scholarly journals Complex and Controversial Roles of Eicosanoids in Fungal Pathogenesis

2021 ◽  
Vol 7 (4) ◽  
pp. 254
Author(s):  
Susana Ruiz Mendoza ◽  
Daniel Zamith-Miranda ◽  
Tamás Takács ◽  
Attila Gacser ◽  
Joshua D. Nosanchuk ◽  
...  
Keyword(s):  
Histoplasma Capsulatum ◽  
Fungal Infections ◽  
Mortality Rates ◽  
Fungal Pathogenesis ◽  
Host Responses ◽  
Fungal Colonization ◽  
Immunocompromised Patients ◽  
Fungal Burden ◽  
Killing Activity ◽  
Host Mortality

The prevalence of fungal infections has increased in immunocompromised patients, leading to millions of deaths annually. Arachidonic acid (AA) metabolites, such as eicosanoids, play important roles in regulating innate and adaptative immune function, particularly since they can function as virulence factors enhancing fungal colonization and are produced by mammalian and lower eukaryotes, such as yeasts and other fungi (Candida albicans, Histoplasma capsulatum and Cryptococcus neoformans). C. albicans produces prostaglandins (PG), Leukotrienes (LT) and Resolvins (Rvs), whereas the first two have been well documented in Cryptococcus sp. and H. capsulatum. In this review, we cover the eicosanoids produced by the host and fungi during fungal infections. These fungal-derived PGs have immunomodulatory functions analogous to their mammalian counterparts. Prostaglandin E2 (PGE2) protects C. albicans and C. parapsilosis cells from the phagocytic and killing activity of macrophages. H. capsulatum PGs augment the fungal burden and host mortality rates in histoplasmosis. However, PGD2 potentiates the effects and production of LTB4, which is a very potent neutrophil chemoattractant that enhances host responses. Altogether, these data suggest that eicosanoids, mainly PGE2, may serve as a new potential target to combat diverse fungal infections.

scholarly journals A Pathogenesis Assay Using Saccharomycescerevisiae and Caenorhabditiselegans Reveals Novel Roles for Yeast AP-1, Yap1, and Host Dual Oxidase BLI-3 in Fungal Pathogenesis

2009 ◽  
Vol 8 (8) ◽  
pp. 1218-1227 ◽  
Author(s):  
Charu Jain ◽  
Meijiang Yun ◽  
Samuel M. Politz ◽  
Reeta Prusty Rao
Keyword(s):  
Fungal Infections ◽  
Fungal Pathogenesis ◽  
Host Responses ◽  
Ros Production ◽  
Oxygen Species ◽  
Fungal Virulence ◽  
Oxidase Gene ◽  
Dual Oxidase ◽  
Chemical Inhibition ◽  
Yeast Mutants

ABSTRACT Treatment of systemic fungal infections is difficult because of the limited number of antimycotic drugs available. Thus, there is an immediate need for simple and innovative systems to assay the contribution of individual genes to fungal pathogenesis. We have developed a pathogenesis assay using Caenorhabditis elegans, an established model host, with Saccharomyces cerevisiae as the invading fungus. We have found that yeast infects nematodes, causing disease and death. Our data indicate that the host produces reactive oxygen species (ROS) in response to fungal infection. Yeast mutants sod1Δ and yap1Δ, which cannot withstand ROS, fail to cause disease, except in bli-3 worms, which carry a mutation in a dual oxidase gene. Chemical inhibition of the NADPH oxidase activity abolishes ROS production in worms exposed to yeast. This pathogenesis assay is useful for conducting systematic, whole-genome screens to identify fungal virulence factors as alternative targets for drug development and exploration of host responses to fungal infections.

scholarly journals Erythropoietin Exacerbates Inflammation and Increases the Mortality ofHistoplasma capsulatum-Infected Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Gisele Aparecida Locachevic ◽  
Priscilla Aparecida Tartari Pereira ◽  
Adriana Secatto ◽  
Caroline Fontanari ◽  
Alyne Fávero Galvão ◽  
...  
Keyword(s):  
Immune Responses ◽  
Fungal Infection ◽  
Lung Inflammation ◽  
Histoplasma Capsulatum ◽  
Fungal Infections ◽  
Cell Formation ◽  
Fungal Burden ◽  
Animal Survival ◽  
The Impact ◽  
First Time

Erythropoietin (EPO) is a key hormone involved in red blood cell formation, but its effects on nonerythroid cells, such as macrophages, have not been described. Macrophages are key cells in controlling histoplasmosis, a fungal infection caused byHistoplasma capsulatum(Hc). Considering that little is known about EPO’s role during fungal infections and its capacity to activate macrophages, in this study we investigated the impact of EPO pretreatment on the alveolar immune response duringHcinfection. The consequence of EPO pretreatment on fungal infection was determined by evaluating animal survival, fungal burden, activation of bronchoalveolar macrophages, inflammatory mediator release, and lung inflammation. Pretreatment with EPO diminished mononuclear cell numbers, increased the recruitment of F4/80+/CD80+and F4/80+/CD86+cells to the bronchoalveolar space, induced higher production of IFN-γ, IL-6, MIP-1α, MCP-1, and LTB4, reduced PGE2concentration, and did not affect fungal burden. As a consequence, we observed an increase in lung inflammation with extensive tissue damage that might account for augmented mouse mortality after infection. Our results demonstrate for the first time that EPO treatment has a deleterious impact on lung immune responses during fungal infection.

scholarly journals Cross-scale interaction of host tree size and climatic water deficit governs bark beetle-induced tree mortality

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Michael J. Koontz ◽  
Andrew M. Latimer ◽  
Leif A. Mortenson ◽  
Christopher J. Fettig ◽  
Malcolm P. North
Keyword(s):  
Water Deficit ◽  
Sierra Nevada ◽  
Bark Beetle ◽  
Ponderosa Pine ◽  
Tree Mortality ◽  
Mortality Rates ◽  
Dendroctonus Brevicomis ◽  
Scale Interactions ◽  
Climatic Water Deficit ◽  
Host Mortality

AbstractThe recent Californian hot drought (2012–2016) precipitated unprecedented ponderosa pine (Pinus ponderosa) mortality, largely attributable to the western pine beetle (Dendroctonus brevicomis; WPB). Broad-scale climate conditions can directly shape tree mortality patterns, but mortality rates respond non-linearly to climate when local-scale forest characteristics influence the behavior of tree-killing bark beetles (e.g., WPB). To test for these cross-scale interactions, we conduct aerial drone surveys at 32 sites along a gradient of climatic water deficit (CWD) spanning 350 km of latitude and 1000 m of elevation in WPB-impacted Sierra Nevada forests. We map, measure, and classify over 450,000 trees within 9 km2, validating measurements with coincident field plots. We find greater size, proportion, and density of ponderosa pine (the WPB host) increase host mortality rates, as does greater CWD. Critically, we find a CWD/host size interaction such that larger trees amplify host mortality rates in hot/dry sites. Management strategies for climate change adaptation should consider how bark beetle disturbances can depend on cross-scale interactions, which challenge our ability to predict and understand patterns of tree mortality.

scholarly journals Diagnosing filamentous fungal infections in immunocompromised patients applying computed tomography-guided percutaneous lung biopsies: a 12-year experience

Infection ◽  
2017 ◽  
Vol 45 (6) ◽  
pp. 867-875 ◽  
Author(s):  
Cornelia Lass-Flörl ◽  
Maria Aigner ◽  
David Nachbaur ◽  
Stephan Eschertzhuber ◽  
Brigitte Bucher ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Fungal Infections ◽  
Immunocompromised Patients ◽  
Lung Biopsies

scholarly journals Molecular Insights into the Fungus-Specific Serine/Threonine Protein Phosphatase Z1 in Candida albicans

mBio ◽  
2016 ◽  
Vol 7 (4) ◽  
Author(s):  
Emily Chen ◽  
Meng S. Choy ◽  
Katalin Petrényi ◽  
Zoltán Kónya ◽  
Ferenc Erdődi ◽  
...  
Keyword(s):  
Candida Albicans ◽  
High Mortality ◽  
Protein Phosphatase ◽  
Cyclic Peptide ◽  
Fungal Infections ◽  
The United States ◽  
Mortality Rates ◽  
Regulatory Proteins ◽  
Structural Elements ◽  
Novel Targets

ABSTRACT The opportunistic pathogen Candida is one of the most common causes of nosocomial bloodstream infections. Because candidemia is associated with high mortality rates and because the incidences of multidrug-resistant Candida are increasing, efforts to identify novel targets for the development of potent antifungals are warranted. Here, we describe the structure and function of the first member of a family of protein phosphatases that is specific to fungi, protein phosphatase Z1 (PPZ1) from Candida albicans . We show that PPZ1 not only is active but also is as susceptible to inhibition by the cyclic peptide inhibitor microcystin-LR as its most similar human homolog, protein phosphatase 1α (PP1α [GLC7 in the yeast Saccharomyces cerevisiae ]). Unexpectedly, we also discovered that, despite its 66% sequence identity to PP1α, the catalytic domain of PPZ1 contains novel structural elements that are not present in PP1α. We then used activity and pulldown assays to show that these structural differences block a large subset of PP1/GLC7 regulatory proteins from effectively binding PPZ1, demonstrating that PPZ1 does not compete with GLC7 for its regulatory proteins. Equally important, these unique structural elements provide new pockets suitable for the development of PPZ1-specific inhibitors. Together, these studies not only reveal why PPZ1 does not negatively impact GLC7 activity in vivo but also demonstrate that the family of fungus-specific phosphatases—especially PPZ1 from C. albicans —are highly suitable targets for the development of novel drugs that specifically target C. albicans without cross-reacting with human phosphatases. IMPORTANCE Candida albicans is a medically important human pathogen that is the most common cause of fungal infections in humans. In particular, approximately 46,000 cases of health care-associated candidiasis occur each year in the United States. Because these infections are associated with high mortality rates and because multiple species of Candida are becoming increasingly resistant to antifungals, there are increasing efforts to identify novel targets that are essential for C. albicans virulence. Here we use structural and biochemical approaches to elucidate how a member of a fungus-specific family of enzymes, serine/threonine phosphatase PPZ1, functions in C. albicans . We discovered multiple unique features of PPZ1 that explain why it does not cross-react with, and in turn compete for, PP1-specific regulators, a long-standing question in the field. Most importantly, however, these unique features identified PPZ1 as a potential target for the development of novel antifungal therapeutics that will provide new, safe, and potent treatments for candidiasis in humans.

scholarly journals In vivo Active Organometallic-containing Antimycotic Agents

2021 ◽  
Author(s):  
Riccardo Rubbiani ◽  
Tobias Weil ◽  
Noemi Tocci ◽  
Luciano Mastrobuoni ◽  
Severin Jeger ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Care Home ◽  
Multidrug Resistant ◽  
Immunocompromised Patients ◽  
Fungal Strains ◽  
Global Problem

Fungal infections represent a global problem, notably for immunocompromised, patients in hospital, covid-19 patient wards and care home settings, and the ever-increasing emergence of multidrug resistant fungal strains is a...

scholarly journals Comparison of the Echinocandin Caspofungin with Amphotericin B for Treatment of Histoplasmosis following Pulmonary Challenge in a Murine Model

2000 ◽  
Vol 44 (7) ◽  
pp. 1850-1854 ◽  
Author(s):  
Steve Kohler ◽  
L. Joseph Wheat ◽  
Patricia Connolly ◽  
Carol Schnizlein-Bick ◽  
Michelle Durkin ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Histoplasma Capsulatum ◽  
Clinical Laboratory ◽  
Antigen Detection ◽  
National Committee ◽  
Slight Effect ◽  
Fungal Burden ◽  
Detection Techniques ◽  
The Mean

ABSTRACT Twenty clinical isolates of Histoplasma capsulatum were tested for their in vitro susceptibilities to caspofungin in comparison to those to amphotericin B by following National Committee for Clinical Laboratory Standards guidelines for yeasts. The mean MICs were 16.6 μg/ml (range, 8 to 32 μg/ml) for caspofungin and 0.56 μg/ml (range, 0.5 to 1.0 μg/ml) for amphotericin B. Survival experiments used a 105 dose in a pulmonary challenge model with B6C3F1 mice. All mice that received amphotericin B at 2 mg/kg of body weight every other day (q.o.d.), 30% of mice that received caspofungin at 8 mg/kg/day, and 20% of mice that received caspofungin at 4 mg/kg/day survived to day 15, while mice that received caspofungin at 2 mg/kg/day and all control mice that received the vehicle died by day 14. Amphotericin B at 2 mg/kg q.o.d. markedly reduced the fungal burden in the lungs and spleens, as measured byHistoplasma antigen detection techniques and quantitative cultures, for each comparison. Caspofungin at 10 mg/kg twice a day (b.i.d.) did not reduce the fungal burden, as measured by antigen detection techniques, but slightly reduced the levels of fungi in both the lungs and spleens, as determined by quantitative cultures. Caspofungin at 5 mg/kg b.i.d. did not affect fungal burden. Overall, caspofungin had only a slight effect on survival or fungal burden.

Mode of Action of Antifungals of Use in Immunocompromised Patients. Focus on Candida Glabrata and Histoplasma Capsulatum

1990 ◽  
pp. 223-243 ◽  
Author(s):  
Hugo Vanden Bossche ◽  
Patrick Marichal ◽  
Jos Gorrens ◽  
Danny Bellens ◽  
Marie-Claire Coene ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Candida Glabrata ◽  
Histoplasma Capsulatum ◽  
Immunocompromised Patients
Sign in / Sign up

Export Citation Format

Share Document