Recent Advances and Future Directions in the Understanding of Mucormycosis

Abstract

Mucormycosis is an emerging infection caused by fungi of the order Mucorales that has recently gained public relevance due to the high incidence among COVID-19 patients in some countries. The reduced knowledge about Mucorales pathogenesis is due, in large part, to the historically low interest for these fungi fostered by their reluctance to be genetically manipulated. The recent introduction of more tractable genetic models together with an increasing number of available whole genome sequences and genomic analyses have improved our understanding of Mucorales biology and mucormycosis in the last ten years. This review summarizes the most significant advances in diagnosis, understanding of the innate and acquired resistance to antifungals, identification of new virulence factors and molecular mechanisms involved in the infection. The increased awareness about the disease and the recent successful genetic manipulation of previous intractable fungal models using CRISPR-Cas9 technology are expected to fuel the characterization of Mucorales pathogenesis, facilitating the development of effective treatments to fight this deadly infection.

Comprehensive Review on the Virulence Factors and Therapeutic Strategies with the Aid of Artificial Intelligence against Mucormycosis

“…Once spores cross the physical barriers, macrophages and neutrophils are rapidly recruited to the infection site. The most common virulence factors include cell wall adhesins aiding in host cell penetration, factors helping the fungi to compete for resources, and spore-associated defense mechanisms to thwart innate and adaptive immune mechanisms including ceasing phagosome maturation in macrophages and neutrophils. ,, Mucorales utilize various strategies to evade host defenses: Rhizopus species maintain dormancy inside macrophages via iron restriction (Fet3 and Ftr1 upregulation inside phagosome) and phagosome maturation inhibition (via melanin surface retention on fungal spores). , M. circinelloides activates specific transcription factors (Activating Transcription Factors: Atf1 and Atf2) for germination inside phagosomes, which inhibits noncanonical RNAi pathway (NCRIP), overcoming the host defenses ,, Other Mucor species impede phagosome maturation via the calcineurin pathway using CnbR mutants R. microsporus interacts with a bacterial endosymbiont, Ralstonia pickettii to shield spores from macrophage clearance. ,, Mucormycosis-induced apoptosis in macrophages was studied by López-Muñoz et al in a zebrafish model. , Spore size influences M. circinelloides ’ fate post-phagocytosis: larger spores destroy host cells, while smaller ones are retained, preventing germination …”

“…Three antifungal drugslipid formulations of amphotericin B, posaconazole, and isavuconazoleare currently used to treat mucormycosis, yet they pose reported toxicities and severe side effects . Managing mucormycosis is challenging due to the lack of effective antifungal drugs and the fungi’s inherent tendency to develop drug resistance and significant variability in susceptibility to available antifungals. , Despite newer antifungal agents, unchanged mortality rates reveal limited understanding of Mucorales’ pathophysiology and molecular pathways, hindering effective treatment development. − Targeted therapy, known for selectivity and efficacy, is revolutionary in treating cancer, chronic immunologic conditions, osteoarthritis, Alzheimer’s disease, and genetic disorders. − In 2022, the U.S. FDA approved 37 new medications21 small molecules and 15 biologicsunderscoring their ongoing impact . Researchers are making strides in drug discovery using AI/ML-based technologies which involve predicting ADMET, high-throughput virtual screening (in CADD), drug interactions, and using predicted protein models in small-molecule design, employing software like MolAICal for 3D protein target predictions and ML-based models for detecting antifungal resistance markers via genome sequencing along with MALDI-TOF MS data analysis. − …”

Post-COVID-19 Fungal Infection in the Aged Population

“…This is crucial for low- and middle-income countries, where a lack of resources has a significant impact on the availability and effectiveness of therapeutic approaches. [ 62 ].…”

“We've got to get out”—Strategies of human pathogenic fungi to escape from phagocytes

“…Alveolar macrophages play a key role in the host defense against and the host response to Mucorales (Montano & Voigt, 2020). Mucorales show species‐specific mechanisms to either survive and persist as dormant spores inside macrophages or geminate and escape (Garre, 2022; Nicolas et al, 2020). Rhizopus spp.…”