Biology:Cruzipain
Cruzipain is a cysteine protease expressed by Trypanosoma cruzi.[1]
It is classified under EC 3.4.22.51.
Cruzipain is expressed by all strains and developmental forms of Trypanosoma cruzi. It is secreted and can be found in the membrane of the parasite.[2]
The study of Trypanosoma cruzi virulence is difficult due to the complexity of the parasite’s biology. Trypanosoma cruzi has two different infective forms which are both biochemically and antigenically distinct. The two forms, MTs and blood trypomastigotes use distinct sets of surface molecules to interact with their respective hosts. Trypanosoma cruzi also uses unique processes for gene expression, such as RNA editing, trans-splicing, and constitutive polycistronic transcription of protein-coding genes. In the absence of mechanisms controlling initiation of transcription, extracellular signals will trigger subsets of Trypanosoma cruzi genes to be post-transcriptionally co-regulated.[3]
Cruzipain is part of clan CA, a group of papain-like protease enzymes. Clan CA is the most studied class of cysteine proteinases in parasitic protozoa. The localization of cruzipain within the cell differs based on which stage of the biological cycle the parasite is in. Cruzipain is involved in aiding the parasite in penetrating and evading the immune response of the host. The cysteine peptidases within parasitic protozoa are pivotal for several biological processes. Metamorphosis, immune evasion, and adaptation to certain hosts are some of the processes that cruzipain can exert influence over.[4]
Cruzipain is a sulfated glycoprotein which plays a role in the parasitic disease known as Chagas disease. It is found to aid the parasite in entering the host cell and in evading an immune response.[5]
Cruzipain can help parasites escape the response from the adaptive immune system by interfering with the functions of immunoglobulins from the immunoglobin G subclasses.[6] These immunoglobulins are bound to receptors[7] and cruzipain interacts with these immunoglobulins by cleaving their hinges.[6]
During smooth muscle cell invasion, cruzipain may mobilize vasoconstricting endothelin receptors, which may interfere with the vasoconstrictor's ability to cause the blood vessels to become narrower.[6]
Cruzipain aids in the process of breaking down host tissue and is prepared to signal the escape mechanism if it detects any response from the host's immune system.[8]
Cruzipain as a DNA-based therapeutic vaccine
It has been reported that cruzipain is an efficient prophylactic vaccine, combined with several adjuvants, and administered through different routes. Results have been found using a cruzipain DNA-based vaccine that has demonstrated a decrease in parasitemia, inflammatory cell infiltrate, and tissue damage in models of infection caused by Trypanosoma cruzi. In the experiment, chagasin, a natural protein of Trypanosoma cruzi, and a tight binding inhibitor of papain-like cysteine proteases is used. Chagasin regulates the activity of cruzipain by controlling the functions that are necessary for parasitic invasion into mammalian cells. By combining the DNA of cruzipain and chagasin to synthesize a vaccine, a balanced immune response that decreases blood and tissue parasites, as well as the tissue damage caused by Trypanosoma cruzi infection can be induced.[2]
Chemotherapy of chronic Chagas disease
There are currently only two drugs in use for the treatment of Chagas disease, specifically nifurtimox and benznidazole. Both of these drugs require long use, cause adverse side effects, and have controversial efficacy in adults infected with Trypanosoma cruzi. Recently, through drug repurposing, a strategy which utilizes existing drugs for new therapeutic purposes, the trypanocidal effects of benidipine and clofazimine have been discovered. These drugs showed the ability to inhibit cruzipain, by diminishing the burden of the parasite in skeletal and cardiac muscles, as well as by reducing the inflammatory response in the tissues of Trypanosoma cruzi infected mice.[9]
References
- ↑ "Congopain from Trypanosoma congolense: drug target and vaccine candidate". Biological Chemistry 383 (5): 739–49. May 2002. doi:10.1515/BC.2002.077. PMID 12108538. http://agritrop.cirad.fr/542066/1/document_542066.pdf.
- ↑ 2.0 2.1 Cerny, Natacha; Bivona, Augusto Ernesto; Sanchez Alberti, Andrés; Trinitario, Sebastián Nicolás; Morales, Celina; Cardoso Landaburu, Alejandro; Cazorla, Silvia Inés; Malchiodi, Emilio Luis (2020). "Cruzipain and Its Physiological Inhibitor, Chagasin, as a DNA-Based Therapeutic Vaccine Against Trypanosoma cruzi" (in English). Frontiers in Immunology 11: 565142. doi:10.3389/fimmu.2020.565142. ISSN 1664-3224. PMID 33162979.
- ↑ Juan San Francisco, Iván Barría, Bessy Gutiérreza, Iván Neira, Christian Muñoza, Hernán Sagua, Jorge E. Araya, Juan Carlos Andradea, Anibal Zailberger, Alejandro Catalána, Francisco Remonsellez, José Luis Vega, Jorge González (January 2017). "Decreased cruzipain and gp85/trans-sialidase family protein expression contributes to loss of Trypanosoma cruzi trypomastigote virulence". Microbes and Infection 19 (1): 55–61. doi:10.1016/j.micinf.2016.08.003. PMID 27553285.
- ↑ Reyes-Espinosa, Francisco, Juárez-Saldivar, Alfredo, Rivera, Gildardo, Herrera-Mayorga, Verónica, Palos, Isidro, García-Pérez, Carlos (Mar 2019). "In Silico Analysis of Homologous Heterodimers of Cruzipain-Chagasin from Structural Models Built by Homology". International Journal of Molecular Sciences 20 (6): 1320. doi:10.3390/ijms20061320. PMID 30875920.
- ↑ "Cruzipain, the major cysteine protease of Trypanosoma cruzi: a sulfated glycoprotein antigen as relevant candidate for vaccine development and drug target. A review". Current Medicinal Chemistry 16 (24): 3174–202. 2009. doi:10.2174/092986709788802971. PMID 19689291.
- ↑ 6.0 6.1 6.2 "Cruzipain promotes Trypanosoma cruzi adhesion to Rhodnius prolixus midgut". PLOS Neglected Tropical Diseases 6 (12): e1958. December 2012. doi:10.1371/journal.pntd.0001958. PMID 23272264.
- ↑ "IgG subclasses and allotypes: from structure to effector functions". Frontiers in Immunology 5: 520. 2014-10-20. doi:10.3389/fimmu.2014.00520. PMID 25368619.
- ↑ "Pilot Field Trial of the EG95 Vaccine Against Ovine Cystic Echinococcosis in Rio Negro, Argentina: Second Study of Impact". PLOS Neglected Tropical Diseases 9 (10): e0004134. 2017-06-01. doi:10.1371/journal.pntd.0004134. PMID 26517877.
- ↑ María L. Sbaraglini, Carolina L. Bellera, Laura Fraccaroli, Luciana Larocca, Carolina Carrillo, Alan Talevi, Catalina D. Alba Soto (July 2016). "Novel cruzipain inhibitors for the chemotherapy of chronic Chagas disease". International Journal of Antimicrobial Agents 48 (1): 91–95. doi:10.1016/j.ijantimicag.2016.02.018. PMID 27216381.
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