T cell infiltration into the brain triggers pulmonary dysfunction in murine Cryptococcus-associated IRIS

Area of Science:

• Immunology
• Neuroscience
• Infectious Diseases

Background:

• Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS) is a significant complication in immunocompromised individuals on antiretroviral therapy.
• Pulmonary distress is a critical symptom of C-IRIS, impacting patient recovery.
• The precise mechanisms underlying C-IRIS-related pulmonary dysfunction remain incompletely understood.

Purpose of the Study:

• To elucidate the immunological and neurological mechanisms driving pulmonary dysfunction in a mouse model of Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS).
• To identify key molecular pathways and cellular interactions involved in C-IRIS-induced pulmonary complications.

Main Methods:

• Utilized a previously established mouse model of unmasking C-IRIS involving CnH99 preinfection and adoptive transfer of CD4+ T cells.
• Investigated the role of the CCL8-CCR5 axis in CD4+ T cell migration to the brain.
• Assessed neuronal damage in the nucleus tractus solitarius (NTS) and the expression of ephrin B3 and semaphorin 6B in CD4+ T cells.

Main Results:

• Demonstrated that pulmonary dysfunction in C-IRIS is linked to CD4+ T cell infiltration into the brain.
• Identified the CCL8-CCR5 axis as a critical pathway mediating this T cell migration.
• Found that upregulated ephrin B3 and semaphorin 6B in CD4+ T cells contribute to NTS neuronal damage and disconnection.

Conclusions:

• Pulmonary dysfunction in C-IRIS is mechanistically linked to CD4+ T cell trafficking to the brain via the CCL8-CCR5 axis.
• Neuronal damage in the NTS, mediated by specific molecular cues on T cells, plays a role in C-IRIS pathogenesis.
• These findings highlight potential therapeutic targets for mitigating pulmonary complications in C-IRIS.