Protection from Direct Cerebral Cryptococcus Infection by Interferon-γ-Dependent Activation of Microglial Cells

Abstract

The brain represents a significant barrier for protective immune responses in both infectious disease and cancer. We have recently demonstrated that immunotherapy with anti-CD40 and IL-2 can protect mice against disseminated Cryptococcus infection. We now applied this immunotherapy using a direct cerebral cryptococcosis model to study direct effects in the brain. Administration of anti-CD40 and IL-2 significantly prolonged the survival time of mice infected intracerebrally with Cryptococcus neoformans. The protection was correlated with activation of microglial cells indicated by the up-regulation of MHC II expression on brain CD45lowCD11b+ cells. CD4+ T cells were not required for either the microglial cell activation or anticryptococcal efficacy induced by this immunotherapy. Experiments with IFN-γ knockout mice and IFN-γR knockout mice demonstrated that IFN-γ was critical for both microglial cell activation and the anticryptococcal efficacy induced by anti-CD40/IL-2. Interestingly, while peripheral IFN-γ production and microglial cell activation were observed early after treatment, negligible IFN-γ was detected locally in the brain. These studies indicate that immunotherapy using anti-CD40 and IL-2 can augment host immunity directly in the brain against C. neoformans infection and that IFN-γ is essential for this effect.

IL-18 Triggered by the Nlrp3 Inflammasome Induces Host Innate Resistance in a Pulmonary Model of Fungal Infection

“…No studies have previously assessed the impact of the inflammasome on the Th1 defense mechanisms during PCM. Because IFN-g is an important cytokine involved in the resistance to P. brasiliensis and other several fungi (11,27,(44)(45)(46)(47)(48)(49)(50), we speculated that IFN-g could play a role in the central mechanism regulated by caspase-1 after P. brasiliensis infection. Confirming this hypothesis, IFN-g production and the Th1 response were lower in infected Asc 2/2 , Casp1 2/2 , and Nlrp3 mice were susceptible to experimental PCM because they exhibited reduced Th1 (and not Th17) immunity.…”

Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis

“…Brain immune cells must maintain a balance between killing invading microbes and preventing robust inflammatory responses to protect fragile neurons 46 . Despite the importance of microglial cells in protection against C. neoformans, the expression of brain proinflammatory cytokines (TNF-a, Interleukin (IL)-12 and IL-1) is low at the early stages of infection 47 . Furthermore, damage to the central nervous system causes inhibition of NF-kB in astrocytes, which, in turn, blocks the expression of a range of cytokines, including mammalian Cu transporter inducers, such as IFN-g 48 .…”

Dual Roles of CD40 on Microbial Containment and the Development of Immunopathology in Response to Persistent Fungal Infection in the Lung

“…infection. 20,21 Although the CD40-signaling pathway remains an attractive target of novel therapeutics, 58,59 these findings highlight the importance of evaluating these strategies using carefully constructed and clinically relevant animal models of infection.…”

“…57 The potential to target CD40 therapeutically is highlighted by studies showing that treatment of mice with disseminated or intracerebral cryptococcal infection with an agonist antibody to CD40 in combination with IL-2 improves survival. 58,59 In this study, we used gene-targeted CD40-deficient mice (on a C57BL/6 genetic background), a clinically relevant model, and assessments of immune function and histopathology in the lung to identify two unique roles for the CD40-signaling pathway in response to persistent cryptococcal lung infection.…”