Iron restriction inside macrophages regulates pulmonary host defense against Rhizopus species

Area of Science:

• Mycology
• Immunology
• Pathogenesis

Background:

• Mucormycosis is a severe fungal infection caused by Rhizopus species.
• The pathogenesis of mucormycosis, especially concerning iron metabolism and immune evasion, is not fully understood.
• Alveolar macrophages (AMs) play a critical role in host defense against fungal pathogens.

Purpose of the Study:

• To elucidate the mechanisms by which Rhizopus species establish intracellular persistence within AMs.
• To investigate the role of melanin and iron metabolism in the interaction between Rhizopus and AMs.
• To understand the host immune response, particularly macrophage-mediated nutritional immunity, against Rhizopus.

Main Methods:

• Investigated intracellular persistence of Rhizopus conidia in AMs.
• Analyzed the role of melanin and conidial swelling in phagocytosis and immune evasion.
• Utilized transcriptomics of host and pathogen, iron supplementation, and genetic manipulation of fungal iron assimilation.
• Conducted infection studies in immunocompetent mice with varying AM levels.

Main Results:

• Rhizopus conidia evade phagocytosis by retaining melanin, leading to phagosome maturation arrest via inhibition of LC3-associated phagocytosis.
• Intracellular inhibition of Rhizopus by AMs is crucial; swollen conidia that evade phagocytosis cause acute lethality in mice.
• AM depletion significantly increases susceptibility to mucormycosis.
• Iron restriction within macrophages modulates the host immune response against Rhizopus.

Conclusions:

• Rhizopus establishes intracellular persistence by evading AM-mediated clearance mechanisms, involving melanin retention and phagosome maturation arrest.
• Macrophage-mediated nutritional immunity, particularly iron restriction, is a key host defense against filamentous fungi like Rhizopus.
• Understanding these pathogenetic mechanisms is vital for developing effective treatments for mucormycosis.