Immunity to Invasive Fungal Diseases

Casadevall, Arturo

doi:10.1146/annurev-immunol-101220-034306

“…Individuals most at risk include HIV/AIDS patients ( 3 – 5 ), cancer patients receiving chemotherapy ( 6 , 7 ), solid organ transplant recipients ( 8 – 10 ), or patients taking medication to control chronic diseases ( 11 – 14 ). Unlike most fungi that do not infect humans, the pathogenicity of invasive fungal species begins with the ability to grow and replicate at human body temperature ( 15 , 16 ), which suggests that climate change, particularly global warming, may play a role in increasing infections from environmental fungi in more temperate climates ( 17 – 19 ). The incidence of invasive fungal infections is expected to further increase as the global immunocompromised population continues to rise due to novel immunosuppressive therapies or comorbidities, such as the current COVID-19 pandemic ( 20 – 25 ).…”

Section: Introductionmentioning

confidence: 99%

Three Models of Vaccination Strategies Against Cryptococcosis in Immunocompromised Hosts Using Heat-Killed Cryptococcus neoformans Δsgl1

Normile

¹

,

Poeta

²

2022

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Vaccines are one of the greatest medical accomplishments to date, yet no fungal vaccines are currently available in humans mainly because opportunistic mycoses generally occur during immunodeficiencies necessary for vaccine protection. In previous studies, a live, attenuated Cryptococcus neoformans Δsgl1 mutant accumulating sterylglucosides was found to be avirulent and protected mice from a subsequent lethal infection even in absence of CD4+ T cells, a condition most associated with cryptococcosis (e.g., HIV). Here, we tested three strategies of vaccination against cryptococcosis. First, in our preventative model, protection was achieved even after a 3-fold increase of the vaccination window. Second, because live C. neoformans Δsgl1-vaccinated mice challenged more than once with WT strain had a significant decrease in lung fungal burden, we tested C. neoformans Δsgl1 as an immunotherapeutic. We found that therapeutic administrations of HK C. neoformans Δsgl1 post WT challenge significantly improves the lung fungal burden. Similarly, therapeutic administration of HK C. neoformans Δsgl1 post WT challenge resulted in 100% or 70% survival depending on the time of vaccine administration, suggesting that HK Δsgl1 is a robust immunotherapeutic option. Third, we investigated a novel model of vaccination in preventing reactivation from lung granuloma using C. neoformans Δgcs1. Remarkably, we show that administration of HK Δsgl1 prevents mice from reactivating Δgcs1 upon inducing immunosuppression with corticosteroids or by depleting CD4+ T cells. Our results suggest that HK Δsgl1 represents a clinically relevant, efficacious vaccine that confers robust host protection in three models of vaccination against cryptococcosis even during CD4-deficiency.

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“…Neutrophils are critical against fungus. The immunocompromise could significantly increase the prevalence of fungal diseases [ 25 ]. Neutropenia, caused by the disease itself or chemotherapy, and both duration and severity increase the infection risk.…”

Section: Discussionmentioning

confidence: 99%

Antifungal Strategy in Patients with Invasive Fungal Disease Associated with Hematological Malignancies Based on Risk Stratification

Chen

¹

,

Luo

²

,

Chen

³

et al. 2022

Canadian Journal of Infectious Diseases and Medical Microbiolog

0

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Patients with hematological malignancies (HM) often develop the invasive fungal disease (IFD), causing important morbidity/mortality. While treatment guidelines are available, risk stratification models for optimizing antifungal therapy strategies are few. Clinical records from 458 HM patients with IFD were retrospectively analyzed. Following Chinese treatment guidelines, patients received empirical (n = 239) or diagnostic-driven therapy (n = 219). The effectiveness rate was 87.9% for the empirical and 81.7% for the diagnostic-driven therapy groups ( P ≥ 0.05 ). The incidence of adverse reactions was 18.4% and 16.9%, respectively ( P ≥ 0.05 ). All risk factors of IFD in HM patients were estimated in the univariate analyses and multivariate analyses by the chi-square test and logistic regression model. Duration ≥14 days (OR = 18.340, P = 0.011 ), relapsed/refractory disease (OR = 11.670, P = 0.005 ), IFD history (OR = 5.270, P = 0.021 ), and diabetes (OR = 3.120, P = 0.035 ) were significantly associated with IFD in the multivariate analysis. Patients with more than 3 of these factors have a significant difference in effective rates between the empirical (85.7%) and diagnostic-driven (41.6%) therapy ( P = 0.008 ). Empirical and diagnostic-driven therapy effective rates were 80.6% and 70.9% in the patients with two risk factors ( P > 0.05 ) and 85.1% and 85.4% in the patients with one risk factor ( P > 0.05 ). Thus, there was no significant difference in effectiveness in patients with one or two risk factors. The abovementioned risk stratification can guide clinical antifungal therapy. The patients with 3 or more risk factors benefit from empirical therapy.

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“…Because macrophages and neutrophils have been reported to be important for the antifungal immunity by phagocytosis and killing mechanisms [4,6,19,24], we thus hypothesized that macrophages and/or neutrophils might mediate the detrimental effect of PGRN on fungal clearance at a later time (day 9, Figs 2EE and 6C and 7H). These results suggest that both macrophages and neutrophils mediated the beneficial effects of PGRN loss upon C.albicans sepsis.…”

Section: Pgrn Negatively Regulated Antifungal Activity Of Macrophages...mentioning

confidence: 99%

“…The host immunity directs the protection against IC in two main ways: clearance of invading fungi and inhibition of fatal infection-related inflammation and damage [4]. C-type lectin receptors (CLRs), such as Dectin-1, Dectin-2, and Mincle, expressed on host immune cells including macrophages and neutrophils, recognize fungal cell wall constituents such as β-glucans, α-mannans, and glycolipids, which initiates the downstream signaling cascades critical for host immunity against IC [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Progranulin aggravates lethal Candida albicans sepsis by regulating inflammatory response and antifungal immunity

Liu

¹

,

Lai

²

,

Yu

³

et al. 2022

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Candida albicans is the most frequent pathogen of fungal sepsis associated with substantial mortality in critically ill patients and those who are immunocompromised. Identification of novel immune-based therapeutic targets from a better understanding of its molecular pathogenesis is required. Here, we reported that the production of progranulin (PGRN) levels was significantly increased in mice after invasive C.albicans infection. Mice that lacked PGRN exhibited attenuated kidney injury and increased survival upon a lethal systemic infection with C. albicans. In mice, PGRN deficiency protected against systemic candidiasis by decreasing aberrant inflammatory reactions that led to renal immune cell apoptosis and kidney injury, and by enhancing antifungal capacity of macrophages and neutrophils that limited fungal burden in the kidneys. PGRN in hematopoietic cell compartment was important for this effect. Moreover, anti-PGRN antibody treatment limited renal inflammation and fungal burden and prolonged survival after invasive C. albicans infection. In vitro, PGRN loss increased phagocytosis, phagosome formation, reactive oxygen species production, neutrophil extracellular traps release, and killing activity in macrophages or neutrophils. Mechanistic studies demonstrated that PGRN loss up-regulated Dectin-2 expression, and enhanced spleen tyrosine kinase phosphorylation and extracellular signal-regulated kinase activation in macrophages and neutrophils. In summary, we identified PGRN as a critical factor that contributes to the immunopathology of invasive C.albicans infection, suggesting that targeting PGRN might serve as a novel treatment for fungal infection.

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Immunity to Invasive Fungal Diseases

Cited by 49 publications

References 132 publications

Three Models of Vaccination Strategies Against Cryptococcosis in Immunocompromised Hosts Using Heat-Killed Cryptococcus neoformans Δsgl1

Three Models of Vaccination Strategies Against Cryptococcosis in Immunocompromised Hosts Using Heat-Killed Cryptococcus neoformans Δsgl1

Antifungal Strategy in Patients with Invasive Fungal Disease Associated with Hematological Malignancies Based on Risk Stratification

Progranulin aggravates lethal Candida albicans sepsis by regulating inflammatory response and antifungal immunity

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