Top

Published in:

05-12-2023 | Toxoplasmosis | Original Article

Modulation of CXCL10 activity as a therapeutic target of ocular toxoplasmosis in diabetic mice

Authors: Mennat-Elrahman Ahmed Fahmy, Amany Ahmed Abdel-Aal, Maisa Ahmed Shalaby, Ragaa Issa, Manal Badawi, Marwa A. Fouly

Published in: Journal of Parasitic Diseases | Issue 1/2024

Abstract

Ocular toxoplasmosis is likely the most common cause of infectious posterior uveitis worldwide. CXCL10 chemokine has an important role in the maintenance of the T-cell response and the control of Toxoplasma gondii in the eye during chronic infection. Drugs that can modulate the chemokine activity could be effective against the parasite. In this work, CXCL10 local retinal expression was investigated in a diabetic mouse model with ocular toxoplasmosis for the first time. In addition, the efficacy of naphthoquinones and quinolones was compared to spiramycin (SP) in treating the infection and modulating the chemokine expression. Our results revealed that chloroquine (CQ) achieved the best results regarding the reduction of cerebral cyst burden (84.36%), improving the retinal histopathological changes, cellular infiltrates, and vasculitis significantly (P < 0.005), and balancing the strong CXCL10 expression caused by the infection. Buparvaquone-treated mice showed a significant percentage of reduction of brain cysts (76.25%), moderate improvement of histopathology, and mild to moderate CXCL10 expression. While SP showed the least efficacy against the parasite in the eye in the form of mild improvement of histopathological changes and downregulation of retinal chemokine expression with the least reduction rate of cerebral parasitic burden (57%). In conclusion, Optimal control of pathogens probably needs a balanced immune response with an optimum expression of chemokines. So, targeting the modulation of retinal CXCL10 may eventually be beneficial in the management of ocular toxoplasmosis plus its potential to act as a marker for predictive local immunological response during the infection.

Arruda S, Vieira BR, Garcia DM, Araújo M, Simões M, Moreto R, Rodrigues MW Jr, Belfort R Jr, Smith JR, Furtado JM (2021) Clinical manifestations and visual outcomes associated with ocular toxoplasmosis in a Brazilian population. Sci Rep 11:3137. https://doi.org/10.1038/s41598-021-82830-zADSCrossRefPubMedPubMedCentral

Ashour D (2018) Toxoplasma gondii: a journey into the brain. Acta Sci Microbiol 1:72–73. https://doi.org/10.31080/ASMI.2018.01.0042CrossRef

Ayachit S, Dunne K, Wagih W (2016) Spiramycin: a safe and effective option for treatment of ocular toxoplasmosis. Bahrain Med Bull 38:116–118. https://doi.org/10.12816/0047618CrossRef

Bonfioli AA, Orefice F (2005) Toxoplasmosis. Semin Ophthalmol 20:129–141CrossRefPubMed

Carr DJ, Chodosh J, Ash J, Lane TE (2003) Effect of anti-CXCL10 monoclonal antibody on herpes simplex virus type 1 keratitis and retinal infection. J Virol 77(18):10037–10046. https://doi.org/10.1128/jvi.77.18.10037-10046.2003CrossRefPubMedPubMedCentral

Catchpole A, Zabriskie BN, Bassett P, Embley B, White D, Gale SD, Hedges D (2023) Association between Toxoplasma gondii infection and type-1 diabetes mellitus: a systematic review and meta-analysis. Int J Environ Res Public Health 20(5):4436. https://doi.org/10.3390/ijerph20054436CrossRefPubMedPubMedCentral

Cecchinato V, Martini V, Pirani E, Ghovehoud E, Uguccioni M (2023) The chemokine landscape: one system multiple shades. Front Immunol 11(14):1176619. https://doi.org/10.3389/fimmu.2023.1176619CrossRef

Chen H, Zhang X, Liao N, Wen F (2017) Assessment of biomarkers using multiplex assays in aqueous humor of patients with diabetic retinopathy. BMC Ophthalmol 17(1):176. https://doi.org/10.1186/s12886-017-0572-6CrossRefPubMedPubMedCentral

Corrado A, Ferrari SM, Ferri C, Ferrannini E, Antonelli A, Fallahi P (2014) Type 1 diabetes and (C-X-C motif) ligand (CXCL) 10 chemokine. Clin Ter 165(2):e181–e185. https://doi.org/10.7471/CT.2014.1706CrossRefPubMed

da Costa-Silva TA, Galisteo AJ Jr, Lindoso JA, Barbosa LR, Tempone AG (2017) Nanoliposomal buparvaquone immunomodulates Leishmania infantum-infected macrophages and is highly effective in a murine model. Antimicrob Agents Chemother 61(4):e02297-e2316. https://doi.org/10.1128/AAC.02297-16CrossRefPubMedPubMedCentral

de Almeida Júnior RF, de Souza KSC, Galdino OA, da Silva Junior AA, Arrais RF, Machado PRL, Farias KJS, de Rezende AA (2020) Chloroquine as a promising adjuvant therapy for type 1 diabetes mellitus. Sci Rep 10(1):12098. https://doi.org/10.1038/s41598-020-69001-2ADSCrossRefPubMedPubMedCentral

Dias RR, Carvalho EC, Leite CC, Tedesco RC, Calabrese Kda S, Silva AC, DaMatta RA, de Fatima S-S (2014) Toxoplasma gondii oral infection induces intestinal inflammation and retinochoroiditis in mice genetically selected for immune oral tolerance resistance. PLoS ONE 9(12):e113374. https://doi.org/10.1371/journal.pone.0113374ADSCrossRefPubMedPubMedCentral

Etewa SE, El-Maaty DAA, Hamza RS, Metwaly AS, Sarhan MH, Abdel-Rahman SA, Fathy GM, El-Shafey MA (2018) Assessment of spiramycin-loaded chitosan nanoparticles treatment on acute and chronic toxoplasmosis in mice. J Parasit Dis 42:102–113. https://doi.org/10.1007/s12639-017-0973-8CrossRefPubMed

Fahmy MEA, Abdel-Aal AA, Hassan SI, Shalaby MA, Esmat M, Abdel Shafi IR, Afife AA, Shaheen HAA (2023) The superior efficacy of chloroquine over buparvaquone in reducing the chronic cerebral Toxoplasma gondii cysts load and improving the ultrastructural pathology in an immunocompromised murine model. Trop Biomed 40(1):115–123. https://doi.org/10.47665/tb.40.1.018CrossRefPubMed

Franco PS, Gomes AO, Barbosa BF, Angeloni MB, Silva NM, Teixeira-Carvalho A, Martins-Filho OA, Silva DA, Mineo JR, Ferro EA (2011) Azithromycin and spiramycin induce anti-inflammatory response in human trophoblastic (BeWo) cells infected by Toxoplasma gondii but are able to control infection. Placenta 32(11):838–844. https://doi.org/10.1016/j.placenta.2011.08.012CrossRefPubMed

Furman BL (2015) Streptozotocin-induced diabetic models in mice and rats. Curr Protoc Pharmacol. https://doi.org/10.1002/0471141755CrossRefPubMed

Gaafar KM, Khedr MI, Bashandy SA, Sharaf OA, El-Zayat SR (2002) Effect of chloroquine on glucose metabolism. Arzneimittelforschung 52(5):400–406. https://doi.org/10.1055/s-0031-1299905CrossRefPubMed

Gamea G, Elmehy D, Salama A, Soliman N, Afifi O, Hassan H, Abo el Gheit R, El-Ebiary A, Tahoon D, Elkholy R, Shoeib S, Eleryan M, Younis S (2022) Direct and indirect antiparasitic effects of chloroquine against the virulent RH strain of Toxoplasma gondii: An experimental study. Acta Trop 232:106508. https://doi.org/10.1016/j.actatropica.2022.106508CrossRefPubMed

Gaynes BI, Torczynski E, Varro Z, Grostern R, Perlman J (2008) Retinal toxicity of chloroquine hydrochloride administered by intraperitoneal injection. J Appl Toxicol 28(7):895–900. https://doi.org/10.1002/jat.1353CrossRefPubMed

Gudowska-Sawczuk M, Mroczko B (2022) What is currently known about the role of CXCL10 in SARS-CoV-2 Infection? Int J Mol Sci 23(7):3673. https://doi.org/10.3390/ijms23073673CrossRefPubMedPubMedCentral

Kang JM, Lee HS, Kim J, Yang DH, Jeong HY, Lee YH, Kim DJ, Park SH, Sung M, Kim J, An HJ, Lee SH, Lee SY (2020) Beneficial effect of chloroquine and amodiaquine on type 1 diabetic Tubulopathy by attenuating mitochondrial Nox4 and endoplasmic reticulum stress. J Korean Med Sci 35(36):e305. https://doi.org/10.3346/jkms.2020.35.e305CrossRefPubMedPubMedCentral

Khan IA, MacLean JA, Lee FS, Casciotti L, DeHaan E, Schwartzman JD, Luster AD (2000) IP-10 is critical for effector T cell trafficking and host survival in toxoplasma gondii infection. Immunity 12(5):483–494. https://doi.org/10.1016/s1074-7613(00)80200-9CrossRefPubMed

Laferriere CA, Leung VS, Pang DS (2020) Evaluating intrahepatic and intraperitoneal sodium pentobarbital or ethanol for mouse Euthanasia. J Am Assoc Lab Anim Sci 59(3):264–268. https://doi.org/10.30802/AALAS-JAALAS-19-000097CrossRefPubMedPubMedCentral

Lee JH, Kim B, Jin WJ, Kim HH, Ha H, Lee ZH (2017) Pathogenic roles of CXCL10 signaling through CXCR3 and TLR4 in macrophages and T cells: relevance for arthritis. Arthritis Res Ther 19(1):163. https://doi.org/10.1186/s13075-017-1353-6CrossRefPubMedPubMedCentral

Li B, Zhang T, Liu W, Wang Y, Xu R, Zeng S, Zhang R, Zhu S, Gillies MC, Zhu L, Du J (2020) Metabolic features of mouse and human retinas: rods versus cones, macula versus periphery. Retina versus RPE Iscience 23(11):101672. https://doi.org/10.1016/j.isci.2020.101672CrossRefPubMed

Lyons RE, Anthony JP, Ferguson DJ, Byrne N, Alexander J, Roberts F, Roberts CW (2001) Immunological studies of chronic ocular toxoplasmosis: up-regulation of major histocompatibility complex class I and transforming growth factor beta and a protective role for interleukin-6. Infect Immun 69(4):2589–2595. https://doi.org/10.1128/IAI.69.4.2589-2595.2001CrossRefPubMedPubMedCentral

Mahon GJ, Anderson HR, Gardiner TA, McFarlane S, Archer DB, Stitt AW (2004) Chloroquine causes lysosomal dysfunction in neural retina and RPE: implications for retinopathy. Curr Eye Res 28(4):277–284. https://doi.org/10.1076/ceyr.28.4.277.27835CrossRefPubMed

Marín-García P-J, Planas N, Llobat L (2022) Toxoplasma gondii in foods: prevalence, control, and safety. Foods 11(16):2542. https://doi.org/10.3390/foods11162542CrossRefPubMedPubMedCentral

McGovern KE, Wilson EH (2013) Role of chemokines and trafficking of immune cells in parasitic infections. Curr Immunol Rev 9(3):157–168. https://doi.org/10.2174/1573395509666131217000000CrossRefPubMedPubMedCentral

Mhadhbi M, Chaouch M, Ajroud K, Darghouth MA, BenAbderrazak S (2015) Sequence polymorphism of cytochrome b gene in Theileria annulata Tunisian isolates and its association with buparvaquone treatment failure. PLoS ONE 2015:10

Mokua Mose J, Muchina Kamau D, Kagira JM, Maina NW, Ngotho M, Njuguna AN, Karanja SM (2017) Development of neurological mouse model for toxoplasmosis using toxoplasma gondii isolated from Chicken in Kenya. Pathol Res Int. https://doi.org/10.1155/2017/4302459CrossRef

Molteni M, Gemma S, Rossetti C (2016) The role of toll-like receptor 4 in infectious and noninfectious inflammation. Mediators Inflamm 2016:6978936. https://doi.org/10.1155/2016/6978936CrossRefPubMedPubMedCentral

Müller J, Aguado-Martínez A, Ortega-Mora LM, Moreno-Gonzalo J, Ferre I, Hulverson MA, Choi R, McCloskey MC, Barrett LK, Maly DJ, Ojo KK, Van Voorhis W, Hemphill A (2017) Development of a murine vertical transmission model for Toxoplasma gondii oocyst infection and studies on the efficacy of bumped kinase inhibitor (BKI)-1294 and the naphthoquinone buparvaquone against congenital toxoplasmosis. J Antimicrob Chemother 72:2334–2341. https://doi.org/10.1093/jac/dkx134CrossRefPubMedPubMedCentral

Norose K, Kikumura A, Luster AD, Hunter CA, Harris TH (2011) CXCL10 is required to maintain T-cell populations and to control parasite replication during chronic ocular toxoplasmosis. Invest Ophthalmol vis Sci 52(1):389–398. https://doi.org/10.1167/iovs.10-5819CrossRefPubMedPubMedCentral

Ramos-Vara JA, Miller MA (2014) When tissue antigens and antibodies get along: revisiting the technical aspects of immunohistochemistry - the red, brown, and blue technique. Vet Pathol 51(1):42–87. https://doi.org/10.1177/0300985813505879CrossRefPubMed

Rashighi M, Harris JE (2015) Interfering with the IFN-γ/CXCL10 pathway to develop new targeted treatments for vitiligo. Ann Transl Med 3(21):343. https://doi.org/10.3978/j.issn.2305-5839.2015.11.36CrossRefPubMedPubMedCentral

Richard SA, Kampo S, Hechavarria ME, Sackey M, Buunaaim ADB, Kuugbee ED, Anabah TW (2020) Elucidating the pivotal immunomodulatory and anti-inflammatory potentials of chloroquine and hydroxychloroquine. J Immunol Res 25:582612. https://doi.org/10.1155/2020/4582612CrossRef

Schrezenmeier E, Dörner T (2020) Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 16(3):155–166. https://doi.org/10.1038/s41584-020-0372-xCrossRefPubMed

Schulthess FT, Paroni F, Sauter NS, Shu L, Ribaux P, Haataja L, Strieter RM, Oberholzer J, King CC, Maedler K (2009) CXCL10 impairs beta cell function and viability in diabetes through TLR4 signaling. Cell Metab 9(2):125–139. https://doi.org/10.1016/j.cmet.2009.01.003CrossRefPubMed

Sokol CL, Luster AD (2015) The chemokine system in innate immunity. Cold Spring Harb Perspect Biol 7(5):a016303. https://doi.org/10.1101/cshperspect.a016303CrossRefPubMedPubMedCentral

Spalenka J, Escotte-Binet S, Bakiri A, Hubert J, Renault JH, Velard F, Duchateau S, Aubert D, Huguenin A, Villena I (2018) Discovery of new inhibitors of toxoplasma gondii via the pathogen box. Antimicrob Agents Chemother 62(2):e01640-e1717. https://doi.org/10.1128/AAC.01640-17CrossRefPubMedPubMedCentral

Sun ZH, Li F, Li YF, Wang M, Li YN, Li L, Yu H, Tang GX, Sun RX (2022) Anti-CXCL10 monoclonal antibody therapy protects against the diabetic retinopathy in the mouse model induced by streptozotocin. Tissue Cell 76:101745. https://doi.org/10.1016/j.tice.2022.101745CrossRefPubMed

Tavares HS, Cardoso JF, Almeida TC, Marques MBF, Mussel WN, Lopes MCP, Oréfice RL, Andrade SN, Varotti FP, Silva GN, Da Silva GR (2021) Spiramyin-loaded PLGA implants for the treatment of ocular toxoplasmosis: development, characterization, biocompatibility, and anti-toxoplasma activity. Pharmazie 76(2):68–76. https://doi.org/10.1691/ph.2021.0100CrossRefPubMed

Tokunaga R, Zhang W, Naseem M, Puccini A, Berger MD, Soni S, McSkane M, Baba H, Lenz HJ (2018) CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation—a target for novel cancer therapy. Cancer Treat Rev 63:40–47. https://doi.org/10.1016/j.ctrv.2017.11.007CrossRefPubMed

Volland S, Esteve-Rudd J, Hoo J, Yee C, Williams DS (2015) A comparison of some organizational characteristics of the mouse central retina and the human macula. PLoS ONE 10(4):e0125631. https://doi.org/10.1371/journal.pone.0125631CrossRefPubMedPubMedCentral

Vujosevic S, Micera A, Bini S, Berton M, Esposito G, Midena E (2016) Proteome analysis of retinal glia cells-related inflammatory cytokines in the aqueous humour of diabetic patients. Acta Ophthalmol 94(1):56–64. https://doi.org/10.1111/aos.12812CrossRefPubMed

Wallace GR, Stanford MR (2008) Immunity and toxoplasma retinochoroiditis. Clin Exp Immunol 153(3):309–315. https://doi.org/10.1111/j.1365-2249.2008.03692.xCrossRefPubMedPubMedCentral

Wittebole X, Castanares-Zapatero D, Laterre PF (2010) Toll-like receptor 4 modulation as a strategy to treat sepsis. Mediators Inflamm. https://doi.org/10.1155/2010/568396CrossRefPubMedPubMedCentral

Wu M, Liu S, Chen Y, Liu D, An R, Cai H, Wang J, Zhou N, Obed C, Han M, Shen J, Chen L, Du J (2022) Live-attenuated ME49Δcdpk3 strain of Toxoplasma gondii protects against acute and chronic toxoplasmosis. NPJ Vaccin 7(1):98. https://doi.org/10.1038/s41541-022-00518-5CrossRef

Wuest TR, Carr DJ (2008) Dysregulation of CXCR3 signaling due to CXCL10 deficiency impairs the antiviral response to herpes simplex virus 1 infection. J Immunol 181(11):7985–7993. https://doi.org/10.4049/jimmunol.181.11.7985CrossRefPubMed

Yang J, Zou T, Yang F, Zhang Z, Sun C, Yang Z, Zhang H (2021) A quick protocol for the preparation of mouse retinal cryosections for immunohistochemistry. Open Biol 11(7):210076. https://doi.org/10.1098/rsob.210076CrossRefPubMedPubMedCentral

Yogeswaran K, Furtado JM, Bodaghi B, Matthews JM (2023) International ocular toxoplasmosis study group; Smith JR. current practice in the management of ocular toxoplasmosis. Br J Ophthalmol 107(7):973–979. https://doi.org/10.1136/bjophthalmol-2022-321091CrossRefPubMed

Yoon KC, Park CS, You IC, Choi HJ, Lee KH, Im SK, Park HY, Pflugfelder SC (2010) Expression of CXCL9, -10, -11, and CXCR3 in the tear film and ocular surface of patients with dry eye syndrome. Invest Ophthalmol vis Sci 51(2):643–650. https://doi.org/10.1167/iovs.09-3425CrossRefPubMedPubMedCentral

Yuan X, Xiao YC, Zhang GP, Hou N, Wu XQ, Chen WL, Luo JD, Zhang GS (2016) Chloroquine improves left ventricle diastolic function in streptozotocin-induced diabetic mice. Drug Des Devel Ther 30(10):2729–2737. https://doi.org/10.2147/DDDT.S111253CrossRef

Zare-Bidaki M, Hakimi H, Abdollahi SH, Zainodini N, Arababadi MK, Kennedy D (2014) TLR4 in Toxoplasmosis; friends or foe? Microb Pathog 69–70:28–32. https://doi.org/10.1016/j.micpath.2014.03.006CrossRefPubMed

Zhou L, He X, Cai P, Li T, Peng R, Dang J, Li Y, Li H, Huang F, Shi G, Xie C, Lu Y, Chen Y (2021) Induced regulatory T cells suppress Tc1 cells through TGF-β signaling to ameliorate STZ-induced type 1 diabetes mellitus. Cell Mol Immunol 18:698–710. https://doi.org/10.1038/s41423-020-00623-2CrossRefPubMedPubMedCentral

Title: Modulation of CXCL10 activity as a therapeutic target of ocular toxoplasmosis in diabetic mice
Authors: Mennat-Elrahman Ahmed Fahmy
Amany Ahmed Abdel-Aal
Maisa Ahmed Shalaby
Ragaa Issa
Manal Badawi
Marwa A. Fouly
Publication date: 05-12-2023
Publisher: Springer India
Keywords: Toxoplasmosis
Chloroquin
Chloroquin
Vasculitis
Vasculitis
Published in: Journal of Parasitic Diseases / Issue 1/2024
Print ISSN: 0971-7196
Electronic ISSN: 0975-0703
DOI: https://doi.org/10.1007/s12639-023-01635-1

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2024

3-styrylcoumarin scaffold-based derivatives as a new approach for leishmaniasis intervention: biological and molecular modeling studies

Intestinal Parasites Associated with American Cockroach (Periplaneta americana) in Akure, Ondo State, Nigeria

Correction: Anthelmintic and therapeutic effects of the biogenic zinc oxide nanoparticles against acute kidney injury induced by Parascaris equorum Infection in rats

Ovicidal, larvicidal and adulticidal activity of black pepper (Piper nigrum L.) essential oil and tea tree oil (Melaleuca alternifolia) against Haemonchus contortus

Anthelmintic efficacy of Phlogacanthus thyrsiflorus leaf extract on juvenile and adult worms of Hymenolepis diminuta (Cestoda)

An investigation of the prevalence of equine filariosis in North and Northeast of Iran

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials