Makoto Inoue

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.

Biography:

Dr. Inoue studied Neuroscience at Nagasaki University, Japan, and graduated with a Ph.D. in 2000. After four years of a postdoctoral fellowship at UCLA (Dr. Chris Evans) and Nagasaki University (Dr. Hiroshi Ueda), he obtained the position of Associate Professor at Nagasaki University. Then, he decided to expand his research fields and joined Duke University in 2009. At Duke University, he studied Immunology. In 2016, he obtained an Assistant Professor at the University of Illinois at Urbana-Champaign and started Neuroimmunology studies. In 2022, he received tenure and was promoted to Associate Professor. He has published 78 peer-reviewed research articles.