scholarly journals Role of Eosinophils in the Pathogenesis ofMycobacterium bovis BCG Infection in Gamma Interferon Receptor-Deficient Mice

2000 ◽  
Vol 68 (5) ◽  
pp. 2976-2978 ◽  
Author(s):  
Joanna Kirman ◽  
Zamsyari Zakaria ◽  
Kathy McCoy ◽  
Brett Delahunt ◽  
Graham Le Gros
Keyword(s):  
Monoclonal Antibody ◽  
Mycobacterium Bovis ◽  
Gamma Interferon ◽  
Eosinophil Infiltration ◽  
Interleukin 5 ◽  
Interferon Receptor ◽  
Mycobacterial Growth ◽  
Deficient Mice

ABSTRACT A profound eosinophil infiltration of granulomas is observed in the lungs of Mycobacterium bovis bacillus Calmette Guérin-infected gamma interferon receptor-deficient mice. Blockade of eosinophil proliferation and recruitment into the lung by treatment with anti-interleukin-5 monoclonal antibody marginally reduced mycobacterial growth within the lung but did not affect dissemination of the infection to other tissues.

scholarly journals Prior Exposure to Live Mycobacterium bovis BCG Decreases Cryptococcus neoformans-Induced Lung Eosinophilia in a Gamma Interferon-Dependent Manner

2003 ◽  
Vol 71 (6) ◽  
pp. 3384-3391 ◽  
Author(s):  
Gerhard Walzl ◽  
Ian R. Humphreys ◽  
Ben G. Marshall ◽  
Lorna Edwards ◽  
Peter J. M. Openshaw ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Mycobacterium Bovis ◽  
Mycobacterial Infection ◽  
Gamma Interferon ◽  
Delayed Type Hypersensitivity ◽  
Infection Model ◽  
Dependent Manner ◽  
Interleukin 5 ◽  
Lung Eosinophilia ◽  
Mycobacterial Antigens

ABSTRACT Some common childhood infections appear to prevent the development of atopy and asthma. In some Mycobacterium bovis BCG-vaccinated populations, strong delayed-type hypersensitivity responses to mycobacterial antigens are associated with a reduced risk of atopy. Although BCG exposure decreases allergen-induced lung eosinophilia in animal models, little attention has been given to the effect of immunity to BCG on responses against live pathogens. We used the murine Cryptococcus neoformans infection model to investigate whether prior BCG infection can alter such responses. The present study shows that persistent pulmonary BCG infection of C57BL/6 mice induced an increase in gamma interferon, a reduction in interleukin-5, and a decrease in lung eosinophilia during subsequent Cryptococcus infection. This effect was long lasting, depended on the presence of live bacteria, and required persistence of mycobacterial infection in the lung. Reduction of eosinophilia was less prominent after infection with a mutant BCG strain (ΔhspR), which was rapidly cleared from the lungs. These observations have important implications for the development of vaccines designed to prevent Th2-mediated disease and indicate that prior lung BCG vaccination can alter the pattern of subsequent host inflammation.

scholarly journals Aberrant Contraction of Antigen-Specific CD4 T Cells after Infection in the Absence of Gamma Interferon or Its Receptor

2006 ◽  
Vol 74 (11) ◽  
pp. 6252-6263 ◽  
Author(s):  
Jodie S. Haring ◽  
John T. Harty
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Gamma Interferon ◽  
Model Systems ◽  
Important Regulator ◽  
Ifn Γ ◽  
And Function ◽  
Deficient Mice

ABSTRACT Several lines of evidence from different model systems suggest that gamma interferon (IFN-γ) is an important regulator of T-cell contraction after antigen (Ag)-driven expansion. To specifically investigate the role of IFN-γ in regulating the contraction of Ag-specific CD4 T cells, we infected IFN-γ−/− and IFN-γR1−/− mice with attenuated Listeria monocytogenes and monitored the numbers of Ag-specific CD4 T cells during the expansion, contraction, and memory phases of the immune response to infection. In the absence of IFN-γ or the ligand-binding portion of its receptor, Ag-specific CD4 T cells exhibited normal expansion in numbers, but in both strains of deficient mice there was very little decrease in the number of Ag-specific CD4 T cells even at time points later than day 90 after infection. This significant delay in contraction was not due to prolonged infection, since mice treated with antibiotics to conclusively eliminate infection exhibited the same defect in contraction. In addition to altering the number of Ag-specific CD4 T cells, the absence of IFN-γ signaling also changed the phenotype of cells generated after infection. IFN-γR1−/− Ag-specific CD4 T cells reacquired expression of CD127 more quickly than wild-type cells, and more IFN-γR1−/− CD4 T cells were capable of producing both IFN-γ and interleukin 2 following Ag stimulation. From these data we conclude that IFN-γ regulates the contraction, phenotype, and function of Ag-specific CD4 T cells generated after infection.

scholarly journals Dependence of Mycobacterium bovis BCG on Anaerobic Nitrate Reductase for Persistence Is Tissue Specific

2002 ◽  
Vol 70 (1) ◽  
pp. 286-291 ◽  
Author(s):  
Christian Fritz ◽  
Silvia Maass ◽  
Andreas Kreft ◽  
Franz-Christoph Bange
Keyword(s):  
Nitrate Reductase ◽  
Mycobacterium Bovis ◽  
Vaccine Development ◽  
Nitrate Respiration ◽  
Apparent Paradox ◽  
Tissue Specific ◽  
Deficient Mice

ABSTRACT Mycobacterium bovis BCG, the only presently available vaccine against tuberculosis, was obtained from virulent M. bovis after serial passages in vitro. The vaccine strain retained at least some of its original virulence, as it persists in immune-competent hosts and occasionally may cause fatal disease in immune-deficient hosts. Mycobacterial persistence in vivo is thought to depend on anaerobic metabolism, an apparent paradox since all mycobacteria are obligate aerobes. Here we report that M. bovis BCG lacking anaerobic nitrate reductase (NarGHJI), an enzyme essential for nitrate respiration, failed to persist in the lungs, liver, and kidneys of immune-competent (BALB/c) mice. In immune-deficient (SCID) mice, however, bacilli caused chronic infection despite disruption of narG, even if growth of the mutant was severely impaired in lungs, liver, and kidneys. Persistence and growth of BCG in the spleens of either mouse strain appeared largely unaffected by lack of anaerobic nitrate reductase, indicating that the role of the enzyme in pathogenesis is tissue specific. These data suggest first that anaerobic nitrate reduction is essential for metabolism of M. bovis BCG in immune-competent but not immune-deficient mice and second that its role in mycobacterial disease is tissue specific, both of which are observations with important implications for pathogenesis of mycobacteria and vaccine development.

L-selectin is required for fMLP- but not C5a-induced margination of neutrophils in pulmonary circulation

2002 ◽  
Vol 282 (4) ◽  
pp. R1245-R1252 ◽  
Author(s):  
Timothy S. Olson ◽  
Kai Singbartl ◽  
Klaus Ley
Keyword(s):  
Monoclonal Antibody ◽  
Peripheral Blood ◽  
Pulmonary Circulation ◽  
Jugular Vein ◽  
Myeloperoxidase Activity ◽  
Wild Type ◽  
Pulmonary Microcirculation ◽  
Deficient Mice

To study the role of L-selectin in neutrophil (PMN) margination and sequestration in the pulmonary microcirculation, maximally active concentrations of C5a (900 pmol/g) and N-formylmethionyl-leucyl-phenylalanine (fMLP; 0.34 pmol/g) were injected into the jugular vein of wild-type or L-selectin-deficient C57BL/6 mice. In wild-type mice administered C5a or fMLP, 92 ± 1% and 34 ± 9%, respectively, of peripheral blood PMN were trapped mostly in the pulmonary circulation as determined by immunohistochemistry and myeloperoxidase activity. In wild-type mice treated with F(ab′)2fragments of the L-selectin monoclonal antibody MEL-14 or in L-selectin-deficient mice, C5a-induced neutropenia was not significantly reduced, but the decrease in peripheral PMN in response to fMLP was completely abolished, indicating that L-selectin is necessary for fMLP- but not C5a-induced pulmonary margination. Immunostained lung sections of fMLP- or C5a-treated mice showed sequestered neutrophils in alveolar capillaries with no evidence of neutrophil aggregates. We conclude that chemoattractant-induced PMN margination in the pulmonary circulation can occur by two separate mechanisms, one of which requires L-selectin.

scholarly journals Toll-Like Receptor-2-Mediated C-C Chemokine Receptor 3 and Eotaxin-Driven Eosinophil Influx Induced by Mycobacterium bovis BCG Pleurisy

2006 ◽  
Vol 75 (3) ◽  
pp. 1507-1511 ◽  
Author(s):  
Heloisa D'Ávila ◽  
Patrícia E. Almeida ◽  
Natália R. Roque ◽  
Hugo C. Castro-Faria-Neto ◽  
Patrícia T. Bozza
Keyword(s):  
Mycobacterium Bovis ◽  
Lipid Body ◽  
Eosinophil Infiltration ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Body Formation ◽  
Pleural Infection ◽  
Toll Like Receptor 2 ◽  
Deficient Mice ◽  
Eosinophil Accumulation

ABSTRACT An acute and persistent eosinophil infiltration is observed during Mycobacterium bovis BCG pleural infection in mice. Eosinophil accumulation, lipid body formation, and eotaxin production were significantly reduced in BCG-infected Toll-like receptor-2 (TLR2)-deficient mice compared to wild-type mice. Neutralization of eotaxin or CCR3 drastically inhibited BCG-induced eosinophil accumulation and lipid body formation, indicating that BCG-induced eosinophil recruitment and activation is largely dependent of TLR2-mediated eotaxin generation.

scholarly journals Gamma Interferon and Interleukin-1 Receptor 1 Regulate Neutrophil Recruitment to the Corneal Stroma in a Murine Model of Onchocerca volvulus Keratitis

2009 ◽  
Vol 77 (4) ◽  
pp. 1606-1612 ◽  
Author(s):  
Katrin Gentil ◽  
Eric Pearlman
Keyword(s):  
Corneal Stroma ◽  
Gamma Interferon ◽  
Neutrophil Recruitment ◽  
Onchocerca Volvulus ◽  
Eosinophil Infiltration ◽  
Chemokine Production ◽  
Corneal Fibroblasts ◽  
Cxc Chemokine ◽  
Ifn Γ

ABSTRACT Toll-like receptor 2 (TLR2) is an essential mediator of corneal inflammation induced by the filarial nematode Onchocerca volvulus, which harbors endosymbiotic Wolbachia bacteria. TLR2 is also required for dendritic cell activation, gamma interferon (IFN-γ) production, and neutrophil recruitment to the cornea. To examine the role of IFN-γ in O. volvulus keratitis, C57BL/6 and IFN-γ−/− mice were immunized subcutaneously, and a soluble antigen extract from O. volvulus adult worms (OvAg) was injected into the corneal stroma of each animal. We found that, in the absence of IFN-γ, neutrophil recruitment to the cornea was significantly impaired, whereas there was no effect on eosinophil infiltration. Since the cornea contains resident macrophages and fibroblasts and our previous studies showed that CXC chemokines mediate neutrophil recruitment, we examined the role of recombinant IFN-γ (rIFN-γ) on each cell type. We found no effect of rIFN-γ on CXC chemokine production by macrophages or corneal fibroblasts, either alone or with filarial extracts; in contrast, rIFN-γ was found to enhance OvAg-induced tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), IL-1α, and IL-1β in macrophages. Furthermore, we found that rTNF-α, rIL-1α, or rIL-1β induced CXC chemokine production by corneal fibroblasts but not by macrophages. To determine the relative contributions of endogenous cytokines, we injected OvAg into the corneal stroma of C57BL/6, IL-1 receptor 1−/− (IL-1R1−/−), and TNF-αR1/2−/− mice and examined neutrophil recruitment. We found that neutrophil infiltration was impaired in IL-1R1−/− mice but not in TNF-αR1/2−/− mice. IFN-γ therefore appears to regulate neutrophil recruitment to the corneal stroma by enhancing TLR2 expression and OvAg-induced IL-1α and IL-1β production by macrophages in the cornea, which then induce IL-1R1-dependent production of CXC chemokine by resident corneal fibroblasts.

scholarly journals Reduced Local Growth and Spread but Preserved Pathogenicity of a ΔpurC Mycobacterium tuberculosis Auxotrophic Mutant in Gamma Interferon Receptor-Deficient Mice after Aerosol Infection

2005 ◽  
Vol 73 (1) ◽  
pp. 666-670 ◽  
Author(s):  
Najmeeyah Brown ◽  
Muazzam Jacobs ◽  
Shreemanta K. Parida ◽  
Tania Botha ◽  
Aldina Santos ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Auxotrophic Mutant ◽  
Gamma Interferon ◽  
Clinical Strain ◽  
Wild Type ◽  
Live Vaccines ◽  
Interferon Receptor ◽  
Mutant Strains ◽  
Aerosol Infection ◽  
Deficient Mice

ABSTRACT We compared the growth levels and pathogenicities of the Mycobacterium tuberculosis MT103 clinical strain with those of the ΔpurC mutant strain MYC1551, which is auxotrophic for purine in wild-type and gamma interferon receptor (IFN-γR)-deficient mice. The ΔpurC strain MYC1551 grew initially in both wild-type and IFN-γR-deficient mice upon aerosol infection, but it grew much less than strain MT103 did. Despite the comparable bacterial burdens of the mice, IFN-γR-deficient mice succumbed to infection with ΔpurC strain MYC1551 from necrotic pneumonia within 6 weeks of those infected with MT103. In conclusion, the ΔpurC mutant MYC1551 displays reduced growth but retains pathogenicity. Therefore, the use of mutant strains of M. tuberculosis as live vaccines may not be recommended.

scholarly journals Gamma Interferon Dominates the Murine Cytokine Response to the Agent of Human Granulocytic Ehrlichiosis and Helps To Control the Degree of Early Rickettsemia

2000 ◽  
Vol 68 (4) ◽  
pp. 1827-1833 ◽  
Author(s):  
Mustafa Akkoyunlu ◽  
Erol Fikrig
Keyword(s):  
Gamma Interferon ◽  
Cytokine Response ◽  
Interleukin 4 ◽  
Infection Model ◽  
Granulocytic Ehrlichiosis ◽  
Human Granulocytic Ehrlichiosis ◽  
Ifn Γ ◽  
Immunocompetent Mice ◽  
Deficient Mice

ABSTRACT The cytokine response to the agent of human granulocytic ehrlichiosis (HGE) was assessed in a murine infection model and the role of gamma interferon (IFN-γ), a cytokine that is crucial for host defenses against intracellular pathogens, was investigated by using IFN-γ-deficient mice. The agent of HGE (aoHGE) is an obligate intracellular bacterium that survives within neutrophils: morulae (vacuoles containing HGE organisms) are evident in polymorphonuclear leukocytes of experimentally infected immunocompetent mice for 1 to 2 weeks. We now show that IFN-γ levels increase during early infection of C3H/HeN or C57BL/6 mice with HGE bacteria. Moreover, in response to aoHGE extracts or concanavalin A, splenocytes from ehrlichia-infected mice produced more IFN-γ and less interleukin-4 than controls, suggesting that aoHGE partially skewed the immune response towards a Th1 phenotype. Absolute concentration of morulae containing neutrophils in blood was 122 ± 22 cells/μl on day 8. The bacterial DNA burden was also highest on day 8 and then declined after IFN-γ levels peaked. In contrast, IFN-γ-deficient mice had a markedly elevated HGE bacteria burden with morulae concentration of 282 ± 48 cells/μl on day 5 (P = 0.004) and 242 ± 63 cells/μl on day 8 (P = 0.005). Rickettsemia resolved in immunocompetent and IFN-γ deficient mice after 2 weeks, while both the immunocompetent and the IFN-γ-deficient mice had increased serum antibodies against aoHGE antigens at this time point. These data demonstrate that the HGE agent elicits a prominent IFN-γ response in mice and that IFN-γ is important in controlling the degree of rickettsemia during the early phase of infection, while IFN-γ independent mechanisms play a role at later time points.

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