D)  Lung: granular basophilic debris  (arrows) in the alveolar spaces with  macrophage and neutrophil infiltration primarily in alveolar walls.  (A–D, hematoxylin and eosin [H  & E] staining) (E) Lung: B. pertussis  antigen in the lumen of alveoli  and a bronchiole (arrow). Anti–B.  pertussis, haematoxylin counterstain. (F) Mesentry: intracytoplasmic deposits of B. pertussis antigen in macrophages in an area of  pyogranulomatous inflammation.  Anti–B. pertussis, haematoxylin  counterstain. Results are representative of 15 mice from two  challenge experiments. Similar  pathological lesions were observed  in tissue from all mice examined,  except for the brain, where lesions  were visible in only 3 out of 7 mice  examined. Original magnifications: (A, C–F) ×400; (B) ×200.
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Related In: Results  -  Collection

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Figure 2: Pathological findings in IFN-γR−/− mice after respiratory infection with B. pertussis. Mice were challenged with 2 × 1010 CFU/ml giving 6 × 104 CFU/lung 2 h later. (A) Liver: aggregates of neutrophils and macrophages with reactive changes in adjoining hepatocytes. (B) Mesentery: macrophages and neutrophils surround a central area of necrosis (necrotic pyogranuloma). (C) Brain: neutrophils, macrophages and fibrin deposits in the leptomeninges. (D) Lung: granular basophilic debris (arrows) in the alveolar spaces with macrophage and neutrophil infiltration primarily in alveolar walls. (A–D, hematoxylin and eosin [H & E] staining) (E) Lung: B. pertussis antigen in the lumen of alveoli and a bronchiole (arrow). Anti–B. pertussis, haematoxylin counterstain. (F) Mesentry: intracytoplasmic deposits of B. pertussis antigen in macrophages in an area of pyogranulomatous inflammation. Anti–B. pertussis, haematoxylin counterstain. Results are representative of 15 mice from two challenge experiments. Similar pathological lesions were observed in tissue from all mice examined, except for the brain, where lesions were visible in only 3 out of 7 mice examined. Original magnifications: (A, C–F) ×400; (B) ×200.
Mentions: Examination of 60 B. pertussis–infected IFN-γR−/− mice killed between 7–100 d after challenge (6 experiments), revealed evidence of gross pathological changes outside the lungs in 80% of animals. The most common examination features were multiple pale, firm nodules up to 10 mm in diameter projecting above the capsular surface of the liver. Similar nodular lesions were visible in the kidneys, spleens, and mesentery, but these were smaller than those in the livers. In two separate experiments histopathological examination was performed on 15 B. pertussis infected IFN-γR−/− 24 d after challenge and atypical liver pathology was observed in 100% of animals. The histological appearance of the lesions was of pyogranulomatous inflammation and postnecrotic scarring. Aggregates of neutrophils and macrophages adjoined the areas of necrosis and infiltrates of lymphocytes and plasma cells (Fig. 2, a and b). Fibroblastic proliferation and collagenization were prominent particularly in the livers. Localized infiltrates of neutrophils, macrophages and lymphoid cells observed in the brains of a minority of surviving IFN-γR−/− mice were largely confined to the leptomeninges (Fig. 2 c and 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