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Different tumor necrosis factor α antagonists have different effects on host susceptibility to disseminated and
Hyunsook Park1, Norma V Solis2, James S Louie3
1California State University Los Angeles; Los Angeles, CA USA.
Abstract:
Tumor necrosis factor α is important for the host defense against intracellular pathogens. We tested the effect of mouse analogs of human TNF-α antagonists, the rat anti-mouse TNF-α monoclonal antibody (XT22) and the soluble mouse 75 kDa TNF-α receptor fused to the Fc portion of mouse IgG1 (p75-Fc), on the susceptibility of mice to hematogenously disseminated candidiasis (HDC) and oropharyngeal candidiasis (OPC). Both XT22 and p75-Fc significantly reduced mice survival, increased kidney fungal burden, and reduced leukocyte recruitment during HDC. However, only XT22 significantly increased the oral fungal burden and reduced leukocyte recruitment during OPC. This result suggests that XT22 and p75-Fc affect host susceptibility to different types of Candida albicans infections by different inhibitory mechanisms.
Insights
Tumor necrosis factor α (TNF-α) antagonists, XT22 and p75-Fc, worsened fungal infections in mice. These TNF-α inhibitors increased susceptibility to candidiasis, impacting survival and fungal burden.
Area of Science:
- Immunology
- Infectious Diseases
- Microbiology
Background:
- Tumor necrosis factor α (TNF-α) is crucial for host defense against intracellular pathogens.
- TNF-α plays a significant role in regulating immune responses to fungal infections.
- Understanding TNF-α's role is vital for developing effective antifungal therapies.
Purpose of the Study:
- To investigate the impact of TNF-α antagonists on experimental fungal infections in mice.
- To evaluate the efficacy of a monoclonal antibody (XT22) and a soluble receptor fusion protein (p75-Fc) against Candida albicans.
- To elucidate the differential effects of these antagonists on systemic and mucosal candidiasis.
Main Methods:
- Utilized mouse models for hematogenously disseminated candidiasis (HDC) and oropharyngeal candidiasis (OPC).
- Administered rat anti-mouse TNF-α monoclonal antibody (XT22) and soluble mouse 75 kDa TNF-α receptor fused to Fc (p75-Fc).
- Assessed outcomes including survival rates, kidney and oral fungal burden, and leukocyte recruitment.
Main Results:
- Both XT22 and p75-Fc significantly reduced survival and increased kidney fungal burden in HDC.
- Leukocyte recruitment was diminished in the kidneys during HDC following antagonist treatment.
- XT22, but not p75-Fc, significantly increased oral fungal burden and reduced leukocyte recruitment in OPC.
Conclusions:
- TNF-α antagonists (XT22 and p75-Fc) exacerbate susceptibility to systemic candidiasis (HDC) in mice.
- The effects of TNF-α antagonism differ between systemic and mucosal candidiasis.
- XT22 demonstrates distinct inhibitory mechanisms impacting oropharyngeal candidiasis (OPC) compared to p75-Fc.
