Search

Emerging fungal pathogens pose a greater threat to biodiversity than any other parasitic group (1), causing declines of many taxa, including bats, corals, bees, snakes and amphibians (1-4). Currently, there [...]

Fungal infections in CD4+ T cell immunocompromised patients have risen sharply in recent years. Although vaccines offer a rational avenue to prevent infections, there are no licensed fungal vaccines available. Inactivated vaccines are safer but less efficacious and require adjuvants that may undesirably bias toward poor protective immune responses. We hypothesized that reducing the TCR signaling threshold could potentiate antifungal CD8+ T cell responses and immunity to inactivated vaccine in the absence of CD4+ T cells. In this study, we show that CBLB, a negative regulator of TCR signaling, suppresses CD8+ T cells in response to inactivated fungal vaccination in a mouse model of CD4+ T cell lymphopenia. Conversely, Cblb deficiency enhanced both the type 1 (e.g., IFN-γ) and type 17 (IL-17A) CD8+ T cell responses to inactivated fungal vaccines and augmented vaccine immunity to lethal fungal pneumonia. Furthermore, we show that immunization with live or inactivated vaccine yeast did not cause detectable pathologic condition in Cblb-/- mice. Augmented CD8+ T cell responses in the absence of CBLB also did not lead to terminal differentiation or adversely affect the expression of transcription factors T-bet, Eomes, and RORγt. Additionally, our adoptive transfer experiments showed that CBLB impedes the effector CD8+ T cell responses in a cell-intrinsic manner. Finally, we showed that ablation of Cblb overcomes the requirement of HIF-1α for expansion of CD8+ T cells upon vaccination. Thus, adjuvants that target CBLB may augment inactivated vaccines and immunity against systemic fungal infections in vulnerable patients. [ABSTRACT FROM AUTHOR]

The chytrid fungus, Batrachochytrium dendrobatidis, causes chytridiomycosis and is a major contributor to global amphibian declines. Although amphibians have robust immune defenses, clearance of this pathogen is impaired. Because inhibition of host immunity is a common survival strategy of pathogenic fungi, we hypothesized that B. dendrobatidis evades clearance by inhibiting immune functions. We found that B. dendrobatidis cells and supernatants impaired lymphocyte proliferation and induced apoptosis; however, fungal recognition and phagocytosis by macrophages and neutrophils was not impaired. Fungal inhibitory factors were resistant to heat, acid, and protease. Their production was absent in zoospores and reduced by nikkomycin Z, suggesting that they may be components of the cell wall. Evasion of host immunity may explain why this pathogen has devastated amphibian populations worldwide. [ABSTRACT FROM AUTHOR]

Fungal infections in CD4 + T cell immunocompromised patients have risen sharply in recent years. Although vaccines offer a rational avenue to prevent infections, there are no licensed fungal vaccines available. Inactivated vaccines are safer but less efficacious and require adjuvants that may undesirably bias toward poor protective immune responses. We hypothesized that reducing the TCR signaling threshold could potentiate antifungal CD8 + T cell responses and immunity to inactivated vaccine in the absence of CD4 + T cells. In this study, we show that CBLB, a negative regulator of TCR signaling, suppresses CD8 + T cells in response to inactivated fungal vaccination in a mouse model of CD4 + T cell lymphopenia. Conversely, Cblb deficiency enhanced both the type 1 (e.g., IFN-γ) and type 17 (IL-17A) CD8 + T cell responses to inactivated fungal vaccines and augmented vaccine immunity to lethal fungal pneumonia. Furthermore, we show that immunization with live or inactivated vaccine yeast did not cause detectable pathologic condition in Cblb -/- mice. Augmented CD8 + T cell responses in the absence of CBLB also did not lead to terminal differentiation or adversely affect the expression of transcription factors T-bet, Eomes, and RORγt. Additionally, our adoptive transfer experiments showed that CBLB impedes the effector CD8 + T cell responses in a cell-intrinsic manner. Finally, we showed that ablation of Cblb overcomes the requirement of HIF-1α for expansion of CD8 + T cells upon vaccination. Thus, adjuvants that target CBLB may augment inactivated vaccines and immunity against systemic fungal infections in vulnerable patients., (Copyright © 2018 by The American Association of Immunologists, Inc.)

The dermal granular glands of the South African clawed frog, Xenopus laevis, contain antimicrobial peptides (AMPs) that are secreted following local nerve stimulation. These natural antibiotics are active against bacteria and fungi including Batrachochytrium dendrobatidis, a fungal pathogen that causes the skin disease chytridiomycosis. Granular gland secretion can be stimulated in the laboratory by norepinephrine injection. We found that two injections of 80nmol/g norepinephrine were necessary to fully deplete the AMP stores. One injection resulted in the secretion of most of the stored peptides. A second injection, 2 days later, released a small amount of additional AMPs that are not compositionally different from those released by the first injection. A third injection, 4 days after the first, did not result in further AMP release. Mass spectrometry and histology confirmed that glands are depleted after two injections. Periodic acid-Schiff staining indicated that mucus gland secretion was also induced by norepinephrine., (Copyright © 2011 Elsevier Ltd. All rights reserved.)