A Murine Model of Invasive Aspergillosis: Variable Benefit of Interferon-Gamma Administration under In Vitro and In Vivo Conditions

Johnson, Christopher P.; Edmiston, Charles E.; Zhu, Yong-Ran; Adams, Mark B.; Roza, Allan M.; Kurup, Viswanath

doi:10.1089/sur.2005.6.397

Cited by 5 publications

(5 citation statements)

References 39 publications

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“…The finding of a sensitizing role for exogenous IFN, while surprising, has been described in other infectious models. Exogenous IFN−γ, while improving phagocytosis in vitro and in vivo , increases mortality in a murine model of invasive aspergillosis [20]. Similar results have been observed in a murine model of invasive candidiasis [21].…”

Section: Discussionsupporting

confidence: 70%

Exogenous Interferon-α and Interferon-γ Increase Lethality of Murine Inhalational Anthrax

et al. 2007

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Background Bacillus anthracis, the etiologic agent of inhalational anthrax, is a facultative intracellular pathogen. Despite appropriate antimicrobial therapy, the mortality from inhalational anthrax approaches 45%, underscoring the need for better adjuvant therapies. The variable latency between exposure and development of disease suggests an important role for the host's innate immune response. Type I and Type II Interferons (IFN) are prominent members of the host innate immune response and are required for control of intracellular pathogens. We have previously described a protective role for exogenous Type I and Type II IFNs in attenuating intracellular B.anthracis germination and macrophage cell death in vitro.Methodology and Principal FindingsWe sought to extend these findings in an in vivo model of inhalational anthrax, utilizing the Sterne strain (34F2) of B.anthracis. Mice devoid of STAT1, a component of IFN-α and IFN-γ signaling, had a trend towards increased mortality, bacterial germination and extrapulmonary spread of B.anthracis at 24 hrs. This was associated with impaired IL-6, IL-10 and IL-12 production. However, administration of exogenous IFN-γ, and to a lesser extent IFN-α, at the time of infection, markedly increased lethality. While IFNs were able to reduce the fraction of germinated spores within the lung, they increased both the local and systemic inflammatory response manifest by increases in IL-12 and reductions in IL-10. This was associated with an increase in extrapulmonary dissemination. The mechanism of IFN mediated inflammation appears to be in part due to STAT1 independent signaling.ConclusionsIn conclusion, while endogenous IFNs are essential for control of B.anthracis germination and lethality, administration of exogenous IFNs appear to increase the local inflammatory response, thereby increasing mortality.

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Section: Discussionsupporting

confidence: 70%

Exogenous Interferon-α and Interferon-γ Increase Lethality of Murine Inhalational Anthrax

et al. 2007

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“…In vivo, systemic IFN-g did not improve phagocytosis or killing by neutrophils or affect mortality. Local nasal IFN-g enhanced phagocytic recruitment to the lungs but worsened mortality (34). IFN-g has also been used as adjunctive therapy to standard antifungal treatment in humans and improved outcomes (35).…”

Section: Discussionmentioning

confidence: 99%

Influenza Suppresses Neutrophil Recruitment to the Lung and Exacerbates Secondary Invasive Pulmonary Aspergillosis

Tobin

Nickolich

Ramanan

et al. 2020

The Journal of Immunology

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Aspergillus fumigatus is an environmental fungus that can cause invasive pulmonary aspergillosis when spores are inhaled into the respiratory tract and invade airway or lung tissue. Influenza is a common respiratory virus that can cause severe respiratory disease, and postinfluenza invasive pulmonary aspergillosis, which is becoming a well-recognized clinical problem, typically occurs in critically ill patients. Mice challenged with influenza A PR/8/34 H1N1 and subsequently challenged with A. fumigatus had increased fungal burden, viral burden, inflammation, and mortality compared with single infected mice. Neutrophil recruitment in the lung of superinfected mice was decreased; however, mice were not neutropenic, and there was no difference in absolute blood neutrophils between groups. Additionally, CXCL1 and CXCL2 were decreased in lungs of superinfected mice compared with controls. IFN levels were increased in mice that received influenza, and deletion of STAT1 resulted in decreased fungal burden, increased airway and lung neutrophils, and increased CXCL1 compared with wild-type mice, whereas deletion of STAT2 did not change fungal burden or airway neutrophilia compared with wild-type mice. These data demonstrate a mechanism by which influenza A-induced STAT1 signaling inhibits neutrophil recruitment and increases susceptibility to postinfluenza invasive pulmonary aspergillosis.

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“…After the initial proinflammatory response to A. fumigatus associated with TLRs, phagocytes use both oxidative and nonoxidative mechanisms in concert to damage the hyphae of A. fumigatus (9,29). While a number of cytokines upregulate these antifungal phagocytic activities (12,14,16), antifungal agents may assist in further damaging hyphae. Sau et al found that amphotericin B induces signal transduction and inflammatory cytokine release from cells expressing TLR2, and the adapter protein MyD88 responds to amphotericin B with NF-B-dependent reporter activity and cytokine release (28a).…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory Effects of Voriconazole on Monocytes Challenged withAspergillus fumigatus: Differential Role of Toll-Like Receptors

Simitsopoulou

Roilides

Paliogianni

et al. 2008

Antimicrob Agents Chemother

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Voriconazole (VRC) has activity against Aspergillus fumigatus, the most frequent cause of invasive aspergillosis in immunocompromised patients. The combination of VRC and A. fumigatus hyphae induced a more pronounced profile of expression of genes encoding inflammatory molecules in human monocytes than Aspergillus alone did. Herein, we provide further evidence of the potential mechanism underlying this immunomodulatory effect of VRC on human monocytes in response to A. fumigatus hyphae. A significant additive antifungal effect was shown when VRC was combined with monocytes against A. fumigatus hyphae. Both A. fumigatus hyphae and VRC induced pronounced profiles of mRNA and protein expression of Toll-like receptor 2 (TLR2) as well as tumor necrosis factor alpha (TNF-␣) in THP-1 monocytic cells compared to untreated cells. The VRC-induced increase was greater than that induced by hyphae. The combination of VRC and hyphae increased mRNA and protein expression of TLR2 and TNF-␣ to even higher levels than did either VRC or hyphae alone. In contrast, TLR4 expression, both at the mRNA and protein levels, was not increased by either VRC or hyphae or their combination. In addition, significantly more NF-B was translocated to the nuclei of THP-1 cells treated with VRC than untreated cells. While VRC induced more NF-B than hyphae did, treatment with the combination of the two factors induced the greatest NF-B expression. The pronounced profile of TLR2 signaling, TNF-␣ expression, and NF-B activation in the presence of VRC suggests an immunomodulatory effect leading to a more efficient response to A. fumigatus.

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A Murine Model of Invasive Aspergillosis: Variable Benefit of Interferon-Gamma Administration under In Vitro and In Vivo Conditions

Abstract: The in vitro and in vivo effects of IFN-gamma in IA are contingent on many variables, including the route of administration and the specific pathogenesis of infection.

Cited by 5 publications

References 39 publications

Exogenous Interferon-α and Interferon-γ Increase Lethality of Murine Inhalational Anthrax

Exogenous Interferon-α and Interferon-γ Increase Lethality of Murine Inhalational Anthrax

Influenza Suppresses Neutrophil Recruitment to the Lung and Exacerbates Secondary Invasive Pulmonary Aspergillosis

Immunomodulatory Effects of Voriconazole on Monocytes Challenged withAspergillus fumigatus: Differential Role of Toll-Like Receptors

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