C5‐C5aR1‐mediated immune responses during fungal infection: Clinical and translational implications DOI Creative Commons
Jigar V. Desai, Michail S. Lionakis

Clinical and Translational Medicine, Год журнала: 2023, Номер 13(9)

Опубликована: Сен. 1, 2023

Systemic fungal infections continue to pose a substantial health challenge worldwide, resulting in considerable morbidity and mortality. These primarily affect immunocompromised patient populations, which are continuously expanding, part due the increasing use of immune pathway-targeting biologics for treatment neoplastic autoimmune disorders.1 Available antifungal treatments limited their vivo effectiveness, often accompanied by significant side effects. Hence, there is an unmet need better understand mechanisms our system combats such infections, as this could lead development personalized risk stratification, prognostication, vaccination therapeutic strategies improve outcomes.2 As pivotal component innate immunity, complement comprises complex network effector proteins that contribute opsonization, inflammation bacterial lysis, providing crucial line defense against pathogens.3 Indeed, patients with inherited deficiency or pharmacological blockade C5 at-risk developing life-threatening systemic encapsulated bacteria meningococcus pneumococcus.4, 5 We recently examined role C5a-C5aR1 axis context infections.6 This research emerged from unexpected clinical finding opportunistic -such candidiasis aspergillosis- receiving Food Drug Administration (FDA)-approved, C5-targeting monoclonal antibody, eculizumab,5, 7 highlighted unanticipated critical host defense. In work, we used several orthogonal vitro, murine human studies analyses demonstrate anaphylatoxin chemoattractant C5a licensing myeloid phagocytes exert sterilizing immunity during via engaging its cognate receptor C5aR1.6 By employing well-established model phagocyte-dependent responses effective kidney primary target organ,2, 8 found essential promoting tissue clearance survival, whereas C5aR2, other receptor, was dispensable.6 Mechanistically, redundant recruitment neutrophils monocytes infected tissue. contrast, accumulation renal macrophages after infection Extracellular signal-regulated kinase (ERK)- Protein B (AKT)-mediated survival through C5a-driven inhibition caspase-dependent apoptosis pyroptosis (Figure 1).6 expands upon previous reports have implicated signaling cell survival.9, 10 Moreover, orchestrating certain functions kidney. Specifically, mediated uptake -via enhancing expression bona fide phagocytic receptors Dectin-1 FcγR1- promoted non-oxidative killing 1), neutrophil extracellular trap formation, macrophage were intact setting C5aR1 deficiency.6 Two additional notable mechanistic insights arose work. First, resulted metabolic rewiring macrophages, exhibited increased glycolysis enhanced mTOR vivo. Pharmacological targeting FDA-approved drug, rapamycin, ameliorated defect, improved function following Second, beyond well-recognized hepatocyte-derived antimicrobial activity, study unveiled contribution produced locally defense, mice lacking specifically burden decreased Candida infection.6 represents first direct demonstration involvement extrahepatic, cell-intrinsic, intracellular production on previously reported settings sterile infection-related immunopathology.11-13 Additional required further define roles production, termed ‘the complosome’, molecular regulation non-infectious inflammatory conditions. Furthermore, establish potential relevance these discoveries, employed experimental approaches translate mouse findings into context. evaluated inhibitor, avacopan, showed avacopan-exposed monocyte-derived same functional defects observed C5aR1-deficient phagocytes.6 parallel functionality strengthens link between suggests avacopan may heighten similarly eculizumab. identified transcriptional module markedly induced candidemic highly predictive candidemia hospitalized patients.6 deepens understanding response shows promise eventual immune-based tools existing diagnostic platforms candidemia. Third, demonstrated independent correlation suboptimal serum levels at time diagnosis underscores system's combating emphasizes importance measuring individualized prognostication strategy patients. Fourth, single nucleotide polymorphism (SNP) gene associated mRNA blood leukocytes poor outcomes patients, namely persistent fungemia.6 genetic variation highlights interplay genetics susceptibility infections14-17 uncovers SNP factor assessment summary, important implications pathogenesis, treatment. They shed light vital activating phagocytes, drives infections. The module, collectively provide foundation devising introduction practice C3, also shown be study,6 increase vulnerable thereby warranting awareness, vigilance surveillance. work supported Division Intramural Research, National Institute Allergy Infectious Diseases: ZIA AI001175. authors declare no conflict interest exists.

Язык: Английский

Cryptococcal Disease in Diverse Hosts DOI
David B. Meya, Peter R. Williamson

New England Journal of Medicine, Год журнала: 2024, Номер 390(17), С. 1597 - 1610

Опубликована: Май 1, 2024

Язык: Английский

Процитировано

21
BTK drives neutrophil activation for sterilizing antifungal immunity DOI Creative Commons
Jigar V. Desai,

Marissa A. Zarakas,

Andrew Wishart

и другие.

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(12)

Опубликована: Май 2, 2024

We describe a previously-unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used treating B-cell lymphoid malignancies. studied BTK-dependent responses neutrophils from diverse populations, including healthy donors, BTKi-treated patients, and X-linked agammaglobulinemia patients. Upon exposure, was activated human TLR2-, Dectin-1-, FcγR-dependent manner, triggering the oxidative burst. inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, fungus-induced burst by abrogating NADPH oxidase subunit p40phox GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion mice enhanced aspergillosis susceptibility impairing neutrophil function, not recruitment or lifespan. Conversely, GM-CSF partially mitigated these deficits enhancing p47phox Our findings underline crucial signaling antifungal immunity provide rationale use offset susceptible

Язык: Английский

Процитировано

7
The Antifungal Potential of Niclosamide and Structurally Related Salicylanilides DOI Open Access
Bernhard Biersack

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(11), С. 5977 - 5977

Опубликована: Май 29, 2024

Human mycoses cover a diverse field of fungal diseases from skin disorders to systemic invasive infections and pose an increasing global health problem based on ineffective treatment options, the hampered development new efficient drugs, emergence resistant strains. Niclosamide is currently applied for worm infections. Its mechanisms action, which include suppression mitochondrial oxidative phosphorylation (also known as uncoupling), among others, has led repurposing this promising anthelmintic drug therapy further human such cancer, diabetes, microbial Given urgent need develop drugs against infections, considerable antifungal properties niclosamide are highlighted in review. chemical pharmacological relevant also briefly mentioned, described mitochondria-targeting action add current arsenal approved drugs. In addition, activities salicylanilide-based analogs pathogens, including agents veterinary medicine many years, discussed their feasibility antifungals humans. Preliminary structure-activity relationships determined discussed. Various salicylanilide derivatives with showed increased oral bioavailabilities when compared niclosamide. The simple synthesis vouchsafes broad cost-effective availability poorer patient groups. Pertinent literature covered until 2024.

Язык: Английский

Процитировано

6
Antifungal immunity: advances in PRR recognition, adaptive responses, and immune-based therapies DOI
Jianlin Zhou, Xinjie Lu,

Rui-Rui He

и другие.

Science China Life Sciences, Год журнала: 2025, Номер unknown

Опубликована: Март 5, 2025

Язык: Английский

Процитировано

0
Human immunity to fungal infections DOI
Donald C. Vinh

The Journal of Experimental Medicine, Год журнала: 2025, Номер 222(6)

Опубликована: Апрель 15, 2025

Fungi increasingly threaten health globally. Mycoses range from life-threatening, often iatrogenic conditions, to enigmatic syndromes occurring without apparent immunosuppression. Despite some recent advances in antifungal drug development, complementary therapeutic strategies are essential for addressing these opportunistic pathogens. One promising avenue is leveraging host immunity combat fungal infections; this necessitates deeper understanding of the molecular immunology human susceptibility differentiate beneficial versus harmful immunopathological responses. Investigating models diseases natural settings, particularly through genetic immunodeficiencies and ethnographic-specific vulnerabilities, reveals crucial immune pathways fighting various yeasts molds. This review highlights diversity intrinsic across individuals populations, genetic- autoantibody-mediated processes, complementing previous principles learned animal studies contexts. Improved will facilitate development host-directed immunotherapies targeted public interventions, paving way precision medicine disease management.

Язык: Английский

Процитировано

0
Bioinformatics-Driven mRNA-Based Vaccine Design for Controlling Tinea Cruris Induced by Trichophyton rubrum DOI Creative Commons
Amir Elalouf, Hanan Maoz,

Amit Yaniv Rosenfeld

и другие.

Pharmaceutics, Год журнала: 2024, Номер 16(8), С. 983 - 983

Опубликована: Июль 25, 2024

Tinea cruris, a dermatophyte fungal infection predominantly caused by

Язык: Английский

Процитировано

2
Host defense mechanisms against Candida auris DOI

Joseph Pechacek,

Michail S. Lionakis

Expert Review of Anti-infective Therapy, Год журнала: 2023, Номер 21(10), С. 1087 - 1096

Опубликована: Сен. 27, 2023

ABSTRACTIntroduction Candida auris is a pathogen of growing public health concern given its rapid spread across the globe, propensity for long-term skin colonization and healthcare-related outbreaks, resistance to variety antifungal medications, high morbidity mortality associated with invasive disease. Despite that, host immune response mechanisms that operate during C. infection remains poorly understood.Areas covered In this manuscript, we review available literature in research field pertaining defenses discuss what known about ability thrive on mammalian skin, role lymphoid cell-mediated, IL-17-dependent controlling cutaneous colonization, contribution myeloid phagocytes curtailing systemic infection.Expert opinion Understanding by which system responds controls developing deeper knowledge tissue-specific host-C. interactions immune-evading may help devise improved strategies decolonization, prognostication, prevention, vaccination, and/or directed treatment vulnerable patient populations.KEYWORDS: aurisyeastfungal infectionIL-17phagocytesemerging pathogenskin Article highlights persistently colonize human environmental surfaces thereby cause outbreaks healthcare settings, as well due prevalence conventional agents.C. grows avidly sweat conditions where it forms multilayer, complex biofilms. Concordantly, effective has been demonstrated porcine models ex vivo mouse model epicutaneous application vivo.IL-17A IL-17F production innate adaptive cells critical accelerating fungal clearance skin. Yet, despite induction potent protective local IL-17 responses, can persist murine surface tissue compartments including hair follicles, potentially concealing detection routine clinical surveillance diagnostic methods.C. exhibits unique mannan structure relative albicans. This a) underlie dependence different C-type lectin receptors (i.e., complement receptor 3 mannose versus Dectin-1) recognition pro-inflammatory cytokine mononuclear albicans b) enable evasion from neutrophil effector functions such uptake, killing, extracellular trap formation.Different strains various geographic clades seem elicit highly variable transcriptional activities monocytes/macrophages. Comparative evaluation large collection will be needed precisely define stain-dependent differences mounting responses phagocyte subsets. • Hyr1p-targeted Als3-based decrease burden auris-infected mice animal hematogenous disseminated candidiasis. These findings show promise eventual development preventive therapeutic interventions patients.Declaration interestsThe authors have no relevant affiliations or financial involvement any organization entity interest conflict subject matter material discussed manuscript. includes employment, consultancies, honoraria, stock ownership options, expert testimony, grants patents received mending, royalties.Reviewer disclosuresPeer reviewers manuscript other relationships disclose.Author contributionsAll substantially contributed conception design article interpreting were involved writing revising intellectual content.Additional informationFundingThis paper was funded Division Intramural Research, National Institute Allergy Infectious Diseases (ZIA AI001175)

Язык: Английский

Процитировано

3
Managing infectious challenges in the age of molecular‐targeted therapies for adult hematological malignancies DOI

Manan Shah,

Firas El Chaer, Dora Y. Ho

и другие.

Transplant Infectious Disease, Год журнала: 2024, Номер 26(3)

Опубликована: Май 2, 2024

Abstract Over the last decade, therapeutic landscape for hematological malignancies (HMs) has witnessed a remarkable surge in development of novel biological and small‐molecule‐targeted immunomodulatory agents. These therapies have drastically improved survival, but some come at cost increased risk bacterial, viral, and/or fungal infections on‐target off‐tumor immunological side effects. To mitigate such risks, physicians must be well informed about infectious complications necessary preventive measures, as screening, vaccinations, antimicrobial prophylaxis. Furthermore, should vigilant noninfectious effects these agents that can mimic understand their potential drug–drug interactions with antimicrobials. Strengthening harmonizing current surveillance reporting system drug‐associated real‐world settings is essential to better ascertain associated In this review, we aimed summarize infection risks used specific HMs outline recommended strategies monitoring

Язык: Английский

Процитировано

0
Immune Adjuvant Therapy With Interleukin-7 in a Lymphopenic Patient With Aplastic Anemia and Mucormycosis DOI Creative Commons
Zachary D. Crees, Dilan A. Patel,

Alexandra Dram

и другие.

Critical Care Explorations, Год журнала: 2023, Номер 5(10), С. e0990 - e0990

Опубликована: Окт. 1, 2023

BACKGROUND: We report the case of a patient with aplastic anemia and pancytopenia on immune-suppressive therapy who developed invasive pulmonary infection mucormycosis was treated immune adjuvant therapy. CASE SUMMARY: Given patient's profound lymphopenia progressive mucor despite dual antifungal drug therapy, interleukin (IL)-7, cytokine that induces lymphocyte activation proliferation, instituted resulted in normalization absolute counts temporally associated clearance fungal pathogens resolution clinical symptoms. CONCLUSION: Patients life-threatening infections are frequently suppressed therapies should be considered patients not responding to drugs source control. Well-designed, double-blind, placebo-controlled trials needed advance field. Although number adjuvants may beneficial sepsis, IL-7 is particularly attractive because its broad immunologic effects key pathways mediate enhanced system activity.

Язык: Английский

Процитировано

1
C5‐C5aR1‐mediated immune responses during fungal infection: Clinical and translational implications DOI Creative Commons
Jigar V. Desai, Michail S. Lionakis

Clinical and Translational Medicine, Год журнала: 2023, Номер 13(9)

Опубликована: Сен. 1, 2023

Systemic fungal infections continue to pose a substantial health challenge worldwide, resulting in considerable morbidity and mortality. These primarily affect immunocompromised patient populations, which are continuously expanding, part due the increasing use of immune pathway-targeting biologics for treatment neoplastic autoimmune disorders.1 Available antifungal treatments limited their vivo effectiveness, often accompanied by significant side effects. Hence, there is an unmet need better understand mechanisms our system combats such infections, as this could lead development personalized risk stratification, prognostication, vaccination therapeutic strategies improve outcomes.2 As pivotal component innate immunity, complement comprises complex network effector proteins that contribute opsonization, inflammation bacterial lysis, providing crucial line defense against pathogens.3 Indeed, patients with inherited deficiency or pharmacological blockade C5 at-risk developing life-threatening systemic encapsulated bacteria meningococcus pneumococcus.4, 5 We recently examined role C5a-C5aR1 axis context infections.6 This research emerged from unexpected clinical finding opportunistic -such candidiasis aspergillosis- receiving Food Drug Administration (FDA)-approved, C5-targeting monoclonal antibody, eculizumab,5, 7 highlighted unanticipated critical host defense. In work, we used several orthogonal vitro, murine human studies analyses demonstrate anaphylatoxin chemoattractant C5a licensing myeloid phagocytes exert sterilizing immunity during via engaging its cognate receptor C5aR1.6 By employing well-established model phagocyte-dependent responses effective kidney primary target organ,2, 8 found essential promoting tissue clearance survival, whereas C5aR2, other receptor, was dispensable.6 Mechanistically, redundant recruitment neutrophils monocytes infected tissue. contrast, accumulation renal macrophages after infection Extracellular signal-regulated kinase (ERK)- Protein B (AKT)-mediated survival through C5a-driven inhibition caspase-dependent apoptosis pyroptosis (Figure 1).6 expands upon previous reports have implicated signaling cell survival.9, 10 Moreover, orchestrating certain functions kidney. Specifically, mediated uptake -via enhancing expression bona fide phagocytic receptors Dectin-1 FcγR1- promoted non-oxidative killing 1), neutrophil extracellular trap formation, macrophage were intact setting C5aR1 deficiency.6 Two additional notable mechanistic insights arose work. First, resulted metabolic rewiring macrophages, exhibited increased glycolysis enhanced mTOR vivo. Pharmacological targeting FDA-approved drug, rapamycin, ameliorated defect, improved function following Second, beyond well-recognized hepatocyte-derived antimicrobial activity, study unveiled contribution produced locally defense, mice lacking specifically burden decreased Candida infection.6 represents first direct demonstration involvement extrahepatic, cell-intrinsic, intracellular production on previously reported settings sterile infection-related immunopathology.11-13 Additional required further define roles production, termed ‘the complosome’, molecular regulation non-infectious inflammatory conditions. Furthermore, establish potential relevance these discoveries, employed experimental approaches translate mouse findings into context. evaluated inhibitor, avacopan, showed avacopan-exposed monocyte-derived same functional defects observed C5aR1-deficient phagocytes.6 parallel functionality strengthens link between suggests avacopan may heighten similarly eculizumab. identified transcriptional module markedly induced candidemic highly predictive candidemia hospitalized patients.6 deepens understanding response shows promise eventual immune-based tools existing diagnostic platforms candidemia. Third, demonstrated independent correlation suboptimal serum levels at time diagnosis underscores system's combating emphasizes importance measuring individualized prognostication strategy patients. Fourth, single nucleotide polymorphism (SNP) gene associated mRNA blood leukocytes poor outcomes patients, namely persistent fungemia.6 genetic variation highlights interplay genetics susceptibility infections14-17 uncovers SNP factor assessment summary, important implications pathogenesis, treatment. They shed light vital activating phagocytes, drives infections. The module, collectively provide foundation devising introduction practice C3, also shown be study,6 increase vulnerable thereby warranting awareness, vigilance surveillance. work supported Division Intramural Research, National Institute Allergy Infectious Diseases: ZIA AI001175. authors declare no conflict interest exists.

Язык: Английский

Процитировано

0