Susceptibility to Cryptococcus neoformans Infection with Bruton's Tyrosine Kinase Inhibition

Area of Science:

• Immunology
• Infectious Diseases
• Pharmacology

Background:

• Patients on Bruton's tyrosine kinase (BTK) inhibitors like ibrutinib show increased fungal infection risk.
• The precise mechanisms linking BTK inhibition to heightened susceptibility to fungal infections remain unclear.

Purpose of the Study:

• To investigate if Cryptococcus neoformans infection severity is dependent on the specific isolate when Bruton's tyrosine kinase (BTK) is inhibited.
• To determine if blocking BTK impacts fungal infection severity in a preclinical mouse model.

Main Methods:

• Comparison of four clinical Cryptococcus neoformans isolates against reference strains (H99, A1-35-8) in BTK knockout (KO) and wild-type (WT) mice.
• Infection was induced via intranasal, oropharyngeal aspiration, and intravenous routes, with severity assessed by survival and fungal burden.
• Mice received daily intraperitoneal injections of ibrutinib (25 mg/kg) or vehicle.

Main Results:

• No isolate-dependent effect on fungal burden was observed in the BTK KO model across different infection routes.
• Neither BTK knockout nor ibrutinib treatment significantly altered infection severity compared to wild-type controls.
• Two of the four clinical isolates exhibited reduced virulence compared to the H99 reference strain, showing longer survival and less brain infection.

Conclusions:

• Cryptococcus neoformans infection severity is not isolate-dependent in the BTK knockout mouse model.
• BTK knockout and ibrutinib treatment did not significantly alter infection severity in this model.
• Further studies are required to refine a mouse model that accurately reflects the increased susceptibility to fungal infections observed in patients treated with BTK inhibitors.