Can Fasciola hepatica modulate the severity of COVID–19?

• Marco Cabrera–González Instituto Nacional de Innovación Agraria, Estación Experimental Baños del Inca, Laboratorio de Biotecnología en Sanidad Animal. Baños del Inca, Cajamarca, Perú
• Carlos Quilcate–Pairazamán Instituto Nacional de Innovación Agraria, Dirección de Desarrollo Tecnológico Agrario. La Molina, Lima, Perú
• Medali Cueva–Rodríguez Instituto Nacional de Innovación Agraria, Estación Experimental Baños del Inca, Laboratorio de Biotecnología en Sanidad Animal. Baños del Inca, Cajamarca, Perú

DOI: https://doi.org/10.52973/rcfcv-e34330

Keywords: Fasciola hepatica, cathepsins L/B, viral entry and replication, SARS–CoV–2, COVID–19

Abstract

Peru is considered a hyperendemic zone of fasciolosis with a prevalence between 6.7 and 47.7% (average 24.4%) in humans. In this area, the efficacy of Triclabendazole in cattle is only 25.2%, therefore the presence of resistant strains is widely distributed. The problem is accentuated by being a zoonotic disease. In addition, Triclabendazole is the only effective drug against the different forms of the parasite. Cathepsins L and B are involved in the migration, nutrition, reproduction, and evasion of the immune response and survival of Fasciola hepatica. When analyzing the process in which the SARS–CoV–2 virus enters the cell, the presence of cellular transmembrane serine protease 2 (TMPRSS2) and Cathepsin L/B (CTSL) is required; where TMPRSS2 activates viral S–glycoprotein to fuse the cell with the viral membrane, whereas viral S–glycoprotein is activated by CTSL, allowing viral and endosomal membrane fusion, virus infecting the host cell is of concern to estimate the possible effect that it could generate in populations infected with F. hepatica because an existing coinfection is needed, as a result of the systemic increase of the Cathepsins L/B secreted by this parasite and the survival within the definitive host, possibly these populations are become more susceptible to viral infection by co–infection with the parasite; calling on the scientific community to identify parasite control alternatives and not have an associated problem in the short term.

References

Gluchowska K, Dzieci T, Atkowski S, Edzikowska A, Zawistowska–Deniziak A, Młocicki D, Sebastiani M, Stefá W. Pandemic–Risk Factors or Protective Agents? J. Clin. Med. [Internet]. 2021; 10(11):2533. doi: https://doi.org/mknx

Muñoz–Zambrano ME, Placencia–Medina M, Del Pozo–Muñoz JA, Sevilla–Andrade C, Huiza–Franco A. Serological diagnosis of Fasciola hepatica infection: a systematic review. Rev. Gastroenterol. Peru. [Internet]. 2020; 40(2):155–161. doi: https://doi.org/dm8c

Peixoto R, Silva LMR, López–Osório S, Zhou E., Gärtner U, Conejeros I, Taubert A, Hermosilla C. Fasciola hepatica induces weak NETosis and low production of intra– and extracellular ROS in exposed bovine polymorphonuclear neutrophils. Develop. Compar. Immunol. [Internet]. 2021; 114:103787. doi: https://doi.org/gqdtfj

Saijuntha W, Tantrawatpan C, Agatsuma T, Wang C, Intapan PM, Maleewong W, Petney TN. Revealing genetic hybridization and DNA recombination of Fasciola hepatica and Fasciola gigantica in nuclear introns of the hybrid Fasciola fl ukes. Molec. Biochem. Parasitol. [Internet]. 2018; 223:31–36. doi: https://doi.org/gd3f6f

Pritchard GC, Forbes AB, Williams DJ, Salimi–Bejestani MR, Daniel RG. Emergence of fasciolosis in cattle in East Anglia. Vet. Rec. [Internet]. 2005;157(19): 578–82. doi: https://doi.org/mknz

Miranda–Miranda E, Cossio–Bayugar R, Aguilar–Díaz H, Narváez–Padilla V, Sachman–Ruíz B, Reynaud E. Transcriptome assembly dataset of anthelmintic response in Fasciola hepatica. Data Brief. [Internet]. 2021; 35:106808. doi: https://doi.org/hvzb

Pinilla JC, Florez AA, Orlandoni G, Tobón JC, Ortíz D. Current status of prevalence and risk factors associated with liver fluke Fasciola hepatica in cattle raised in different altitudinal regions of Colombia. Vet. Parasitol: Regional Studies Reports. [Internet]. 2020; 22:100487. doi: https://doi.org/hvzp

Beesley NJ, Attree E, Vázquez–Prieto S, Vilas R, Paniagua E, Ubeira FM, Jensen O, Pruzzo C, Álvarez JD, Malandrini JB, Solana H, Hodgkinson JE. Evidence of population structuring following population genetic analyses of Fasciola hepatica from Argentina. Intern. J. Parasitol [Internet]. 2021; 51(6):471–480. doi: https://doi.org/htj6

Calvani NED, Ichikawa–Seki M, Bush RD, Khounsy S, Šlapeta J. Which species is in the faeces at a time of global livestock movements: single nucleotide polymorphism genotyping assays for the differentiation of Fasciola spp. Intern. J. Parasitol. [Internet]. 2020; 50(2):91–101. doi: https://doi.org/htj9

Addy F, Gyan K, Arhin E, Wassermann M. Prevalence of bovine fasciolosis from the Bolgatanga abattoir, Ghana. Scientific. African. [Internet]. 2020; 8:e00469. doi: https://doi.org/htc6

Mas–Coma S. Epidemiology of fascioliasis in human endemic areas. J. Helminthol. [Internet]. 2005; 79:207–216. doi: https://doi.org/b43x3r

Walsh TR, Ainsworth S, Armstrong S, Hodgkinson J, Williams D. Differences in the antibody response to adult Fasciola hepatica excretory/secretory products in experimentally and naturally infected cattle and sheep. Vet. Parasitol. [Internet]. 2021; 289:109321. doi: https://doi.org/gtkznx

Ramírez JD, Sordillo EM, Gotuzzo E, Zavaleta C, Caplivski D, Navarro JC, Crainey JL, Luz SLB, Delgado LA, Schaub R, Rousseau C, Herrera G, Oliveira–Miranda MA, Quispe–Vargas MT, Hotez PJ, Mondolfi AP. Sars–cov–2 in the amazon region: A harbinger of doom for amerindians. PLoS Neglect. Trop. Dis. [Internet]. 2020; 14(10):1–10. doi: https://doi.org/gm5wmt

Rinaldi L, Gonzalez S, Guerrero J, Aguilera LC, Musella V, Genchi C, Cringoli G. A One–Health integrated approach to control fascioliasis in the Cajamarca valley of Peru. Geospat. Health. [Internet]. 2012; 6(3):67–73. doi: https://doi.org/mkn2

Valero MA, Perez–Crespo I, Khoubbane M, Artigas P, Panova M, Ortiz P, Maco V, Espinoza JR, Mas–Coma S. Fasciola hepatica phenotypic characterization in Andean human endemic areas: valley versus altiplanic patterns analysed in liver flukes from sheep from Cajamarca and Mantaro, Perú. Infect. Genet. Evol. [Internet]. 2012; 12(2):403–410. doi: https://doi.org/fzv728

González LC, Esteban JG, Bargues MD, Valero MA, Ortiz P, Náquira C, Mas–Coma S. Hyperendemic human fascioliasis in Andean valleys: an altitudinal transect analysis in children of Cajamarca province, Peru. Acta Trop. [Internet]. 2011;120(1–2):119–129. doi: https://doi.org/fsjsqr

Rodríguez–Ulloa C, Rivera–Jacinto M, Del Valle–Mendoza J, Cerna C, Hoban C, Chilón S. Ortiz P. Risk factors for human fascioliasis in schoolchildren in Baños del Inca, Cajamarca, Perú. Trans. R Soc. Trop. Med. Hyg. [Internet]. 2018; 112(5):216–222. doi: https://doi.org/gnvc2v

Ortiz P, Scarcella S, Cerna C, Rosales C, Cabrera M, Guzmán M, Lamenza P, Solana H. Resistance of Fasciola hepatica against Triclabendazole in cattle in Cajamarca (Perú): a clinical trial and an in vivo efficacy test in sheep. Vet. Parasitol. [Internet]. 2013; 195(1–2):118–121. doi: https://doi.org/f437bh

Donnelly S, O’Neill SM, Sekiya M, Mulcahy G, Dalton JP. Thioredoxin peroxidase secreted by Fasciola hepatica induces the alternative activation of macrophages. Infect. Immun. [Internet]. 2005; 73:166–173. doi: https://doi.org/dtvp2j

Dowling DJ, Hamilton CM, Donnelly S, La Course J, Brophy PM, Dalton J. Major secretory antigens of the helminth Fasciola hepatica activate a suppressive dendritic cell phenotype that attenuates Th17 cells but fails to activate Th2 immune responses. Infect. Immun. [Internet]. 2010; 78:793–801. doi: https://doi.org/c5ccsn

O’Neill SM, Brady MT, Callanan JJ, Mulcahy G, Joyce P, Mills KHG, Dalton JP. Fasciola hepatica Infection Downregulates Th1 Responses in Mice. Parasite Immunol. [Internet]. 2000; 22(3):147–155. doi: https://doi.org/b2mqch

Tort J, Brindley PJ, Knox D, Wolfe KH, Dalton JP. Proteinases and Associated Genes of Parasitic Helminths. Adv. Parasitol. [Internet]. 1999; 43:161–266. doi: https://doi.org/b3mk8k

Sajid M, McKerrow JH. Cysteine Proteases of Parasitic Organisms. Mol. Biochem. Parasitol. [Internet]. 2002; 120(1):1–21. doi: https://doi.org/frqdnq

Robinson MW, Dalton JP, Donnelly S. Helminth Pathogen Cathepsin Proteases: It's a Family Affair. Trends Biochem. Sci. [Internet]. 2008; 33(12):601–608. doi: https://doi.org/fqrqnr

Berasain P, Carmona C, Frangione B, Dalton JP, Goñi F. Fasciola hepatica: Parasite–Secreted Proteinases Degrade All Human IgG Subclasses: Determination of the Specific Cleavage Sites and Identification of the Immunoglobulin Fragments Produced. Exp. Parasitol. [Internet]. 2000; 94(2): 99–110. doi: https://doi.org/dfjdq8

Smith AM, Dowd AJ, Heffernan M, Robertson CD, Dalton JP. Fasciola hepatica: A Secreted Cathepsin L–like Proteinase Cleaves Host Immunoglobulin. Intern. J. Parasitol. [Internet]. 1993; 23(8):977–983. doi: https://doi.org/dzj8ff

Hays R, Pierce D, Giacomin P, Loukas A, Bourke P, McDermott R. Helminth coinfection and covid–19: An alternate hypothesis. PLoS Neglect. Trop. Dis. [Internet]. 2020; 14(8):1–3. doi: https://doi.org/gg9vtw

Abdoli A. Helminths and COVID–19 Co–Infections: A Neglected Critical Challenge. ACS Pharmacol. Translat. Sci. [Internet]. 2020; 3(5):1039–1041. doi: https://doi.org/gmzz4n

Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, Hu Y, Tao ZW, Tian JH, Pei YY, Yuan ML, Zhang YL, Dai FH, Liu Y, Wang QM, Zheng JJ, Xu L, Holmes EC, Zhang YZ. A new coronavirus associated with human respiratory disease in China. Nature. [Internet]. 2020; 579:265–269. doi: https://doi.org/dk2w

Mittal A, Manjunath K, Ranjan RK, Kaushik S, Kumar S, Verma V. COVID–19 pandemic: Insights into structure, function, and hACE2 receptor recognition by SARS–CoV–2. PLoS Pathog. [Internet]. 2020; 16(8):e1008762. doi: https://doi.org/ghtr89

Zhong NS, Zheng BJ, Li YM, Poon LLM, Xie ZH, Chan KH, Li PH, Tan SY. Chang, Q, Xie JP. Epidemiology and cause of severe acute respiratory syndrome (SARS) in 304 Guangdong, People’s Republic of China. Lancet. [Internet]. 2003; 362(9393):1353–1358. doi: https://doi.org/fhgzs9

Zaki AM, Van–Boheemen S, Bestebroer TM, Osterhaus A, Fouchier R. Isolation of a Novel Coronavirus From a Man With Pneumonia in Saudi Arabia. N Engl. J. Med. [Internet]. 2012; 367(19):1814–1820. doi: https://doi.org/f4czx5

Chacin–Bonilla L, Chacón–Fonseca N, Rodriguez–Morales AJ. Emerging issues in COVID–19 vaccination in tropical areas: Impact of the immune response against helminths in endemic areas. Travel Med. Infect. Dis. [Internet]. 2021; 42: 2–4. doi: https://doi.org/gnvj3x

Hoffmann M. SARS–CoV–2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhib. Cell. [Internet]. 2020; 181(2):271–280. doi: https://doi.org/ggnq74

Yan R. Structural Basis for the Recognition of SARS–CoV–2 by Full–Length Human ACE2. Sci. [Internet]. 2020; 367(6485):1444–1448. doi: https://doi.org/ggpxc8

Wrapp D. Cryo–EM structure of the 2019–nCoV spike in the prefusion conformation. Sci. [Internet]. 2020; 367 (6483):1260–1263. doi: https://doi.org/ggmtk2

Bittmann S, Weissenstein A, Villalon G, Moschuring–Alieva E, Luchter E. Simultaneous Treatment of COVID–19 With Serine Protease Inhibitor Camostat and/or Cathepsin L Inhibitor. J. Clin. Med. Res. [Internet]. 2020; 12(5):320–322. doi: https://doi.org/gjvhjr

Smieszek SP, Przychodzen BP, Polymeropoulos MiH. Amantadine Disrupts Lysosomal Gene Expression: A Hypothesis for COVID 19 Treatment. Intern. J. Antimicrob. Agents. [Internet]. 2020; 55(6):106004. doi: https://doi.org/ggv28s

Huang Y, Yang C, Xu X Feng, Xu W, Liu S. Wen. Structural and functional properties of SARS–CoV–2 spike protein: potential antivirus drug development for COVID–19. Acta Pharmacol. Sinica. [Internet]. 2020; 41(9):1141–1149. doi: https://doi.org/ghk6wr

Monserrat J, Gómez AM, Oliva R. Papel del sistema inmune en la infección por el SARS–CoV–2: inmunopatología de la COVID–19. Med. [Internet]. 2021; 13(33):1917–1931. doi: https://doi.org/mkn4

Chaolin H, Yeming W, Xingwang L, Lili R. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. [Internet]. 2020; 395 (10223):497–506. doi: https://doi.org/ggjfnn

De León J, Pareja A, Aguilar P, Enriquez Y, Quiroz C, Valencia E. SARS–CoV–2 y sistema inmune: una batalla de titanes. Horizonte Med. [Internet]. 2020; 20(2):e1209. doi: https://doi.org/mkn5

Bradbury RS, Piedrafita D, Greenhill A, Mahanty S. Will helminth co–infection modulate COVID–19 severity in endemic regions? Nature Rev. Immunol. [Internet]. 2020; 20(6):342. doi: https://doi.org/ggtzdp

Harris NL, Loke P. Recent Advances in Type–2–Cell–Mediated Immunity: Insights from Helminth Infection. Immunity. [Internet]. 2017; 47(6):1024–1036. doi: https://doi.org/gcr6fp

Caffrey CR, Goupil L, Rebello KM, Dalton JP, Smith D. Cysteine proteases as digestive enzymes in parasitic helminths. PLoS Negl. Trop. Dis. [Internet]. 2018; 12(8):5840. doi: https://doi.org/gd5cp8

Mabbott NA. The Influence of Parasite Infections on Host Immunity to Co–infection With Other Pathogens. Front. Immunol. [Internet]. 2018; 9:2579. doi: https://doi.org/gfqc4f

Siles–Lucas M, González–Miguel J, Geller R, Sanjuan R, Pérez–Arévalo J, Martínez–Moreno Á. Potential Influence of Helminth Molecules on COVID–19 Pathol. Trends Parasitol. [Internet]. 2021; 37(1):11–14. https://doi.org/gmcq9d

Ministerio de la Salud. Boletín Epidemiológico del Perú. [Internet]. 2020 [Consultado 22 Jul 2023]; 31 p. Disponible en: https://goo.su/KVf2D7

Luis Raul Rosas–Hostos Infantes LR, Paredes–Yataco GA. Prevalencia global de fasciolosis humana desde 1985 al 2021. [tesis de grado en Internet]. Perú: Universidad Peruana Cayetano Heredia. 2022 [Consultado 12 Jul 2023]. 53 p. Disponible en: https://goo.su/5Tu2uy