Perforin is required for primary immunity to Histoplasma capsulatum

Area of Science:

• Immunology
• Mycology
• Infectious Diseases

Background:

• Protective immunity against Histoplasma capsulatum (HC) involves innate and adaptive immune responses.
• Interferon-gamma (IFN-gamma) and Tumor Necrosis Factor-alpha (TNF-alpha) are known to limit fungal growth.
• The role of cytolytic mechanisms, such as perforin, in HC immunity is less understood.

Purpose of the Study:

• To investigate the role of perforin in mediating immunity against primary and secondary Histoplasma capsulatum infections.
• To explore the contribution of CD8(+) T cells to HC immunity, including perforin-dependent and independent mechanisms.

Main Methods:

• Utilized perforin-deficient knockout (PfKO) mice and wild-type controls for challenge studies.
• Depleted CD8(+) T cells in PfKO mice to assess their role.
• Performed adoptive transfer of CD8(+) T cells from PfKO mice into IFN-gamma(-/-) mice.

Main Results:

• Perforin-deficient mice exhibited accelerated mortality and increased fungal burden after HC challenge, highlighting perforin's essential role.
• Depletion of CD8(+) T cells in PfKO mice exacerbated disease, suggesting perforin-independent CD8(+) T cell functions.
• Adoptive transfer of CD8(+) T cells from PfKO mice reduced fungal burden in IFN-gamma(-/-) mice, indicating perforin-independent protective mechanisms.

Conclusions:

• Perforin is critical for effective immunity against systemic Histoplasma capsulatum infection.
• CD8(+) T cells contribute to Histoplasma capsulatum immunity through both perforin-dependent and independent pathways, with the latter being significant in the absence of IFN-gamma.