GRP78 and Integrins Play Different Roles in Host Cell Invasion during Mucormycosis

Area of Science:

• Mycology
• Infectious Diseases
• Immunology

Background:

• Mucormycosis, a severe fungal infection caused by Rhizopus species, poses a significant threat to immunocompromised individuals.
• Patients with diabetic ketoacidosis (DKA) are particularly susceptible to rhinoorbital/cerebral mucormycosis, while those with hematologic malignancies often develop pulmonary infections.
• The distinct disease manifestations in different patient groups infected by the same fungus remain poorly understood.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying the differential tropism of Rhizopus delemar in various host cell types.
• To explain the specific susceptibility of DKA patients to rhinoorbital/cerebral mucormycosis.
• To identify potential therapeutic targets for combating mucormycosis.

Main Methods:

• Investigated the interaction between Rhizopus delemar spore coat proteins (CotH3 and CotH7) and host cell receptors (GRP78 and integrin β1).
• Analyzed the role of host factors, including high glucose, iron, and ketone bodies, in enhancing fungal-host interactions.
• Utilized anti-integrin β1 antibodies to inhibit fungal invasion and assess protection in a mouse model of pulmonary mucormycosis.

Main Results:

• Rhizopus delemar utilizes CotH3 to bind GRP78 on nasal epithelial cells, with expression upregulated by DKA-associated factors, leading to rhinoorbital/cerebral mucormycosis.
• In contrast, CotH7 interacts with integrin β1 on alveolar epithelial cells, activating EGFR and causing pulmonary invasion.
• Anti-integrin β1 antibodies effectively inhibited fungal invasion and protected against pulmonary mucormycosis in mice.

Conclusions:

• Rhizopus delemar employs distinct host cell receptors (GRP78 and integrin β1) for invasion, explaining the differential disease tropism.
• Host factors characteristic of DKA significantly contribute to the pathogenesis of rhinoorbital/cerebral mucormycosis by upregulating specific fungal and host proteins.
• Targeting niche-specific host-fungal interactions presents a promising strategy for developing novel mucormycosis therapies.