Title : CCR5-mediated T Cell infiltration into the brain triggers pulmonary dysfunction in murine cryptococcus-associated IRIS
Abstract:
Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS) is identified upon immune reconstitution in immunocompromised patients who have previously contracted an infection of Cryptococcus neoformans (Cn). C-IRIS can be lethal, but how the immune system triggers life-threatening outcomes in patients is still poorly understood. We recently established a mouse model for C-IRIS with Cn serotype A strain H99 (CnH99), which is highly virulent and the most intensively studied. C-IRIS in mice is induced by the adoptive transfer of CD4+ T cells in Tcra1-/- mice, lack of T cells, which are pre-infected with a low inoculum of CnH99. The C-IRIS mice exhibit symptoms that mimic clinical presentations of C-IRIS, such as brain edema, pulmonary dysfunction, and mortality. Interestingly, the lungs of C-IRIS mice do not indicate significant histopathology change, even though C-IRIS mice show severe pulmonary dysfunction. Instead, we demonstrate that pulmonary dysfunction associated with the C-IRIS condition in mice could be attributed to the infiltrated CD4+ T cell-mediated brainstem neuron damage. We also demonstrated that infiltration of CD4+ T cells is mediated via the CCL8-CCR5 axis in C-IRIS mice. These findings provide unique insight into the mechanism behind pulmonary dysfunction in C-IRIS and nominate potential therapeutic targets for treatment.
Audience Take Away
- The research uses a mouse model of C-IRIS, a helpful and relevant research model for investigating pathology and mechanisms of the cryptococcus-associated immune response
- Equally of interest to neuroscientists and immunologists, this research provides that infiltrated peripheral immune cells in the brain impact peripheral organ function in patients with C-IRIS
- Identifying neuroimmune functions may prompt further investigation into their potential as a therapeutic strategy
This work could benefit both basic scientists investigating the mechanism of IRIS and clinicians treating IRIS patients.
