Modulating host immune responses to fight invasive fungal infections

Abstract

Modulation of host immunity in invasive fungal infection is an appealing but as yet mostly elusive treatment strategy. Animal studies in invasive candidiasis and aspergillosis have demonstrated beneficial effects of colony stimulating factors, interferon-gamma and monoclonal antibodies. More recent studies transfusing leukocytes pre-loaded with lipophilic anti-fungal drugs, or modulated T-cells, along with novel vaccination strategies show great promise. The translation of immune therapies into clinical studies has been limited to date but this is changing and the results of new Candida vaccine trials are eagerly awaited. Immune modulation in HIV-associated mycoses remains complicated by the risk of immune reconstitution inflammatory syndrome and although exogenous interferon-gamma therapy may be beneficial in cryptococcal meningitis, early initiation of anti-retroviral therapy leads to increased mortality. Further study is required to better target protective immune responses.

Protective effect of fungal extracellular vesicles against murine candidiasis

“…Considering that systemic candidiasis is usually associated with altered immune status, such as neutrophil or CD4 + T cells immunodeficiencies, adjunctive therapies that stimulate effector functions in the immune response are potential alternatives (Cassone, 2013;Cassone & Rappuoli, 2010;Kullberg & van de Veerdonk, 2014;Scriven, Tenforde, Levitz, & Jarvis, 2017). This stimulation should be specially effective when the pre-existing immunity is modified or strongly reduced by immunosuppressing conditions (Cassone, 2013).…”

Innate Inspiration: Antifungal Peptides and Other Immunotherapeutics From the Host Immune Response

“…Another small study (8 patients with leukaemia (n = 7) or breast cancer (n = 1) demonstrated that adjuvant therapy with G-CSF in addition to amphotericin B resulted in cure (n = 4), partial response (n = 2) or failure (n = 2), indicating potential utility of G-CSF in resolving fungal infection in patients with malignancy (350). In another study, G-CSF in combination with fluconazole resulted in faster infection resolution in nonneutropenic patients with invasive candidiasis/candidemia (324,351). Treatment with G-CSF before chemotherapy resulted in a dose-dependent increase in the number of neutrophils and treatment after chemotherapy initiation reduced the number of days on which the neutrophil count was ≤1,000/µl, the number of days on which antibiotics were used to treat fever and the incidence and severity of mucositis was decreased (352).…”

“…In cases of invasive aspergillosis or systemic candidiasis, clinical practice guidelines recommend reduction or reversal of immune suppression ( 31 , 322 , 323 ), but in many cases this is simply not feasible due to the initial pathology in cases of stem cell malignancy. In some cases, the reversal of immune suppression can result in immune reconstitution inflammatory syndrome (IRIS), causing increased morbidity and mortality due to “cytokine storm” and an exaggerated host inflammatory response ( 324 , 325 ). Identifying patients, therefore, for whom particular antifungal immunotherapies are appropriate is critical.…”

Immunomodulation for the Treatment of Fungal Infections: Opportunities and Challenges

“…GM-CSF stimulates maturation of dendritic cells from monocyte precursors, differentiation of macrophages, and proliferation and activation of macrophages, monocytes, neutrophils, eosinophils, dendritic cells, and microglia (Shiomi and Usui, 2015 ). In this regard, GM-CSF has a theoretical advantage against wide range of fungal pathogens for which host defense is dependent on both neutrophil and macrophage function (Shiomi and Usui, 2015 ; Scriven et al, 2017 ). In a study by Giles et al prophylaxis with GM-CSF for patients receiving chemotherapy to treat acute myelogenous leukemia led to a lower frequency of fatal fungal infections (1.9%) as compared to placebo (19%) (Giles, 1998 ).…”