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The spore coat protein H (CotH) has been identified among virulence factors of Mucorales that mediate fungal invasion by glucose-regulated protein 78 (GRP78) ligand on endothelial cells. The aim of this study was to examine the gene expressions of spore coat protein homologs 3 (CotH3) and GRP78, along with their target miRNAs, in infected human macrophages, mice models, and mucormycosis patients. To assess changes in the relative expressions of the GPR78 and CotH3 genes, this study used the Real-time quantitative PCR method to quantify their target miRNAs (hsa-miR-16-5p, hsa-miR-93-3p, hsa-miR-335-5p, and mmu-miR-181b-5p) in macrophages derived from human monocytes (MDMs), mice models, and sinus tissue from diabetic patients with mucormycosis. In this study, expressions of GRP78 and CotH3 genes were elevated in infected MDMs and non-diabetic Balb/c mice infected with Rhizopus oryzae (R. oryzae), and the expression of the GRP78 gene was up-regulated in the non-infected diabetic mice. However, the infected diabetic mice displayed a decline in the GRP78 gene expression. Moreover, although the expression of the GRP78 gene increased in the sinus tissue of diabetic patients with mucormycosis, it significantly decreased in the same patients after treatment. The relative expression of the hsa-miR-16-5p, hsa-miR-93-3p, and hsa-miR-335-5p was down-regulated in the MDMs. The increased gene expression levels of CotH3 and GPR78 observed in infected macrophages provide insight into the mechanism of interactions between the pathogen and macrophages. Prolonged encounters lead to changes in the expression levels of CotH3 and GPR78 gene.