Th1-Dependent Cryptococcus-Associated Immune Reconstitution Inflammatory Syndrome Model With Brain Damage

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. Here, we establish a mouse model for C-IRIS with Cn serotype A strain H99, which is highly virulent and the most intensively studied. C-IRIS in mice is induced by the adoptive transfer of CD4 + T cells in immunocompromised Rag1 -deficient mice infected with a low inoculum of Cn. The mice with C-IRIS exhibit symptoms which mimic clinical presentations of C-IRIS. This C-IRIS model is Th1-dependent and shows host mortality. This model is characterized with minimal lung injury, but infiltration of Th1 cells in the brain. C-IRIS mice also exhibited brain swelling with resemblance to edema and upregulation of aquaporin-4, a critical protein that regulates water flux in the brain in a Th1-dependent fashion. Our C-IRIS model may be used to advance our understanding of the paradoxical inflammatory phenomenon of C-IRIS in the context of neuroinflammation.

Immune reconstitution inflammatory syndrome in non‐HIV cryptococcal meningitis: Cross‐talk between pathogen and host

“…Once the immune suppression is relieved by effective antifungal treatment, aberrant immune responses and excessive CNS inflammation would same occur, and finally results in IRIS events in non-HIV patients. Our data showed that IL-12/IL-10 ratio that represented Th-1/Th-2 balance was significantly lower at baseline in the IRIS group, and increased inversely at IRIS occurrence, which is consistent with the study from Panackal et al,28 and indicated an immune reconstitution.Associations between high chemokine expressions and IRIS development were identified in HIV and non-HIV populations as previously reported 9,12,29. Elevated CSF IFNγ, IL-4, IL-10, IL-17, CXCL10, CCL3 and MCP-1 levels were recognised as biomarkers for IRIS in HIV population, whereas our data showed th1 cytokines (TNFα), th2 cytokines (IL-4, IL-10) and chemokines (MCP-1, MIP-1α, MIP-1β) all increased at baseline CSF, indicating that IRIS is a complicated immune response in both HIV and non-HIV populations.…”

Systemic Inflammation Associated with Immune Reconstitution Inflammatory Syndrome in Persons Living with HIV

“…Khaw et al recently demonstrated Th1 mediated brain damage in IRIS by Cryptococcus neoformans in mice [122]. Curiously, this appears associated with an aquaporin critical for brain water flow regulation that depends on Th1 [122]. In another report, Meya et al…”

“…Jarvis et al evaluated cytokine responses in HIV-associated cryptococcal meningitis finding that macrophage activation linked to Th1 and Th17 activation in CSF was associated with cryptococci clearance and survival at 2 weeks [ 121 ]. Khaw et al recently demonstrated Th1 mediated brain damage in IRIS by Cryptococcus neoformans in mice [ 122 ]. Curiously, this appears associated with an aquaporin critical for brain water flow regulation that depends on Th1 [ 122 ].…”

“…Khaw et al recently demonstrated Th1 mediated brain damage in IRIS by Cryptococcus neoformans in mice [ 122 ]. Curiously, this appears associated with an aquaporin critical for brain water flow regulation that depends on Th1 [ 122 ]. In another report, Meya et al showed that aberrant T-cell function leads to subsequent increases in cytokine responses, with a lower frequency of memory subsets of CD4 and CD8 T-cells expressing IL-2, IL-17 and IFN-γ [ 123 ].…”

CCR2 Signaling Promotes Brain Infiltration of Inflammatory Monocytes and Contributes to Neuropathology during Cryptococcal Meningoencephalitis

“…Likewise, noncompromised CM patients often develop severe neurological pathology that is steroid responsive ( 6 ). CD4 + T cells also orchestrate lethal immune pathology in animal models ( 12 , 13 , 15 ). However, CD4 + cells do not perform their immune functions on their own but require antigen-presenting cellular partners to become activated and to execute their effector functions in neuroinflammatory diseases ( 16 ).…”