The invasive diseases caused by fungi, the so-called systemic mycoses, profoundly impact human health. ...the Global Action Fund for Fungal Infections (GAFFI) also highlights the devastating impact ...of focal fungal diseases in individuals who often have intact immune systems. According to the Centers for Disease Control and Prevention (CDC), fungi are among the leading causes of opportunistic infections affecting patients with HIV/AIDS 16. ...they afflict the poorest people without access to safe drinking water, sanitation, and basic health services. ...neglected tropical diseases can cause severe pain and disability throughout life, with long-term consequences for patients and families of the affected person.
The production of melanin significantly enhances the virulence of many important human pathogenic fungi. Despite fungal melanin's importance in human disease, as well as melanin's contribution to the ...ability of fungi to survive in diverse hostile environments, the structure of melanin remains unsolved. Nevertheless, ongoing research efforts have progressively revealed several notable structural characteristics of this enigmatic pigment, which will be the focus of this review. These compositional and organizational insights could further our ability to develop novel therapeutic approaches to combat fungal disease and enhance our understanding of how melanin is inserted into the cell wall.
Melanin pigments are ubiquitous in nature. Melanized microorganisms are often the dominating species in certain extreme environments, such as soils contaminated with radionuclides, suggesting that ...the presence of melanin is beneficial in their life cycle. We hypothesized that ionizing radiation could change the electronic properties of melanin and might enhance the growth of melanized microorganisms.
Ionizing irradiation changed the electron spin resonance (ESR) signal of melanin, consistent with changes in electronic structure. Irradiated melanin manifested a 4-fold increase in its capacity to reduce NADH relative to non-irradiated melanin. HPLC analysis of melanin from fungi grown on different substrates revealed chemical complexity, dependence of melanin composition on the growth substrate and possible influence of melanin composition on its interaction with ionizing radiation. XTT/MTT assays showed increased metabolic activity of melanized C. neoformans cells relative to non-melanized cells, and exposure to ionizing radiation enhanced the electron-transfer properties of melanin in melanized cells. Melanized Wangiella dermatitidis and Cryptococcus neoformans cells exposed to ionizing radiation approximately 500 times higher than background grew significantly faster as indicated by higher CFUs, more dry weight biomass and 3-fold greater incorporation of (14)C-acetate than non-irradiated melanized cells or irradiated albino mutants. In addition, radiation enhanced the growth of melanized Cladosporium sphaerospermum cells under limited nutrients conditions.
Exposure of melanin to ionizing radiation, and possibly other forms of electromagnetic radiation, changes its electronic properties. Melanized fungal cells manifested increased growth relative to non-melanized cells after exposure to ionizing radiation, raising intriguing questions about a potential role for melanin in energy capture and utilization.
Affected individuals may have significant mental health issues associated with this rare and chronic condition 4. Another way of measuring the impact of fungi on public health is to determine their ...overall burden of disease using the disability-adjusted life year (DALY). ...the Coronavirus Disease 2019 (COVID-19) pandemic exacerbated the epidemiology of fungal diseases 19, proving the concept that globally transmitted diseases can make worse an already complex epidemiologic scenario. In a broader analysis, a relatively recent study on the 28 most transformative medicines approved for clinical use by the US Food and Drug Administration (FDA) between 1985 and 2009 revealed that approximately 80% of the medicines in this group could be traced back to one or several basic discoveries 24. ...although innovation-oriented programs are of unquestionable relevance, continued fostering of fundamental research is indispensable to generate translational tools.
Abstract Burn wounds are often complicated by bacterial infection, contributing to morbidity and mortality. Agents commonly used to treat burn wound infection are limited by toxicity, incomplete ...microbial coverage, inadequate penetration, and rising resistance. Curcumin is a naturally derived substance with innate antimicrobial and wound healing properties. Acting by multiple mechanisms, curcumin is less likely than current antibiotics to select for resistant bacteria. Curcumin's poor aqueous solubility and rapid degradation profile hinder usage; nanoparticle encapsulation overcomes this pitfall and enables extended topical delivery of curcumin. In this study, we synthesized and characterized curcumin nanoparticles (curc-np), which inhibited in vitro growth of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa in dose-dependent fashion, and inhibited MRSA growth and enhanced wound healing in an in vivo murine wound model. Curc-np may represent a novel topical antimicrobial and wound healing adjuvant for infected burn wounds and other cutaneous injuries. From the Clinical Editor This team of authors created curcumin nanoparticles in an effort to overcome curcumin’s endogenously poor aqueous solubility and demonstrated in a murine model its antimicrobial and wound healing properties that also resulted in growth inhibition of MRSA and Pseudomonas aeruginosa.
The interaction between fungal pathogens with the host frequently results in morphological changes, such as hyphae formation. The encapsulated pathogenic fungus Cryptococcus neoformans is not ...considered a dimorphic fungus, and is predominantly found in host tissues as round yeast cells. However, there is a specific morphological change associated with cryptococcal infection that involves an increase in capsule volume. We now report another morphological change whereby gigantic cells are formed in tissue. The paper reports the phenotypic characterization of giant cells isolated from infected mice and the cellular changes associated with giant cell formation. C. neoformans infection in mice resulted in the appearance of giant cells with cell bodies up to 30 microm in diameter and capsules resistant to stripping with gamma-radiation and organic solvents. The proportion of giant cells ranged from 10 to 80% of the total lung fungal burden, depending on infection time, individual mice, and correlated with the type of immune response. When placed on agar, giant cells budded to produce small daughter cells that traversed the capsule of the mother cell at the speed of 20-50 m/h. Giant cells with dimensions that approximated those in vivo were observed in vitro after prolonged culture in minimal media, and were the oldest in the culture, suggesting that giant cell formation is an aging-dependent phenomenon. Giant cells recovered from mice displayed polyploidy, suggesting a mechanism by which gigantism results from cell cycle progression without cell fission. Giant cell formation was dependent on cAMP, but not on Ras1. Real-time imaging showed that giant cells were engaged, but not engulfed by phagocytic cells. We describe a remarkable new strategy for C. neoformans to evade the immune response by enlarging cell size, and suggest that gigantism results from replication without fission, a phenomenon that may also occur with other fungal pathogens.
Nitric oxide (NO) is a short-lived, diatomic, lipophilic gas that plays an integral role in defending against pathogens. Among its many functions are involvement in immune cell signaling and in the ...biochemical reactions by which immune cells defend against bacteria, fungi, viruses and parasites. NO signaling directs a broad spectrum of processes, including the differentiation, proliferation, and apoptosis of immune cells. When secreted by activated immune cells, NO diffuses across cellular membranes and exacts nitrosative and oxidative damage on invading pathogens. These observations led to the development of NO delivery systems that can harness the antimicrobial properties of this evanescent gas. The innate microbicidal properties of NO, as well as the antimicrobial activity of the various NO delivery systems, are reviewed.
Summary
Melanins are enigmatic pigments that are produced by a wide variety of microorganisms including several species of pathogenic bacteria, fungi and helminthes. The study of melanin is difficult ...because these pigments defy complete biochemical and structural analysis. Nevertheless, the availability of new reagents in the form of monoclonal antibodies and melanin‐binding peptides, combined with the application of various physical techniques, has provided insights into the process of melanization. Melanization is important in microbial pathogenesis because it has been associated with virulence in many microorganisms. Melanin appears to contribute to virulence by reducing the susceptibility of melanized microbes to host defence mechanisms. However, the interaction of melanized microbes and the host is complex and includes immune responses to melanin‐related antigens. Production of melanin has also been linked to protection against environmental insults. Interference with melanization is a potential strategy for antimicrobial drug and pesticide development. The process of melanization poses fascinating problems in cell biology and provides a type of pathogenic strategy that is common to highly diverse pathogens.
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