Reinforcing the Immunocompromised Host Defense against Fungi: Progress beyond the Current State of the Art

Karavalakis, Georgios; Yannaki, Evangelia; Παπαδοπούλου, Αναστασία

doi:10.3390/jof7060451

Cited by 8 publications

(7 citation statements)

References 146 publications

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“…Finally, the autophagy machinery has already been suggested as a target for HDT design against several infections [ 11 , 13 ]. For example, autophagy processes are crucial in the defense against mycobacteria [ 68 ], and have been proposed as potential HDTs to fight drug-resistant tuberculosis [ 69 ], one of the most common IA comorbidities.…”

Section: Discussionmentioning

confidence: 99%

Stimulating the autophagic-lysosomal axis enhances host defense against fungal infection in a zebrafish model of invasive Aspergillosis

et al. 2022

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The increasing prevalence of antifungal-resistant human pathogenic fungi, particularly azole-resistant Aspergillus fumigatus , is a life-threatening challenge to the immunocompromised population. Autophagy-related processes such as LC3-associated phagocytosis have been shown to be activated in the host response against fungal infection, but their overall effect on host resistance remains uncertain. To analyze the relevance of these processes in vivo , we used a zebrafish animal model of invasive Aspergillosis. To confirm the validity of this model to test potential treatments for this disease, we confirmed that immunosuppressive treatments or neutropenia rendered zebrafish embryos more susceptible to A. fumigatus . We used GFP-Lc3 transgenic zebrafish to visualize the autophagy-related processes in innate immune phagocytes shortly after phagocytosis of A. fumigatus conidia, and found that both wild-type and melanin-deficient conidia elicited Lc3 recruitment. In macrophages, we observed GFP-Lc3 accumulation in puncta after phagocytosis, as well as short, rapid events of GFP-Lc3 decoration of single and multiple conidia-containing vesicles, while neutrophils covered single conidia-containing vesicles with bright and long-lasting GFP-Lc3 signal. Next, using genetic and pharmacological stimulation of three independent autophagy-inducing pathways, we showed that the antifungal autophagy response improves the host survival against A. fumigatus infection, but only in the presence of phagocytes. Therefore, we provide proof-of-concept that stimulating the (auto)phagolysosomal pathways is a promising approach to develop host-directed therapies against invasive Aspergillosis, and should be explored further either as adjunctive or stand-alone therapy for drug-resistant Aspergillus infections. Abbreviations: DMSO: dimethyl sulfoxide; HR: hazard ratio; HDT: host-directed therapy; Hpf: hours post fertilization; IA: invasive Aspergillosis; LAP: LC3-associated phagocytosis; MTZ: metronidazole; PTU: N-phenylthiourea; ROS: reactive oxygen species.

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Section: Discussionmentioning

confidence: 99%

Stimulating the autophagic-lysosomal axis enhances host defense against fungal infection in a zebrafish model of invasive Aspergillosis

et al. 2022

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“…Pneumonia is the most common manifestation of IM in patients with severe immunosuppression (1,2). As immunological recovery is a major determinant of therapeutic success (3,4), facile adjunct immune enhancement strategies are a major unmet need to improve the detrimental outcomes of invasive mold infections (5,6). Although cellular immune therapeutics such as adoptive T-cell transfer yielded promising results in-vitro and in animal models of IM (7)(8)(9), the clinical translation of these approaches is hampered by feasibility concerns (e.g., time-consuming production of cellular products), high cost, and regulatory obstacles (3,5,10).…”

Section: Introductionmentioning

confidence: 99%

Blockade of the PD-1/PD-L1 Immune Checkpoint Pathway Improves Infection Outcomes and Enhances Fungicidal Host Defense in a Murine Model of Invasive Pulmonary Mucormycosis

et al. 2022

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Anecdotal clinical reports suggested a benefit of adjunct immune checkpoint inhibitors (ICIs) to treat invasive mucormycosis. However, proof-of-concept data in animal models and mechanistic insights into the effects of ICIs on host defense against Mucorales are lacking. Therefore, we studied the effects of PD-1 and PD-L1 inhibitors (4 doses of 250 µg/kg) on outcomes and immunopathology of invasive pulmonary mucormycosis (IPM) in cyclophosphamide- and cortisone acetate-immunosuppressed mice. Rhizopus arrhizus-infected mice receiving either of the ICI treatments had significantly improved survival, less morbidity, and lower fungal burden compared to isotype-treated infected mice. While early improvement of morbidity/mortality was comparable between the ICI treatments, anti-PD-L1 provided more consistent sustained protection through day 7 post-infection than anti-PD-1. Both ICIs enhanced the fungicidal activity of ex-vivo splenocytes and effectively counteracted T-cell exhaustion; however, macrophages of ICI-treated mice showed compensatory upregulation of other checkpoint markers. Anti-PD-1 elicited stronger pulmonary release of proinflammatory cytokines and chemokines than anti-PD-L1, but also induced cytokines associated with potentially unfavorable type 2 T-helper-cell and regulatory T-cell responses. Although no signs of hyperinflammatory toxicity were observed, mice with IPM receiving ICIs, particularly anti-PD-1, had elevated serum levels of IL-6, a cytokine linked to ICI toxicities. Altogether, inhibition of the PD-1/PD-L1 pathway improved clinical outcomes of IPM in immunosuppressed mice, even without concomitant antifungals. PD-L1 inhibition yielded more favorable immune responses and more consistent protection from IPM-associated morbidity and mortality than PD-1 blockade. Future dose-effect studies are needed to define the “sweet spot” between ICI-induced augmentation of antifungal immunity and potential immunotoxicities.

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“…Over the past 20 years, many groups designed cellular immune therapeutics to restore and augment antifungal immunity, including adoptive T cell transfer, chimeric antigen receptor T cells, ex-vivo -pulsed dendritic cells (DCs), and azole-loaded neutrophils ( 7 – 12 ). However, despite a multitude of promising preclinical data, only few of these approaches eventually entered small-scale clinical studies, which is not surprising, as cellular immune therapeutics are costly, difficult to scale, time- and labor-intensive, logistically challenging, and subject to considerable regulatory hurdles ( 11 , 12 ). These obstacles for clinical translation of cellular immune therapeutics have reinvigorated the interest in non-cellular immune enhancement strategies to bolster host defense against opportunistic pathogens ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

“…However, despite a multitude of promising preclinical data, only few of these approaches eventually entered small-scale clinical studies, which is not surprising, as cellular immune therapeutics are costly, difficult to scale, time- and labor-intensive, logistically challenging, and subject to considerable regulatory hurdles ( 11 , 12 ). These obstacles for clinical translation of cellular immune therapeutics have reinvigorated the interest in non-cellular immune enhancement strategies to bolster host defense against opportunistic pathogens ( 12 ). For instance, recombinant interferon-gamma (IFN-γ), a cytokine that is considered a pivotal driver of protective antifungal immunity, has been studied as an adjunct immune-stimulatory therapy in patients with IFIs ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

Checkpoint inhibitors as immunotherapy for fungal infections: Promises, challenges, and unanswered questions

2022

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Opportunistic fungal infections have high mortality in patients with severe immune dysfunction. Growing evidence suggests that the immune environment of invasive fungal infections and cancers share common features of immune cell exhaustion through activation of immune checkpoint pathways. This observation gave rise to several preclinical studies and clinical case reports describing blockade of the Programmed Cell Death Protein 1 and Cytotoxic T-Lymphocyte Antigen 4 immune checkpoint pathways as an adjunct immune enhancement strategy to treat opportunistic fungal infections. The first part of this review summarizes the emerging evidence for contributions of checkpoint pathways to the immunopathology of fungal sepsis, opportunistic mold infections, and dimorphic fungal infections. We then review the potential merits of immune checkpoint inhibitors (ICIs) as an antifungal immunotherapy, including the incomplete knowledge of the mechanisms involved in both immuno-protective effects and toxicities. In the second part of this review, we discuss the limitations of the current evidence and the many unknowns about ICIs as an antifungal immune enhancement strategy. Based on these gaps of knowledge and lessons learned from cancer immunology studies, we outline a research agenda to determine a “sweet spot” for ICIs in medical mycology. We specifically discuss the importance of more nuanced animal models, the need to study ICI-based combination therapy, potential ICI resistance, the role of the immune microenvironment, and the impact of ICIs given as part of oncological therapies on the natural immunity to various pathogenic fungi.

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Reinforcing the Immunocompromised Host Defense against Fungi: Progress beyond the Current State of the Art

Cited by 8 publications

References 146 publications

Stimulating the autophagic-lysosomal axis enhances host defense against fungal infection in a zebrafish model of invasive Aspergillosis

Stimulating the autophagic-lysosomal axis enhances host defense against fungal infection in a zebrafish model of invasive Aspergillosis

Blockade of the PD-1/PD-L1 Immune Checkpoint Pathway Improves Infection Outcomes and Enhances Fungicidal Host Defense in a Murine Model of Invasive Pulmonary Mucormycosis

Checkpoint inhibitors as immunotherapy for fungal infections: Promises, challenges, and unanswered questions

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