A Polymorphism in the Chitotriosidase Gene Associated with Risk of Mycetoma Due to Madurella mycetomatis Mycetoma–A Retrospective Study

Abstract

Background Madurella mycetomatis is the most prevalent causative agent of eumycetoma in Sudan, an infection characterized by the formation of grains. Many patients are exposed to the causative agent, however only a small number develop infection. M. mycetomatis contains chitin in its cell wall, which can trigger the human immune system. Polymorphisms in the genes encoding for the chitin-degrading enzymes chitotriosidase and AMCase were described, resulting in altered chitinase activity. We investigated the association between 4 of these polymorphisms and the incidence of M. mycetomatis mycetoma in a Sudanese population.MethodologyPolymorphisms studied in 112 eumycetoma patients and 103 matched controls included a 24-bp insertion in the chitotriosidase gene (rs3831317), resulting in impaired chitinase activity and single nucleotide polymorphism (SNP) in the AMCase gene (rs61756687), resulting in decreased AMCase activity. Also, a SNP (rs41282492) and a 10-bp insertion in the 5’UTR region of the AMCase gene (rs143789088) were studied, both resulting in increased AMCase activity. DNA was isolated from blood and genotypes were determined using PCR-RFLP.Principal FindingsHistological staining proved the presence of chitin in the fungal grain. The polymorphism resulting in decreased chitotriosidase activity was associated with increased odds of eumycetoma (odds ratio 2.9; p = 0.004). No association was found for the polymorphisms in the genes for AMCase (all p>0.05).ConclusionDecreased chitotriosidase activity was associated with increased risk of M. mycetomatis mycetoma.

Mycetoma: reviewing a neglected disease

“…found that the chititriosidase enzyme binds to fungal chitin in the mycetoma grain, accounting for the pathogen‐eliminating immune response. A polymorphism resulting in decreased chitotriosidase activity was associated with increased likelihood of eumycetoma . Different pathogens secrete various enzymes, immunomodulators and melanin, which help in their survival in human tissue, evading the first‐line immune mechanism.…”

Proteomic analysis of the processes leading to Madurella mycetomatis grain formation in Galleria mellonella larvae

“…These grains are considered the key feature of mycetoma and are thought to be formed as a defence mechanism by the fungus against the host immune system [4]. Although it is currently not known how these grains are formed, we do know that grains consist of melanin, chitin, lipids and proteins [5][6][7][8][9]. Chitin and melanin are present as thick layers on hyphal walls [6,7] and proteins were found both on the cells as well as in the cement material [8,9] surrounding the hyphae.…”

“…Although it is currently not known how these grains are formed, we do know that grains consist of melanin, chitin, lipids and proteins [5][6][7][8][9]. Chitin and melanin are present as thick layers on hyphal walls [6,7] and proteins were found both on the cells as well as in the cement material [8,9] surrounding the hyphae. Furthermore, zinc, copper and calcium concentrations were significantly higher in M. mycetomatis infected tissues than in control tissue which could be contributed to the formation of the grain cement matrix [10].…”

Addressing the Most Neglected Diseases through an Open Research Model: the Discovery of Fenarimols as Novel Drug Candidates for Eumycetoma

“…Within the grain, intrahyphal growth is observed [47] and the hyphae themselves are embedded in cement material, which makes it difficult for each drug to reach the metabolically active part of the fungus. Although the exact constituents of this cement material are still unknown, chitin [49] and beta-glucan [50] are known to be involved. These constituents are implicated in the reduced antifungal susceptibility of fungal biofilms [51].…”