Parasite Cystatin: Immunomodulatory Molecule with Therapeutic Activity against Immune Mediated Disorders

Abstract

The use of parasites or their products for treating chronic inflammation associated diseases (CIADs) has generated significant attention recently. Findings from basic and clinical research have provided valuable information on strengthening the notion that parasites’ molecules can be developed as biotherapeutic agents. Completion of the genome, secreotome, and proteome of the parasites has provided an excellent platform for screening and identifying several host immunomodulatory molecules from the parasites and evaluate their therapeutic potential for CIADs. One of the widely studied host immunomodulatory molecules of the parasites is the cysteine protease inhibitor (cystatin), which is primarily secreted by the parasites to evade host immune responses. In this review, we have attempted to summarize the findings to date on the use of helminth parasite-derived cystatin as a therapeutic agent against CIADs. Although several studies suggest a role for alternatively activated macrophages, other regulatory cells, and immunosuppressive molecules, in this immunoregulatory activity of the parasite-derived cystatin, there is still no clear demonstration as to how cystatin induces its anti-inflammatory effect in suppressing CIADs.

Helminth-derived cystatins: the immunomodulatory properties of an Ascaris lumbricoides cystatin

“…2b). Cystatins regulate physiological processes such as larval moulting and play a critical role as immunomodulators in host–parasite interactions by inhibiting cathepsins, antigen processing and presentation, the expression of pattern recognition receptors and modulating cytokines and nitric oxide production (Khatri et al ., 2020). Some of these immunomodulatory properties have been also described for cystatins in the Platyhelminthes Fasciola hepatica and Schistosoma spp.…”

Evolutionary Analysis of Cystatins of Early-Emerging Metazoans Reveals a Novel Subtype in Parasitic Cnidarians

“…In parasites, cystatins are involved in immunomodulation of host cells and represent important immunogenicity and pathogenicity factors involved in host–parasite interactions [ 8 , 9 , 10 , 11 , 12 , 13 ]. They facilitate parasite survival within the host [ 14 , 15 ] by inhibiting host proteases and by interfering with antigen processing and presentation [ 16 , 17 , 18 , 19 ]. The increased capacity of parasite cystatins to induce anti-inflammatory cytokine IL-10 [ 16 , 17 , 20 ] was suggested to be an adaptation to the parasitic lifestyle [ 21 , 22 ].…”

“…They facilitate parasite survival within the host [ 14 , 15 ] by inhibiting host proteases and by interfering with antigen processing and presentation [ 16 , 17 , 18 , 19 ]. The increased capacity of parasite cystatins to induce anti-inflammatory cytokine IL-10 [ 16 , 17 , 20 ] was suggested to be an adaptation to the parasitic lifestyle [ 21 , 22 ]. These molecules have been used as effective markers in diagnosis and vaccine development and as chemotherapeutic targets against various parasitic infections [ 23 , 24 , 25 , 26 , 27 ].…”

Schistosoma japonicum cystatin suppresses osteoclastogenesis via manipulating the NF‑κB signaling pathway

“…Cystatins, endogenous, reversible, and tight-binding inhibitors of cysteine proteinases, have been successfully extracted, cloned, and characterized in different taxonomic groups, from viruses to vertebrates ( 15 ). Based on amino acid sequence similarity and crystal structure variation, the cystatin family is categorized into three distinct subgroups.…”

“…To date, cystatins have been widely researched and confirmed to participate in various physiopathological processes. Mammalian cystatins serve vital roles in immunomodulation, tumorigenesis, and bone remodeling, whereas parasite cystatins significantly contribute to immunosuppression in humans and may be biotherapeutic candidates for autoimmune or allergic diseases, such as asthma and inflammatory colitis ( 15 , 18 – 20 ).…”