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Effect of amphotericin B lipid formulation on immune response in aspergillosis
S Saxena1, P K Bhatnagar, P C Ghosh
1Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi, India.
Abstract:
The immune response against Aspergillus fumigatus has been studied during infection and therapy in order to understand the mechanism of pathogenesis and the effect of treatment with amphotericin B. With this in view an animal model of aspergillosis was developed in Balb/c mice by intravenous injection of an optimized dose of 3. 6x10(6) A. fumigatus spores. Infection due to Aspergillus was well established by histopathological examination and fungal load in the animal. Lesions and eosinophil infiltration was observed in the infected tissues which indicated the involvement of a Type I hypersensitivity response. Evaluation of serological parameters indicated high levels of interleukin-4 (IL-4) and A. fumigatus specific IgG antibodies. The reduction in fungal load and modulation of immune response in the infected mice was studied following treatment with amphotericin B/cholesterol hemisuccinate vesicles (ABCV). The results clearly indicated significant reduction in the fungal load, disappearance of eosinophils and lesions with the appearance of macrophages and neutrophils in the infected lung tissue, a decrease in IL-4 (fourfold) and a concomitant increase of interferon-gamma (IFN-gamma; twofold) with an improvement in general condition of mice. In the non-treated mice, the rise of IL-4 level indicated the association of T(H)2 cell response with susceptibility to infection while the increase of IFN-gamma in the treated group suggested that T(H)1 cell response may be involved in resistance to Aspergillus infection.
Insights
This study reveals that T(H)2 cell response correlates with susceptibility to Aspergillus fumigatus infection. Treatment with amphotericin B promotes a T(H)1 cell response, aiding resistance.
Area of Science:
- Immunology
- Mycology
- Pharmacology
Background:
- Understanding the immune response to Aspergillus fumigatus is crucial for treating invasive fungal infections.
- Aspergillosis pathogenesis and treatment efficacy require detailed investigation.
- The role of specific immune responses, like T helper cell subsets, in susceptibility and resistance is not fully elucidated.
Purpose of the Study:
- To investigate the immune mechanisms underlying Aspergillus fumigatus infection in a murine model.
- To evaluate the therapeutic effect of amphotericin B/cholesterol hemisuccinate vesicles (ABCV) on infection and immune modulation.
- To determine the association between T helper cell responses (T(H)1 vs. T(H)2) and susceptibility or resistance to aspergillosis.
Main Methods:
- Development of a Balb/c mouse model of invasive aspergillosis via intravenous injection of Aspergillus fumigatus spores.
- Histopathological examination and fungal load assessment to confirm infection.
- Measurement of serological parameters, including interleukin-4 (IL-4) and interferon-gamma (IFN-gamma), and specific IgG antibodies; assessment of treatment effects with ABCV.
Main Results:
- Infection established with observable lesions and eosinophil infiltration, indicative of a Type I hypersensitivity response and high IL-4 levels.
- Amphotericin B/cholesterol hemisuccinate vesicles treatment significantly reduced fungal load, lesions, and eosinophils, while increasing macrophages and neutrophils.
- Treated mice showed decreased IL-4 and increased IFN-gamma, suggesting a shift from T(H)2 to T(H)1 response, correlating with improved condition.
Conclusions:
- A T(H)2 cell-dominant response, characterized by high IL-4, is associated with susceptibility to Aspergillus fumigatus infection.
- Treatment with amphotericin B/cholesterol hemisuccinate vesicles effectively reduces fungal burden and modulates the immune response.
- The shift towards a T(H)1 cell response, indicated by increased IFN-gamma, may be critical for resistance against Aspergillus infection.