scholarly journals In vitro infection models to study fungal-host interactions

2021 ◽  
Author(s):  
Antonia Last ◽  
Michelle Maurer ◽  
Alexander S Mosig ◽  
Mark S Gresnigt ◽  
Bernhard Hube
Keyword(s):  
Fungal Infections ◽  
In Vitro Models ◽  
Fungal Host ◽  
Host Interactions ◽  
Mucosal Surfaces ◽  
Life Threatening ◽  
On Chip ◽  
Fungal Interactions

Abstract Fungal infections (mycoses) affect over a billion people per year. Approximately two million of these infections are life-threatening, especially for patients with a compromised immune system. Fungi of the genera Aspergillus, Candida, Histoplasma, and Cryptococcus are opportunistic pathogens that contribute to a substantial number of mycoses. To optimize the diagnosis and treatment of mycoses, we need to understand the complex fungal-host interplay during pathogenesis, the fungal attributes causing virulence, and how the host resists infection via immunological defenses. In vitro models can be used to mimic fungal infections of various tissues and organs and the corresponding immune responses at near-physiological conditions. Furthermore, models can include fungal interactions with the host-microbiota to mimic the in vivo situation on skin and mucosal surfaces. This article reviews currently used in vitro models of fungal infections ranging from cell monolayers to microfluidic 3D organ-on-chip (OOC) platforms. We also discuss how OOC models can expand the toolbox for investigating interactions of fungi and their human hosts in the future.

scholarly journals Overview of medically important antifungal azole derivatives.

1988 ◽  
Vol 1 (2) ◽  
pp. 187-217 ◽  
Author(s):  
R A Fromtling
Keyword(s):  
Adverse Reactions ◽  
Fungal Infections ◽  
Chemotherapeutic Agents ◽  
Skin Infections ◽  
Life Threatening ◽  
Major Chemical ◽  
Systemic Infections ◽  
Selection Of

Fungal infections are a major burden to the health and welfare of modern humans. They range from simply cosmetic, non-life-threatening skin infections to severe, systemic infections that may lead to significant debilitation or death. The selection of chemotherapeutic agents useful for the treatment of fungal infections is small. In this overview, a major chemical group with antifungal activity, the azole derivatives, is examined. Included are historical and state of the art information on the in vitro activity, experimental in vivo activity, mode of action, pharmacokinetics, clinical studies, and uses and adverse reactions of imidazoles currently marketed (clotrimazole, miconazole, econazole, ketoconazole, bifonazole, butoconazole, croconazole, fenticonazole, isoconazole, oxiconazole, sulconazole, and tioconazole) and under development (aliconazole and omoconazole), as well as triazoles currently marketed (terconazole) and under development (fluconazole, itraconazole, vibunazole, alteconazole, and ICI 195,739).

scholarly journals In Vitro or in Vivo Models, the Next Frontier for Unraveling Interactions between Malassezia spp. and Hosts. How Much do We Know?

2020 ◽  
Author(s):  
Maritza Torres ◽  
Hans De Cock ◽  
Adriana Marcela Celis Ramírez
Keyword(s):  
Galleria Mellonella ◽  
Fungal Infections ◽  
Ex Vivo ◽  
Model Organisms ◽  
In Vivo Models ◽  
Fungal Host ◽  
Alternative Models ◽  
Malassezia Spp

Malassezia is a lipid-dependent genus of yeasts known for being an important part of the skin mycobiota. These yeasts have been associated in the development of skin disorders and cataloged as a causal agent of systemic infections under specific conditions, making them opportunistic pathogens. Little is known about the host-microbe interaction of Malassezia spp., and unraveling this implies the implementation of infection models. In this mini review we present different models that have been implemented in the fungal infections study with greater attention in Malassezia spp. infections. These models range from in vitro (cell cultures and ex vivo tissue), to in vivo (murine models, rabbits, guinea pigs, insects, nematodes, and amoebas). We additionally highlight the alternative models that reduce the use of mammals as model organisms, which have been gaining importance in the study of fungal host-microbe interactions. This is due to the fact that these systems have shown to have reliable results, which correlate with those obtained from mammalian models. Example of alternative models are Caenorhabditis elegans, Drosophila melanogaster, Tenebrio molitor, and Galleria mellonella. These are invertebrates that have been implemented in the study of Malassezia spp. infections in order to identify differences in virulence between Malassezia species.

scholarly journals DC-SIGN targets amphotericin B-loaded liposomes to diverse pathogenic fungi

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Suresh Ambati ◽  
Tuyetnhu Pham ◽  
Zachary A. Lewis ◽  
Xiaorong Lin ◽  
Richard B. Meagher
Keyword(s):  
Amphotericin B ◽  
Fungal Infections ◽  
Pathogenic Fungi ◽  
Antifungal Drugs ◽  
Protein Isoforms ◽  
Viral Pathogens ◽  
Life Threatening ◽  
Better Than

Abstract Background Life-threatening invasive fungal infections are treated with antifungal drugs such as Amphotericin B (AmB) loaded liposomes. Our goal herein was to show that targeting liposomal AmB to fungal cells with the C-type lectin pathogen recognition receptor DC-SIGN improves antifungal activity. DC-SIGN binds variously crosslinked mannose-rich and fucosylated glycans and lipomannans that are expressed by helminth, protist, fungal, bacterial and viral pathogens including three of the most life-threatening fungi, Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans. Ligand recognition by human DC-SIGN is provided by a carbohydrate recognition domain (CRD) linked to the membrane transit and signaling sequences. Different combinations of the eight neck repeats (NR1 to NR8) expressed in different protein isoforms may alter the orientation of the CRD to enhance its binding to different glycans. Results We prepared two recombinant isoforms combining the CRD with NR1 and NR2 in isoform DCS12 and with NR7 and NR8 in isoform DCS78 and coupled them to a lipid carrier. These constructs were inserted into the membrane of pegylated AmB loaded liposomes AmB-LLs to produce DCS12-AmB-LLs and DCS78-AmB-LLs. Relative to AmB-LLs and Bovine Serum Albumin coated BSA-AmB-LLs, DCS12-AmB-LLs and DCS78-AmB-LLs bound more efficiently to the exopolysaccharide matrices produced by A. fumigatus, C. albicans and C. neoformans in vitro, with DCS12-AmB-LLs performing better than DCS78-AmB-LLs. DCS12-AmB-LLs inhibited and/or killed all three species in vitro significantly better than AmB-LLs or BSA-AmB-LLs. In mouse models of invasive candidiasis and pulmonary aspergillosis, one low dose of DCS12-AmB-LLs significantly reduced the fungal burden in the kidneys and lungs, respectively, several-fold relative to AmB-LLs. Conclusions DC-SIGN’s CRD specifically targeted antifungal liposomes to three highly evolutionarily diverse pathogenic fungi and enhanced the antifungal efficacy of liposomal AmB both in vitro and in vivo. Targeting significantly reduced the effective dose of antifungal drug, which may reduce drug toxicity, be effective in overcoming dose dependent drug resistance, and more effectively kill persister cells. In addition to fungi, DC-SIGN targeting of liposomal packaged anti-infectives have the potential to alter treatment paradigms for a wide variety of pathogens from different kingdoms including protozoans, helminths, bacteria, and viruses which express its cognate ligands.

Clinically Relevant Tissue Scale Responses as New Readouts from Organs-on-a-Chip for Precision Medicine

2020 ◽  
Vol 13 (1) ◽  
pp. 111-133 ◽  
Author(s):  
Olivier T. Guenat ◽  
Thomas Geiser ◽  
François Berthiaume
Keyword(s):  
Morphological Changes ◽  
Tissue Level ◽  
In Vitro Models ◽  
Tissue Properties ◽  
Metabolic Functions ◽  
Level Information ◽  
On Chip ◽  
And Function

Organs-on-chips (OOC) are widely seen as being the next generation in vitro models able to accurately recreate the biochemical-physical cues of the cellular microenvironment found in vivo. In addition, they make it possible to examine tissue-scale functional properties of multicellular systems dynamically and in a highly controlled manner. Here we summarize some of the most remarkable examples of OOC technology's ability to extract clinically relevant tissue-level information. The review is organized around the types of OOC outputs that can be measured from the cultured tissues and transferred to clinically meaningful information. First, the creation of functional tissues-on-chip is discussed, followed by the presentation of tissue-level readouts specific to OOC, such as morphological changes, vessel formation and function, tissue properties, and metabolic functions. In each case, the clinical relevance of the extracted information is highlighted.

scholarly journals Innovative In Vitro Models for the Study of Lung Diseases

2020 ◽  
Author(s):  
Vittorio Picchio ◽  
Vittoria Cammisotto ◽  
Francesca Pagano ◽  
Roberto Carnevale ◽  
Isotta Chimenti
Keyword(s):  
In Vitro Models ◽  
New Drugs ◽  
In Vivo Studies ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Physiological Relevance ◽  
Complex Models ◽  
On Chip

Basic and translational research on lung biology and pathology can greatly benefit from the development of 3D in vitro models with physiological relevance. Lung organoids and lungs-on-chip allow the creation of different kinds of in vitro microenvironments, that can be useful for the elucidation of novel pathogenetic pathways, for example concerning tissue fibrosis in chronic diseases. Moreover, they represent important translational models for the identification of novel therapeutic targets, and for preliminary testing of new drugs. In this chapter, we provide a selected overview of recent studies on innovative 3D in vitro models that have enhanced our knowledge on chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), particularly concerning oxidative stress and pro-fibrotic pathogenetic mechanisms. Despite several limitations, these complex models must be considered as complementary in all respects to in vivo studies on animal models and clinical research.

scholarly journals Experimental Models for Fungal Keratitis: An Overview of Principles and Protocols

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1713
Author(s):  
Micaela L. Montgomery ◽  
Kevin K. Fuller
Keyword(s):  
Ex Vivo ◽  
Treatment Options ◽  
In Vitro Models ◽  
Experimental Models ◽  
Fungal Keratitis ◽  
Corneal Tissue ◽  
Host Determinants ◽  
Fungal Interactions

Fungal keratitis is a potentially blinding infection of the cornea that afflicts diverse patient populations worldwide. The development of better treatment options requires a more thorough understanding of both microbial and host determinants of pathology, and a spectrum of experimental models have been developed toward this end. In vivo (animal) models most accurately capture complex pathological outcomes, but protocols may be challenging to implement and vary widely across research groups. In vitro models allow for the molecular dissection of specific host cell–fungal interactions, but they do so without the appropriate environmental/structural context; ex vivo (corneal explant) models provide the benefits of intact corneal tissue, but they do not provide certain pathological features, such as inflammation. In this review, we endeavor to outline the key features of these experimental models as well as describe key technical variations that could impact study design and outcomes.

scholarly journals Blood and Lymphatic Vasculatures On-Chip Platforms and Their Applications for Organ-Specific In Vitro Modeling

Micromachines ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 147 ◽  
Author(s):  
Aria R. Henderson ◽  
Hyoann Choi ◽  
Esak Lee
Keyword(s):  
Cardiovascular System ◽  
Lymphatic System ◽  
Lymphatic Vessels ◽  
In Vitro Models ◽  
The Body ◽  
Interstitial Tissue ◽  
Organ Specific ◽  
On Chip

The human circulatory system is divided into two complementary and different systems, the cardiovascular and the lymphatic system. The cardiovascular system is mainly concerned with providing nutrients to the body via blood and transporting wastes away from the tissues to be released from the body. The lymphatic system focuses on the transport of fluid, cells, and lipid from interstitial tissue spaces to lymph nodes and, ultimately, to the cardiovascular system, as well as helps coordinate interstitial fluid and lipid homeostasis and immune responses. In addition to having distinct structures from each other, each system also has organ-specific variations throughout the body and both systems play important roles in maintaining homeostasis. Dysfunction of either system leads to devastating and potentially fatal diseases, warranting accurate models of both blood and lymphatic vessels for better studies. As these models also require physiological flow (luminal and interstitial), extracellular matrix conditions, dimensionality, chemotactic biochemical gradient, and stiffness, to better reflect in vivo, three dimensional (3D) microfluidic (on-a-chip) devices are promising platforms to model human physiology and pathology. In this review, we discuss the heterogeneity of both blood and lymphatic vessels, as well as current in vitro models. We, then, explore the organ-specific features of each system with examples in the gut and the brain and the implications of dysfunction of either vasculature in these organs. We close the review with discussions on current in vitro models for specific diseases with an emphasis on on-chip techniques.

scholarly journals Fosmanogepix (APX001) Is Effective in the Treatment of Pulmonary Murine Mucormycosis Due to Rhizopus arrhizus

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Teclegiorgis Gebremariam ◽  
Sondus Alkhazraji ◽  
Abdullah Alqarihi ◽  
Nathan P. Wiederhold ◽  
Karen Joy Shaw ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Surface Proteins ◽  
Rhizopus Arrhizus ◽  
Minimum Effective Concentration ◽  
Content Type ◽  
Log Reduction ◽  
Infection Models ◽  
Life Threatening

ABSTRACT Mucormycosis is a life-threatening infection with high mortality that occurs predominantly in immunocompromised patients. Manogepix (MGX) is a novel antifungal that targets Gwt1, a protein involved in an early step in the conserved glycosylphosphotidyl inositol (GPI) posttranslational modification pathway of surface proteins in eukaryotic cells. Inhibition of fungal inositol acylation by MGX results in pleiotropic effects, including inhibition of maturation of GPI-anchored proteins necessary for growth and virulence. MGX has been previously shown to have in vitro activity against some strains of Mucorales. Here, we assessed the in vivo activity of the prodrug fosmanogepix, currently in clinical development for the treatment of invasive fungal infections, against two Rhizopus arrhizus strains with high (4.0 μg/ml) and low (0.25 μg/ml) minimum effective concentration (MEC) values. In both invasive pulmonary infection models, treatment of mice with 78 mg/kg or 104 mg/kg fosmanogepix, along with 1-aminobenzotriazole to enhance the serum half-life of MGX in mice, significantly increased median survival time and prolonged overall survival by day 21 postinfection compared to placebo. In addition, administration of fosmanogepix resulted in a 1 to 2 log reduction in both lung and brain fungal burden. For the 104 mg/kg fosmanogepix dose, tissue clearance and survival were comparable to clinically relevant doses of isavuconazole (ISA), which is FDA approved for the treatment of mucormycosis. These results support continued development of fosmanogepix as a first-in-class treatment for invasive mucormycosis.

scholarly journals Gut-on-chip: Recreating human intestine in vitro

2020 ◽  
Vol 11 ◽  
pp. 204173142096531
Author(s):  
Yunqing Xiang ◽  
Hui Wen ◽  
Yue Yu ◽  
Mingqiang Li ◽  
Xiongfei Fu ◽  
...  
Keyword(s):  
Cell Biology ◽  
Intestinal Flora ◽  
In Vitro Models ◽  
Intestinal Microbiome ◽  
Human Gut ◽  
Intestinal Microbes ◽  
Number Of Microorganisms ◽  
On Chip

The human gut is important for food digestion and absorption, as well as a venue for a large number of microorganisms that coexist with the host. Although numerous in vitro models have been proposed to study intestinal pathology or interactions between intestinal microbes and host, they are far from recapitulating the real intestinal microenvironment in vivo. To assist researchers in further understanding gut physiology, the intestinal microbiome, and disease processes, a novel technology primarily based on microfluidics and cell biology, called “gut-on-chip,” was developed to simulate the structure, function, and microenvironment of the human gut. In this review, we first introduce various types of gut-on-chip systems, then highlight their applications in drug pharmacokinetics, host–gut microbiota crosstalk, and nutrition metabolism. Finally, we discuss challenges in this field and prospects for better understanding interactions between intestinal flora and human hosts, and then provide guidance for clinical treatment of related diseases.

scholarly journals Critical Assessment of Cell Wall Integrity Factors Contributing to in vivo Echinocandin Tolerance and Resistance in Candida glabrata

2021 ◽  
Vol 12 ◽  
Author(s):  
Rocio Garcia-Rubio ◽  
Rosa Y. Hernandez ◽  
Alissa Clear ◽  
Kelley R. Healey ◽  
Erika Shor ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Glabrata ◽  
Fungal Infections ◽  
Critical Role ◽  
Cell Wall Integrity ◽  
Fungal Cell ◽  
Fungal Host

Fungal infections are on the rise, and emergence of drug-resistant Candida strains refractory to treatment is particularly alarming. Resistance to azole class antifungals, which have been extensively used worldwide for several decades, is so high in several prevalent fungal pathogens, that another drug class, the echinocandins, is now recommended as a first line antifungal treatment. However, resistance to echinocandins is also prominent, particularly in certain species, such as Candida glabrata. The echinocandins target 1,3-β-glucan synthase (GS), the enzyme responsible for producing 1,3-β-glucans, a major component of the fungal cell wall. Although echinocandins are considered fungicidal, C. glabrata exhibits echinocandin tolerance both in vitro and in vivo, where a subset of the cells survives and facilitates the emergence of echinocandin-resistant mutants, which are responsible for clinical failure. Despite this critical role of echinocandin tolerance, its mechanisms are still not well understood. Additionally, most studies of tolerance are conducted in vitro and are thus not able to recapitulate the fungal-host interaction. In this study, we focused on the role of cell wall integrity factors in echinocandin tolerance in C. glabrata. We identified three genes involved in the maintenance of cell wall integrity – YPS1, YPK2, and SLT2 – that promote echinocandin tolerance both in vitro and in a mouse model of gastrointestinal (GI) colonization. In particular, we show that mice colonized with strains carrying deletions of these genes were more effectively sterilized by daily caspofungin treatment relative to mice colonized with the wild-type parental strain. Furthermore, consistent with a role of tolerant cells serving as a reservoir for generating resistant mutations, a reduction in tolerance was associated with a reduction in the emergence of resistant strains. Finally, reduced susceptibility in these strains was due both to the well described FKS-dependent mechanisms and as yet unknown, FKS-independent mechanisms. Together, these results shed light on the importance of cell wall integrity maintenance in echinocandin tolerance and emergence of resistance and lay the foundation for future studies of the factors described herein.

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