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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

The Role of PCSK9 in Infectious Diseases

Author(s): Laura Magnasco, Chiara Sepulcri, Roberta Maria Antonello , Stefano Di Bella, Laura Labate , Roberto Luzzati , Daniele Roberto Giacobbe* and Matteo Bassetti

Volume 29, Issue 6, 2022

Published on: 14 July, 2021

Page: [1000 - 1015] Pages: 16

DOI: 10.2174/0929867328666210714160343

Price: $65

Open Access Journals Promotions 2
Abstract

Background: In recent years, many aspects of the physiological role of PCSK9 have been elucidated, in particular regarding its role in lipid metabolism, cardiovascular risk but also its role in innate immunity. Increasing evidence is available on the involvement of PCSK9 in the pathogenesis of viral infections, mainly HCV, as well as in the regulation of host response to bacterial infections, mainly sepsis and septic shock. Moreover, the action of PCSK9 has been investigated as a crucial step in the pathogenesis of malaria infection and disease severity.

Objective: Aim of this paper is to review available published literature on the role of PCSK9 in a wide array of infectious diseases.

Conclusion: Besides the ongoing investigation on PCSK9 inhibition among HIV-infected patients for the treatment of HIV- and ART-related hyperlipidemia, preclinical studies indicate how PCSK9 is involved in reducing the replication of HCV. Moreover, a protective role of PCSK9 inhibition has also been proposed against dengue and SARS-CoV-2 viral infections. Interestingly, high plasmatic PCSK9 levels have been described in patients with sepsis. Finally, a loss of function in the PCSK9-encoding gene has been reported to possibly reduce mortality in malaria infection.

Keywords: HCV, HIV, sepsis, protozoal infection, viral infection, bacterial infection, immunity.

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[1]
Urban, D.; Pöss, J.; Böhm, M.; Laufs, U. Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. J. Am. Coll. Cardiol., 2013, 62(16), 1401-1408.
[http://dx.doi.org/10.1016/j.jacc.2013.07.056] [PMID: 23973703]
[2]
Kosmas, C.E.; Skavdis, A.; Sourlas, A.; Papakonstantinou, E.J.; Peña Genao, E.; Echavarria Uceta, R.; Guzman, E. Safety and tolerability of PCSK9 inhibitors: current insights. Clin. Pharmacol., 2020, 12, 191-202.
[http://dx.doi.org/10.2147/CPAA.S288831] [PMID: 33335431]
[3]
Page, M.M.; Watts, G.F. PCSK9 inhibitors - mechanisms of action. Aust. Prescr., 2016, 39(5), 164-167.
[http://dx.doi.org/10.18773/austprescr.2016.060] [PMID: 27789927]
[4]
Moşteoru, S.; Gaiţă, D.; Banach, M. An update on PCSK9 inhibitors- pharmacokinetics, drug interactions, and toxicity. Expert Opin. Drug Metab. Toxicol., 2020, 16(12), 1199-1205.
[http://dx.doi.org/10.1080/17425255.2020.1828343] [PMID: 32966148]
[5]
Koskinas, K.C.; Gencer, B.; Nanchen, D.; Branca, M.; Carballo, D.; Klingenberg, R.; Blum, M.R.; Carballo, S.; Muller, O.; Matter, C.M.; Lüscher, T.F.; Rodondi, N.; Heg, D.; Wilhelm, M.; Räber, L.; Mach, F.; Windecker, S. Eligibility for PCSK9 Inhibitors Based on the 2019 ESC/EAS and 2018 ACC/AHA Guidelines. Eur. J. Prev. Cardiol., 2020., 2047487320940102.
[http://dx.doi.org/10.1177/2047487320940102] [PMID: 33755142]
[6]
Ploss, A.; Evans, M.J.; Hepatitis, C. Hepatitis C virus host cell entry. Curr. Opin. Virol., 2012, 2(1), 14-19.
[http://dx.doi.org/10.1016/j.coviro.2011.12.007] [PMID: 22440961]
[7]
Labonté, P.; Begley, S.; Guévin, C.; Asselin, M-C.; Nassoury, N.; Mayer, G.; Prat, A.; Seidah, N.G. PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression. Hepatology, 2009, 50(1), 17-24.
[http://dx.doi.org/10.1002/hep.22911] [PMID: 19489072]
[8]
Momtazi, A.A.; Banach, M.; Sahebkar, A. PCSK9 inhibitors in sepsis: a new potential indication? Expert Opin. Investig. Drugs, 2017, 26(2), 137-139.
[http://dx.doi.org/10.1080/13543784.2017.1272570] [PMID: 27967260]
[9]
Paciullo, F.; Fallarino, F.; Bianconi, V.; Mannarino, M.R.; Sahebkar, A.; Pirro, M. PCSK9 at the crossroad of cholesterol metabolism and immune function during infections. J. Cell. Physiol., 2017, 232(9), 2330-2338.
[http://dx.doi.org/10.1002/jcp.25767] [PMID: 28063230]
[10]
Topchiy, E.; Cirstea, M.; Kong, H.J.; Boyd, J.H.; Wang, Y.; Russell, J.A.; Walley, K.R. Lipopolysaccharide is cleared from the circulation by hepatocytes via the low density lipoprotein receptor. PLoS One, 2016, 11(5), e0155030.
[http://dx.doi.org/10.1371/journal.pone.0155030] [PMID: 27171436]
[11]
Walley, K.R.; Thain, K.R.; Russell, J.A.; Reilly, M.P.; Meyer, N.J.; Ferguson, J.F.; Christie, J.D.; Nakada, T.A.; Fjell, C.D.; Thair, S.A.; Cirstea, M.S.; Boyd, J.H. PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci. Transl. Med., 2014, 6(258), 258ra143.
[http://dx.doi.org/10.1126/scitranslmed.3008782] [PMID: 25320235]
[12]
Boyd, J.H.; Fjell, C.D.; Russell, J.A.; Sirounis, D.; Cirstea, M.S.; Walley, K.R. Increased plasma pcsk9 levels are associated with reduced endotoxin clearance and the development of acute organ failures during sepsis. J. Innate Immun., 2016, 8(2), 211-220.
[http://dx.doi.org/10.1159/000442976] [PMID: 26756586]
[13]
Dwivedi, D.J.; Grin, P.M.; Khan, M.; Prat, A.; Zhou, J.; Fox-Robichaud, A.E.; Seidah, N.G.; Liaw, P.C. Differential expression of pcsk9 modulates infection, inflammation, and coagulation in a murine model of sepsis. Shock, 2016, 46(6), 672-680.
[http://dx.doi.org/10.1097/SHK.0000000000000682] [PMID: 27405064]
[14]
Samuel, B.U.; Mohandas, N.; Harrison, T.; McManus, H.; Rosse, W.; Reid, M.; Haldar, K. The role of cholesterol and glycosylphosphatidylinositol-anchored proteins of erythrocyte rafts in regulating raft protein content and malarial infection. J. Biol. Chem., 2001, 276(31), 29319-29329.
[http://dx.doi.org/10.1074/jbc.M101268200] [PMID: 11352913]
[15]
Mbikay, M.; Mayne, J.; Seidah, N.G.; Chrétien, M. Of PCSK9, cholesterol homeostasis and parasitic infections: possible survival benefits of loss-of-function PCSK9 genetic polymorphisms. Med. Hypotheses, 2007, 69(5), 1010-1017.
[http://dx.doi.org/10.1016/j.mehy.2007.03.018] [PMID: 17502126]
[16]
Sabatine, M.S.; Giugliano, R.P.; Keech, A.C.; Honarpour, N.; Wiviott, S.D.; Murphy, S.A.; Kuder, J.F.; Wang, H.; Liu, T.; Wasserman, S.M.; Sever, P.S.; Pedersen, T.R. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med., 2017, 376(18), 1713-1722.
[http://dx.doi.org/10.1056/NEJMoa1615664] [PMID: 28304224]
[17]
Cheng, J.M.; Oemrawsingh, R.M.; Garcia-Garcia, H.M.; Boersma, E.; van Geuns, R-J.; Serruys, P.W.; Kardys, I.; Akkerhuis, K.M. PCSK9 in relation to coronary plaque inflammation: Results of the atheroremo-ivus study. Atherosclerosis, 2016, 248, 117-122.
[http://dx.doi.org/10.1016/j.atherosclerosis.2016.03.010] [PMID: 27015246]
[18]
Ding, Z.; Wang, X.; Liu, S.; Shahanawaz, J.; Theus, S.; Fan, Y.; Deng, X.; Zhou, S.; Mehta, J.L. PCSK9 expression in the ischaemic heart and its relationship to infarct size, cardiac function, and development of autophagy. Cardiovasc. Res., 2018, 114(13), 1738-1751.
[http://dx.doi.org/10.1093/cvr/cvy128] [PMID: 29800228]
[19]
Norata, G.D.; Tavori, H.; Pirillo, A.; Fazio, S.; Catapano, A.L. Biology of proprotein convertase subtilisin kexin 9: beyond low-density lipoprotein cholesterol lowering. Cardiovasc. Res., 2016, 112(1), 429-442.
[http://dx.doi.org/10.1093/cvr/cvw194] [PMID: 27496869]
[20]
Ricci, C.; Ruscica, M.; Camera, M.; Rossetti, L.; Macchi, C.; Colciago, A.; Zanotti, I.; Lupo, M.G.; Adorni, M.P.; Cicero, A.F.G.; Fogacci, F.; Corsini, A.; Ferri, N. PCSK9 induces a pro-inflammatory response in macrophages. Sci. Rep., 2018, 8(1), 2267.
[http://dx.doi.org/10.1038/s41598-018-20425-x] [PMID: 29396513]
[21]
Tang, Z-H.; Peng, J.; Ren, Z.; Yang, J.; Li, T-T.; Li, T-H.; Wang, Z.; Wei, D-H.; Liu, L-S.; Zheng, X-L.; Jiang, Z-S. New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-κB pathway. Atherosclerosis, 2017, 262, 113-122.
[http://dx.doi.org/10.1016/j.atherosclerosis.2017.04.023] [PMID: 28535426]
[22]
Ding, Z.; Liu, S.; Wang, X.; Deng, X.; Fan, Y.; Shahanawaz, J.; Shmookler Reis, R.J.; Varughese, K.I.; Sawamura, T.; Mehta, J.L. Cross-talk between LOX-1 and PCSK9 in vascular tissues. Cardiovasc. Res., 2015, 107(4), 556-567.
[http://dx.doi.org/10.1093/cvr/cvv178] [PMID: 26092101]
[23]
Ding, Z.; Pothineni, N.V.K.; Goel, A.; Lüscher, T.F.; Mehta, J.L. PCSK9 and inflammation: role of shear stress, pro-inflammatory cytokines, and LOX-1. Cardiovasc. Res., 2020, 116(5), 908-915.
[http://dx.doi.org/10.1093/cvr/cvz313] [PMID: 31746997]
[24]
Feingold, K.R.; Moser, A.H.; Shigenaga, J.K.; Patzek, S.M.; Grunfeld, C. Inflammation stimulates the expression of PCSK9. Biochem. Biophys. Res. Commun., 2008, 374(2), 341-344.
[http://dx.doi.org/10.1016/j.bbrc.2008.07.023] [PMID: 18638454]
[25]
Grin, P.M.; Dwivedi, D.J.; Chathely, K.M.; Trigatti, B.L.; Prat, A.; Seidah, N.G.; Liaw, P.C.; Fox-Robichaud, A.E. Low-density lipoprotein (LDL)-dependent uptake of Gram-positive lipoteichoic acid and Gram-negative lipopolysaccharide occurs through LDL receptor. Sci. Rep., 2018, 8(1), 10496.
[http://dx.doi.org/10.1038/s41598-018-28777-0] [PMID: 30002483]
[26]
Wendel, M.; Paul, R.; Heller, A.R. Lipoproteins in inflammation and sepsis. II. Clinical aspects. Intensive Care Med., 2007, 33(1), 25-35.
[http://dx.doi.org/10.1007/s00134-006-0433-x] [PMID: 17093984]
[27]
Berger, J-M.; Loza Valdes, A.; Gromada, J.; Anderson, N.; Horton, J.D. Inhibition of PCSK9 does not improve lipopolysaccharide-induced mortality in mice. J. Lipid Res., 2017, 58(8), 1661-1669.
[http://dx.doi.org/10.1194/jlr.M076844] [PMID: 28600283]
[28]
Atreya, M.R.; Whitacre, B.E.; Cvijanovich, N.Z.; Bigham, M.T.; Thomas, N.J.; Schwarz, A.J.; Weiss, S.L.; Fitzgerald, J.C.; Allen, G.L.; Lutfi, R.; Nowak, J.E.; Quasney, M.W.; Shah, A.S.; Wong, H.R. Proprotein convertase subtilisin/kexin type 9 loss-of-function is detrimental to the juvenile host with septic shock. Crit. Care Med., 2020, 48(10), 1513-1520.
[http://dx.doi.org/10.1097/CCM.0000000000004487] [PMID: 32769621]
[29]
Ferraz-Amaro, I.; Winchester, R.; Gregersen, P.K.; Reynolds, R.J.; Wasko, M.C.; Oeser, A.; Chung, C.P.; Stein, C.M.; Giles, J.T.; Bathon, J.M. Coronary artery calcification and rheumatoid arthritis: lack of relationship to risk alleles for coronary artery disease in the general population. Arthritis Rheumatol., 2017, 69(3), 529-541.
[http://dx.doi.org/10.1002/art.39862] [PMID: 27696788]
[30]
Brown, M.; Ahmed, S. Emerging role of proprotein convertase subtilisin/kexin type-9 (PCSK-9) in inflammation and diseases. Toxicol. Appl. Pharmacol., 2019, 370, 170-177.
[http://dx.doi.org/10.1016/j.taap.2019.03.018] [PMID: 30914377]
[31]
Effects of immunization against PCSK9 in an experimental model of breast cancer - PubMed Available from: https://pubmed.ncbi.nlm.nih.gov/31110521/ [Accessed Jan 3, 2021]
[32]
X, L.; X, B.; M, H.; H, C.; M, J.; J, C.; L, X.; Q, H.; F, L.; Cy, L.. Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer. Available from: https://pubmed.ncbi.nlm.nih.gov/33177715/ [Accessed Jan 3, 2021]
[33]
Marcus, J.L.; Leyden, W.A.; Alexeeff, S.E.; Anderson, A.N.; Hechter, R.C.; Hu, H.; Lam, J.O.; Towner, W.J.; Yuan, Q.; Horberg, M.A.; Silverberg, M.J. Comparison of overall and comorbidity-free life expectancy between insured adults with and without hiv infection, 2000-2016. JAMA Netw. Open, 2020, 3(6), e207954.
[http://dx.doi.org/10.1001/jamanetworkopen.2020.7954] [PMID: 32539152]
[34]
Cui, H.L.; Ditiatkovski, M.; Kesani, R.; Bobryshev, Y.V.; Liu, Y.; Geyer, M.; Mukhamedova, N.; Bukrinsky, M.; Sviridov, D. HIV protein Nef causes dyslipidemia and formation of foam cells in mouse models of atherosclerosis. FASEB J., 2014, 28(7), 2828-2839.
[http://dx.doi.org/10.1096/fj.13-246876] [PMID: 24642731]
[35]
Brown, T.T.; Glesby, M.J. Management of the metabolic effects of HIV and HIV drugs. Nat. Rev. Endocrinol., 2011, 8(1), 11-21.
[http://dx.doi.org/10.1038/nrendo.2011.151] [PMID: 21931374]
[36]
Feingold, K.R.; Krauss, R.M.; Pang, M.; Doerrler, W.; Jensen, P.; Grunfeld, C. The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B. J. Clin. Endocrinol. Metab., 1993, 76(6), 1423-1427.
[http://dx.doi.org/10.1210/jcem.76.6.8501146] [PMID: 8501146]
[37]
Gori, E.; Mduluza, T.; Nyagura, M.; Stray-Pedersen, B.; Gomo, Z.A. Inflammation-modulating cytokine profile and lipid interaction in HIV-related risk factors for cardiovascular diseases. Ther. Clin. Risk Manag., 2016, 12, 1659-1666.
[http://dx.doi.org/10.2147/TCRM.S117980] [PMID: 27956833]
[38]
Flint, O.P.; Noor, M.A.; Hruz, P.W.; Hylemon, P.B.; Yarasheski, K.; Kotler, D.P.; Parker, R.A.; Bellamine, A. The role of protease inhibitors in the pathogenesis of HIV-associated lipodystrophy: cellular mechanisms and clinical implications. Toxicol. Pathol., 2009, 37(1), 65-77.
[http://dx.doi.org/10.1177/0192623308327119] [PMID: 19171928]
[39]
Gorwood, J.; Bourgeois, C.; Pourcher, V.; Pourcher, G.; Charlotte, F.; Mantecon, M.; Rose, C.; Morichon, R.; Atlan, M.; Le Grand, R.; Desjardins, D.; Katlama, C.; Fève, B.; Lambotte, O.; Capeau, J.; Béréziat, V.; Lagathu, C. The integrase inhibitors dolutegravir and raltegravir exert proadipogenic and profibrotic effects and induce insulin resistance in human/simian adipose tissue and human adipocytes. Clin. Infect. Dis., 2020, 71(10), e549-e560.
[http://dx.doi.org/10.1093/cid/ciaa259] [PMID: 32166319]
[40]
Kauppinen, K.J.; Kivelä, P.; Sutinen, J. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide significantly worsens the lipid profile in a real-world setting. AIDS Patient Care STDS, 2019, 33(12), 500-506.
[http://dx.doi.org/10.1089/apc.2019.0236] [PMID: 31742421]
[41]
Sosner, P.; Wangermez, M.; Chagneau-Derrode, C.; Le Moal, G.; Silvain, C. Atherosclerosis risk in HIV-infected patients: The influence of hepatitis C virus co-infection. Atherosclerosis, 2012, 222(1), 274-277.
[http://dx.doi.org/10.1016/j.atherosclerosis.2012.02.027] [PMID: 22417840]
[42]
Feinstein, M.J.; Hsue, P.Y.; Benjamin, L.A.; Bloomfield, G.S.; Currier, J.S.; Freiberg, M.S.; Grinspoon, S.K.; Levin, J.; Longenecker, C.T.; Post, W.S. Characteristics, prevention, and management of cardiovascular disease in people living with hiv: A scientific statement from the american heart association. Circulation, 2019, 140(2), e98-e124.
[http://dx.doi.org/10.1161/CIR.0000000000000695] [PMID: 31154814]
[43]
2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Atherosclerosis, 2019, 290, 140-205.
[http://dx.doi.org/10.1016/j.atherosclerosis.2019.08.014] [PMID: 31591002]
[44]
Kohli, P.; Ganz, P.; Ma, Y.; Scherzer, R.; Hur, S.; Weigel, B.; Grunfeld, C.; Deeks, S.; Wasserman, S.; Scott, R.; Hsue, P.Y. HIV and hepatitis c-coinfected patients have lower low-density lipoprotein cholesterol despite higher proprotein convertase subtilisin kexin 9 (pcsk9): An apparent “pcsk9-lipid paradox”. J. Am. Heart Assoc., 2016, 5(5), e002683.
[http://dx.doi.org/10.1161/JAHA.115.002683] [PMID: 27130349]
[45]
Zanni, M.V.; Stone, L.A.; Toribio, M.; Rimmelin, D.E.; Robinson, J.; Burdo, T.H.; Williams, K.; Fitch, K.V.; Lo, J.; Grinspoon, S.K. Proprotein convertase subtilisin/kexin 9 levels in relation to systemic immune activation and subclinical coronary plaque in hiv. Open Forum Infect. Dis., 2017, 4(4), ofx227.
[http://dx.doi.org/10.1093/ofid/ofx227] [PMID: 29226174]
[46]
Leucker, T.M.; Weiss, R.G.; Schär, M.; Bonanno, G.; Mathews, L.; Jones, S.R.; Brown, T.T.; Moore, R.; Afework, Y.; Gerstenblith, G.; Hays, A.G. Coronary endothelial dysfunction is associated with elevated serum pcsk9 levels in people with hiv independent of low-density lipoprotein cholesterol. J. Am. Heart Assoc., 2018, 7(19), e009996.
[http://dx.doi.org/10.1161/JAHA.118.009996] [PMID: 30371326]
[47]
Boccara, F.; Kumar, P.N.; Caramelli, B.; Calmy, A.; López, J.A.G.; Bray, S.; Cyrille, M.; Rosenson, R.S. Evolocumab in hiv-infected patients with dyslipidemia: Primary results of the randomized, double-blind beijerinck study. J. Am. Coll. Cardiol., 2020, 75(20), 2570-2584.
[http://dx.doi.org/10.1016/j.jacc.2020.03.025] [PMID: 32234462]
[48]
MD, P. H. Effect of pcsk9 inhibition on cardiovascular risk in treated hiv infection (EPIC-HIV Study), 2020. Clinical trial registration NCT03207945; clinicaltrials.gov
[49]
Johns Hopkins University Effect of evolocumab on coronary endothelial function, NCT03500302, July 24,. 2020.https://clinicaltrials.gov/ct2/show/record/NCT03500302
[50]
World Health Organization. Effect of evolocumab on coronary endothelial function., 2017. Clinical trial registration NCT03500302; clinicaltrials.gov.
[51]
Ryerson, A.B.; Eheman, C.R.; Altekruse, S.F.; Ward, J.W.; Jemal, A.; Sherman, R.L.; Henley, S.J.; Holtzman, D.; Lake, A.; Noone, A.M.; Anderson, R.N.; Ma, J.; Ly, K.N.; Cronin, K.A.; Penberthy, L.; Kohler, B.A. Annual report to the nation on the status of cancer, 1975-2012, featuring the increasing incidence of liver cancer.Cancer; John Wiley and Sons Inc., 2016, pp. 1312-1337.
[52]
Di Bisceglie, A.M. Hepatitis c and hepatocellular carcinoma. Hepatology; John Wiley and Sons Inc., 1997, p. 26.
[53]
Zeisel, M.B.; Felmlee, D.J.; Baumert, T.F. Hepatitis, C. Virus entry. Curr. Top. Microbiol. Immunol., 2013, 369, 87-112.
[http://dx.doi.org/10.1007/978-3-642-27340-7_4] [PMID: 23463198]
[54]
Popescu, C.I.; Riva, L.; Vlaicu, O.; Farhat, R.; Rouillé, Y.; Dubuisson, J. Hepatitis c virus life cycle and lipid metabolism.Biology; MDPI AG, 2014, pp. 892-921.
[55]
Younossi, Z.M.; Otgonsuren, M.; Henry, L.; Venkatesan, C.; Mishra, A.; Erario, M.; Hunt, S. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology, 2015, 62(6), 1723-1730.
[http://dx.doi.org/10.1002/hep.28123] [PMID: 26274335]
[56]
André, P.; Komurian-Pradel, F.; Deforges, S.; Perret, M.; Berland, J.L.; Sodoyer, M.; Pol, S.; Bréchot, C.; Paranhos-Baccalà, G.; Lotteau, V. Characterization of low- and very-low-density hepatitis C virus RNA-containing particles. J. Virol., 2002, 76(14), 6919-6928.
[http://dx.doi.org/10.1128/JVI.76.14.6919-6928.2002] [PMID: 12072493]
[57]
Boyer, A.; Dumans, A.; Beaumont, E.; Etienne, L.; Roingeard, P.; Meunier, J.C. The association of hepatitis C virus glycoproteins with apolipoproteins E and B early in assembly is conserved in lipoviral particles. J. Biol. Chem., 2014, 289(27), 18904-18913.
[http://dx.doi.org/10.1074/jbc.M113.538256] [PMID: 24838241]
[58]
Merz, A.; Long, G.; Hiet, M.S.; Brügger, B.; Chlanda, P.; Andre, P.; Wieland, F.; Krijnse-Locker, J.; Bartenschlager, R. Biochemical and morphological properties of hepatitis C virus particles and determination of their lipidome. J. Biol. Chem., 2011, 286(4), 3018-3032.
[http://dx.doi.org/10.1074/jbc.M110.175018] [PMID: 21056986]
[59]
Corey, K.E.; Kane, E.; Munroe, C.; Barlow, L.L.; Zheng, H.; Chung, R.T.; Hepatitis, C. Hepatitis C virus infection and its clearance alter circulating lipids: implications for long-term follow-up. Hepatology, 2009, 50(4), 1030-1037.
[http://dx.doi.org/10.1002/hep.23219] [PMID: 19787818]
[60]
Ferri, N.; Corsini, A.; Macchi, C.; Magni, P.; Ruscica, M. Proprotein convertase subtilisin kexin type 9 and high-density lipoprotein metabolism: Experimental animal models and clinical evidence.Translational Research; Mosby Inc., 2016, pp. 19-29.
[61]
Ferri, N.; Ruscica, M. Proprotein convertase subtilisin/kexin type 9 (pcsk9) and metabolic syndrome: Insights on insulin resistance, inflammation, and atherogenic dyslipidemia.Endocrine; Humana Press Inc., 2016, pp. 588-601.
[62]
Pirro, M.; Bianconi, V.; Francisci, D.; Schiaroli, E.; Bagaglia, F.; Sahebkar, A.; Baldelli, F.; Hepatitis, C. Hepatitis C virus and proprotein convertase subtilisin/kexin type 9: a detrimental interaction to increase viral infectivity and disrupt lipid metabolism. J. Cell. Mol. Med., 2017, 21(12), 3150-3161.
[http://dx.doi.org/10.1111/jcmm.13273] [PMID: 28722331]
[63]
Ramanathan, A.; Gusarova, V.; Stahl, N.; Gurnett-Bander, A.; Kyratsous, C.A. Alirocumab, a therapeutic human antibody to pcsk9, does not affect cd81 levels or hepatitis C virus entry and replication into hepatocytes. PLoS One, 2016, 11(4), e0154498.
[http://dx.doi.org/10.1371/journal.pone.0154498] [PMID: 27115873]
[64]
Adorni, M.P.; Cipollari, E.; Favari, E.; Zanotti, I.; Zimetti, F.; Corsini, A.; Ricci, C.; Bernini, F.; Ferri, N. Inhibitory effect of PCSK9 on Abca1 protein expression and cholesterol efflux in macrophages. Atherosclerosis, 2017, 256, 1-6.
[http://dx.doi.org/10.1016/j.atherosclerosis.2016.11.019] [PMID: 27940374]
[65]
Li, Z.; Liu, Q. Proprotein convertase subtilisin/kexin type 9 inhibits hepatitis C virus replication through interacting with NS5A. J. Gen. Virol., 2018, 99(1), 44-61.
[http://dx.doi.org/10.1099/jgv.0.000987] [PMID: 29235977]
[66]
Li, Z.; Liu, Q.; Hepatitis, C. Hepatitis C virus regulates proprotein convertase subtilisin/kexin type 9 promoter activity. Biochem. Biophys. Res. Commun., 2018, 496(4), 1229-1235.
[http://dx.doi.org/10.1016/j.bbrc.2018.01.176] [PMID: 29397939]
[67]
Fasolato, S.; Pigozzo, S.; Pontisso, P.; Angeli, P.; Ruscica, M.; Savarino, E.; De Martin, S.; Lupo, M.G.; Ferri, N. PCSK9 Levels Are Raised in Chronic HCV Patients with Hepatocellular Carcinoma. J. Clin. Med., 2020, 9(10), 3134.
[http://dx.doi.org/10.3390/jcm9103134] [PMID: 32998342]
[68]
Andriulli, A.; Mangia, A.; Iacobellis, A.; Ippolito, A.; Leandro, G.; Zeuzem, S. Meta-analysis: the outcome of anti-viral therapy in HCV genotype 2 and genotype 3 infected patients with chronic hepatitis. Aliment. Pharmacol. Ther., 2008, 28(4), 397-404.
[http://dx.doi.org/10.1111/j.1365-2036.2008.03763.x] [PMID: 18549461]
[69]
Hyrina, A.; Olmstead, A.D.; Steven, P.; Krajden, M.; Tam, E.; Jean, F. Treatment-induced viral cure of hepatitis c virus-infected patients involves a dynamic interplay among three important molecular players in lipid homeostasis: Circulating microrna (mir)-24, mir-223, and proprotein convertase subtilisin/kexin type 9. EBioMedicine, 2017, 23, 68-78.
[http://dx.doi.org/10.1016/j.ebiom.2017.08.020] [PMID: 28864162]
[70]
Ichikawa, T.; Miyaaki, H.; Miuma, S.; Taura, N.; Motoyoshi, Y.; Akahoshi, H.; Nakamura, J.; Takahashi, Y.; Honda, T.; Yajima, H.; Uehara, R.; Hino, N.; Narita, S.; Tanaka, H.; Sasaki, S.; Nakao, K. Changes in serum LDL, PCSK9 and microRNA-122 in patients with chronic HCV infection receiving Daclatasvir/Asunaprevir. Biomed. Rep., 2019, 10(3), 156-164.
[http://dx.doi.org/10.3892/br.2019.1189] [PMID: 30906544]
[71]
Esau, C.; Davis, S.; Murray, S.F.; Yu, X.X.; Pandey, S.K.; Pear, M.; Watts, L.; Booten, S.L.; Graham, M.; McKay, R.; Subramaniam, A.; Propp, S.; Lollo, B.A.; Freier, S.; Bennett, C.F.; Bhanot, S.; Monia, B.P. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab., 2006, 3(2), 87-98.
[http://dx.doi.org/10.1016/j.cmet.2006.01.005] [PMID: 16459310]
[72]
Janssen, H.L.A.; Reesink, H.W.; Lawitz, E.J.; Zeuzem, S.; Rodriguez-Torres, M.; Patel, K.; van der Meer, A.J.; Patick, A.K.; Chen, A.; Zhou, Y.; Persson, R.; King, B.D.; Kauppinen, S.; Levin, A.A.; Hodges, M.R. Treatment of HCV infection by targeting microRNA. N. Engl. J. Med., 2013, 368(18), 1685-1694.
[http://dx.doi.org/10.1056/NEJMoa1209026] [PMID: 23534542]
[73]
Blanchet, M.; Le, Q.T.; Seidah, N.G.; Labonté, P. Statins can exert dual, concentration dependent effects on HCV entry in vitro. Antiviral Res., 2016, 128, 43-48.
[http://dx.doi.org/10.1016/j.antiviral.2016.02.006] [PMID: 26868875]
[74]
Yang, Y.H.; Chen, W.C.; Tsan, Y.T.; Chen, M.J.; Shih, W.T.; Tsai, Y.H.; Chen, P.C. Statin use and the risk of cirrhosis development in patients with hepatitis C virus infection. J. Hepatol., 2015, 63(5), 1111-1117.
[http://dx.doi.org/10.1016/j.jhep.2015.07.006] [PMID: 26196278]
[75]
Tsan, Y.T.; Lee, C.H.; Ho, W.C.; Lin, M.H.; Wang, J.D.; Chen, P.C. Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection. J. Clin. Oncol., 2013, 31(12), 1514-1521.
[http://dx.doi.org/10.1200/JCO.2012.44.6831] [PMID: 23509319]
[76]
Seidah, N.G.; Prat, A. The proprotein convertases are potential targets in the treatment of dyslipidemia. J. Mol. Med. (Berl.), 2007, 85(7), 685-696.
[http://dx.doi.org/10.1007/s00109-007-0172-7] [PMID: 17351764]
[77]
Blanchet, M.; Seidah, N.G.; Labonté, P. SKI-1/S1P inhibition: a promising surrogate to statins to block hepatitis C virus replication. Antiviral Res., 2012, 95(2), 159-166.
[http://dx.doi.org/10.1016/j.antiviral.2012.05.006] [PMID: 22626636]
[78]
Blanchet, M.; Sureau, C.; Guévin, C.; Seidah, N.G.; Labonté, P. SKI-1/S1P inhibitor PF-429242 impairs the onset of HCV infection. Antiviral Res., 2015, 115, 94-104.
[http://dx.doi.org/10.1016/j.antiviral.2014.12.017] [PMID: 25573299]
[79]
Gan, E.S.; Tan, H.C.; Le, D.H.T.; Huynh, T.T.; Wills, B.; Seidah, N.G.; Ooi, E.E.; Yacoub, S. Dengue virus induces PCSK9 expression to alter antiviral responses and disease outcomes. J. Clin. Invest., 2020, 130(10), 5223-5234.
[http://dx.doi.org/10.1172/JCI137536] [PMID: 32644974]
[80]
Osuna-Ramos, J.F.; Reyes-Ruiz, J.M.; Del Ángel, R.M. The Role of Host Cholesterol During Flavivirus Infection. Front. Cell. Infect. Microbiol., 2018, 8, 388.
[http://dx.doi.org/10.3389/fcimb.2018.00388] [PMID: 30450339]
[81]
Welsch, S.; Miller, S.; Romero-Brey, I.; Merz, A.; Bleck, C.K.E.; Walther, P.; Fuller, S.D.; Antony, C.; Krijnse-Locker, J.; Bartenschlager, R. Composition and three-dimensional architecture of the dengue virus replication and assembly sites. Cell Host Microbe, 2009, 5(4), 365-375.
[http://dx.doi.org/10.1016/j.chom.2009.03.007] [PMID: 19380115]
[82]
Biswas, H.H.; Gordon, A.; Nuñez, A.; Perez, M.A.; Balmaseda, A.; Harris, E. Lower low-density lipoprotein cholesterol levels are associated with severe dengue outcome. PLoS Negl. Trop. Dis., 2015, 9(9), e0003904.
[http://dx.doi.org/10.1371/journal.pntd.0003904] [PMID: 26334914]
[83]
Whitehorn, J.; Nguyen, C.V.V.; Khanh, L.P.; Kien, D.T.H.; Quyen, N.T.H.; Tran, N.T.T.; Hang, N.T.; Truong, N.T.; Hue Tai, L.T.; Cam Huong, N.T.; Nhon, V.T.; Van Tram, T.; Farrar, J.; Wolbers, M.; Simmons, C.P.; Wills, B. Lovastatin for the treatment of adult patients with dengue: A randomized, double-blind, placebo-controlled trial. Clin. Infect. Dis., 2016, 62(4), 468-476.
[http://dx.doi.org/10.1093/cid/civ949] [PMID: 26565005]
[84]
Zhang, Y.; Gao, F.; Li, L.; Zhao, K.; Jiang, S.; Jiang, Y.; Yu, L.; Zhou, Y.; Liu, C.; Tong, G. Porcine reproductive and respiratory syndrome virus antagonizes pcsk9's antiviral effect via nsp11 endoribonuclease activity. Viruses, 2020, 12(6), E655.
[http://dx.doi.org/10.3390/v12060655] [PMID: 32560445]
[85]
Yan, B.; Chu, H.; Yang, D.; Sze, K-H.; Lai, P-M.; Yuan, S.; Shuai, H.; Wang, Y.; Kao, R.Y-T.; Chan, J.F-W.; Yuen, K-Y. Characterization of the lipidomic profile of human coronavirus-infected cells: Implications for lipid metabolism remodeling upon coronavirus replication. Viruses, 2019, 11(1), E73.
[http://dx.doi.org/10.3390/v11010073] [PMID: 30654597]
[86]
Neufeldt, C.J.; Cortese, M.; Acosta, E.G.; Bartenschlager, R. Rewiring cellular networks by members of the Flaviviridae family. Nat. Rev. Microbiol., 2018, 16(3), 125-142.
[http://dx.doi.org/10.1038/nrmicro.2017.170] [PMID: 29430005]
[87]
Vuorio, A.; Watts, G.F.; Kovanen, P.T. Familial hypercholesterolaemia and COVID-19: triggering of increased sustained cardiovascular risk. J. Intern. Med., 2020, 287(6), 746-747.
[http://dx.doi.org/10.1111/joim.13070] [PMID: 32242993]
[88]
Vuorio, A.; Kovanen, P.T. Prevention of endothelial dysfunction and thrombotic events in COVID-19 patients with familial hypercholesterolemia. J. Clin. Lipidol., 2020, 14(5), 617-618.
[http://dx.doi.org/10.1016/j.jacl.2020.06.006] [PMID: 32653497]
[89]
Singer, M.; Deutschman, C.S.; Seymour, C.W.; Shankar-Hari, M.; Annane, D.; Bauer, M.; Bellomo, R.; Bernard, G.R.; Chiche, J-D.; Coopersmith, C.M.; Hotchkiss, R.S.; Levy, M.M.; Marshall, J.C.; Martin, G.S.; Opal, S.M.; Rubenfeld, G.D.; van der Poll, T.; Vincent, J-L.; Angus, D.C. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA, 2016, 315(8), 801-810.
[http://dx.doi.org/10.1001/jama.2016.0287] [PMID: 26903338]
[90]
Levels, J.H.M.; Abraham, P.R.; van Barreveld, E.P.; Meijers, J.C.M.; van Deventer, S.J.H. Distribution and kinetics of lipoprotein-bound lipoteichoic acid. Infect. Immun., 2003, 71(6), 3280-3284.
[http://dx.doi.org/10.1128/IAI.71.6.3280-3284.2003] [PMID: 12761109]
[91]
Trinel, P.A.; Plancke, Y.; Gerold, P.; Jouault, T.; Delplace, F.; Schwarz, R.T.; Strecker, G.; Poulain, D. The Candida albicans phospholipomannan is a family of glycolipids presenting phosphoinositolmannosides with long linear chains of beta-1,2-linked mannose residues. J. Biol. Chem., 1999, 274(43), 30520-30526.
[http://dx.doi.org/10.1074/jbc.274.43.30520] [PMID: 10521433]
[92]
Levels, J.H.M.; Marquart, J.A.; Abraham, P.R.; van den Ende, A.E.; Molhuizen, H.O.F.; van Deventer, S.J.H.; Meijers, J.C.M. Lipopolysaccharide is transferred from high-density to low-density lipoproteins by lipopolysaccharide-binding protein and phospholipid transfer protein. Infect. Immun., 2005, 73(4), 2321-2326.
[http://dx.doi.org/10.1128/IAI.73.4.2321-2326.2005] [PMID: 15784577]
[93]
Gautier, T.; Lagrost, L. Plasma PLTP (phospholipid-transfer protein): an emerging role in ‘reverse lipopolysaccharide transport’ and innate immunity. Biochem. Soc. Trans., 2011, 39(4), 984-988.
[http://dx.doi.org/10.1042/BST0390984] [PMID: 21787334]
[94]
Walley, K.R. Role of lipoproteins and proprotein convertase subtilisin/kexin type 9 in endotoxin clearance in sepsis. Curr. Opin. Crit. Care, 2016, 22(5), 464-469.
[http://dx.doi.org/10.1097/MCC.0000000000000351] [PMID: 27552305]
[95]
Khademi, F.; Momtazi-Borojeni, A.A.; Reiner, Ž.; Banach, M.; Al-Rasadi, K.A.; Sahebkar, A. PCSK9 and infection: A potentially useful or dangerous association? J. Cell. Physiol., 2018, 233(4), 2920-2927.
[http://dx.doi.org/10.1002/jcp.26040] [PMID: 28574577]
[96]
Russell, J.A.; Walley, K.R.; Singer, J.; Gordon, A.C.; Hébert, P.C.; Cooper, D.J.; Holmes, C.L.; Mehta, S.; Granton, J.T.; Storms, M.M.; Cook, D.J.; Presneill, J.J.; Ayers, D. Vasopressin versus norepinephrine infusion in patients with septic shock. N. Engl. J. Med., 2008, 358(9), 877-887.
[http://dx.doi.org/10.1056/NEJMoa067373] [PMID: 18305265]
[97]
Kozlitina, J.; Smagris, E.; Stender, S.; Nordestgaard, B.G.; Zhou, H.H.; Tybjærg-Hansen, A.; Vogt, T.F.; Hobbs, H.H.; Cohen, J.C. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet., 2014, 46(4), 352-356.
[http://dx.doi.org/10.1038/ng.2901] [PMID: 24531328]
[98]
Rannikko, J.; Jacome Sanz, D.; Ortutay, Z.; Seiskari, T.; Aittoniemi, J.; Huttunen, R.; Syrjänen, J.; Pesu, M. Reduced plasma PCSK9 response in patients with bacteraemia is associated with mortality. J. Intern. Med., 2019, 286(5), 553-561.
[http://dx.doi.org/10.1111/joim.12946] [PMID: 31166632]
[99]
Walley, K.R.; Boyd, J.H.; Kong, H.J.; Russell, J.A. Low low-density lipoprotein levels are associated with, but do not causally contribute to, increased mortality in sepsis. Crit. Care Med., 2019, 47(3), 463-466.
[http://dx.doi.org/10.1097/CCM.0000000000003551] [PMID: 30394916]
[100]
Genga, K.R.; Lo, C.; Cirstea, M.S.; Leitao Filho, F.S.; Walley, K.R.; Russell, J.A.; Linder, A.; Francis, G.A.; Boyd, J.H. Impact of PCSK9 loss-of-function genotype on 1-year mortality and recurrent infection in sepsis survivors. EBioMedicine, 2018, 38, 257-264.
[http://dx.doi.org/10.1016/j.ebiom.2018.11.032] [PMID: 30473376]
[101]
Leung, A.K.K.; Genga, K.R.; Topchiy, E.; Cirstea, M.; Shimada, T.; Fjell, C.; Russell, J.A.; Boyd, J.H.; Walley, K.R. Reduced proprotein convertase subtilisin/kexin 9 (pcsk9) function increases lipoteichoic acid clearance and improves outcomes in gram positive septic shock patients. Sci. Rep., 2019, 9(1), 10588.
[http://dx.doi.org/10.1038/s41598-019-46745-0] [PMID: 31332258]
[102]
Le Bras, M.; Roquilly, A.; Deckert, V.; Langhi, C.; Feuillet, F.; Sébille, V.; Mahé, P-J.; Bach, K.; Masson, D.; Lagrost, L.; Costet, P.; Asehnoune, K.; Cariou, B. Plasma PCSK9 is a late biomarker of severity in patients with severe trauma injury. J. Clin. Endocrinol. Metab., 2013, 98(4), E732-E736.
[http://dx.doi.org/10.1210/jc.2012-4236] [PMID: 23450051]
[103]
Jamialahmadi, T.; Panahi, Y.; Safarpour, M.A.; Ganjali, S.; Chahabi, M.; Reiner, Z.; Solgi, S.; Vahedian-Azimi, A.; Kianpour, P.; Banach, M.; Sahebkar, A. Association of serum pcsk9 levels with antibiotic resistance and severity of disease in patients with bacterial infections admitted to intensive care units. J. Clin. Med., 2019, 8(10), E1742.
[http://dx.doi.org/10.3390/jcm8101742] [PMID: 31635200]
[104]
Bahekar, A.A.; Singh, S.; Saha, S.; Molnar, J.; Arora, R. The prevalence and incidence of coronary heart disease is significantly increased in periodontitis: a meta-analysis. Am. Heart J., 2007, 154(5), 830-837.
[http://dx.doi.org/10.1016/j.ahj.2007.06.037] [PMID: 17967586]
[105]
Miyazawa, H.; Honda, T.; Miyauchi, S.; Domon, H.; Okui, T.; Nakajima, T.; Tabeta, K.; Yamazaki, K. Increased serum PCSK9 concentrations are associated with periodontal infection but do not correlate with LDL cholesterol concentration. Clin. Chim. Acta, 2012, 413(1-2), 154-159.
[http://dx.doi.org/10.1016/j.cca.2011.09.023] [PMID: 22001517]
[106]
Tabeta, K.; Hosojima, M.; Nakajima, M.; Miyauchi, S.; Miyazawa, H.; Takahashi, N.; Matsuda, Y.; Sugita, N.; Komatsu, Y.; Sato, K.; Ishikawa, T.; Akiishi, K.; Yamazaki, K.; Kato, K.; Saito, A.; Yoshie, H. Increased serum PCSK9, a potential biomarker to screen for periodontitis, and decreased total bilirubin associated with probing depth in a Japanese community survey. J. Periodontal Res., 2018, 53(3), 446-456.
[http://dx.doi.org/10.1111/jre.12533] [PMID: 29516504]
[107]
Yokoji-Takeuchi, M.; Tabeta, K.; Takahashi, N.; Arimatsu, K.; Miyazawa, H.; Matsuda-Matsukawa, Y.; Sato, K.; Yamada, M.; Yamazaki, K. Indirect regulation of PCSK9 gene in inflammatory response by Porphyromonas gingivalis infection. Heliyon, 2019, 5(1), e01111.
[http://dx.doi.org/10.1016/j.heliyon.2018.e01111] [PMID: 30671557]
[108]
Sun, H.L.; Wu, Y.R.; Song, F.F.; Gan, J.; Huang, L.Y.; Zhang, L.; Huang, C. Role of pcsk9 in the development of mouse periodontitis before and after treatment: A double-edged sword. J. Infect. Dis., 2018, 217(4), 667-680.
[http://dx.doi.org/10.1093/infdis/jix574] [PMID: 29294034]
[109]
Lauer, S.; VanWye, J.; Harrison, T.; McManus, H.; Samuel, B.U.; Hiller, N.L.; Mohandas, N.; Haldar, K. Vacuolar uptake of host components, and a role for cholesterol and sphingomyelin in malarial infection. EMBO J., 2000, 19(14), 3556-3564.
[http://dx.doi.org/10.1093/emboj/19.14.3556] [PMID: 10899110]
[110]
Coppens, I.; Joiner, K.A. Host but not parasite cholesterol controls Toxoplasma cell entry by modulating organelle discharge. Mol. Biol. Cell, 2003, 14(9), 3804-3820.
[http://dx.doi.org/10.1091/mbc.e02-12-0830] [PMID: 12972565]
[111]
Sein, K.K.; Aikawa, M. The prime role of plasma membrane cholesterol in the pathogenesis of immune evasion and clinical manifestations of falciparum malaria. Med. Hypotheses, 1998, 51(2), 105-110.
[http://dx.doi.org/10.1016/S0306-9877(98)90102-5] [PMID: 9881815]
[112]
Silvie, O.; Charrin, S.; Billard, M.; Franetich, J-F.; Clark, K.L.; van Gemert, G-J.; Sauerwein, R.W.; Dautry, F.; Boucheix, C.; Mazier, D.; Rubinstein, E. Cholesterol contributes to the organization of tetraspanin-enriched microdomains and to CD81-dependent infection by malaria sporozoites. J. Cell Sci., 2006, 119(Pt 10), 1992-2002.
[http://dx.doi.org/10.1242/jcs.02911] [PMID: 16687736]
[113]
Arama, C.; Diarra, I.; Kouriba, B.; Sirois, F.; Fedoryak, O.; Thera, M.A.; Coulibaly, D.; Lyke, K.E.; Plowe, C.V.; Chrétien, M.; Doumbo, O.K.; Mbikay, M. Malaria severity: Possible influence of the E670G PCSK9 polymorphism: A preliminary case-control study in Malian children. PLoS One, 2018, 13(2), e0192850.
[http://dx.doi.org/10.1371/journal.pone.0192850] [PMID: 29447211]
[114]
Fedoryak, O.; Arama, C.; Diarra, I.; Kouriba, B.; Chrétien, M.; Mbikay, M. Association of the rs562556 pcsk9 gene polymorphism with reduced mortality in severe malaria among malian children. Can. J. Infect. Dis. Med. Microbiol., 2020, 2020, 9340480.
[http://dx.doi.org/10.1155/2020/9340480] [PMID: 33029265]
[115]
Wyss, K.; Wångdahl, A.; Vesterlund, M.; Hammar, U.; Dashti, S.; Naucler, P.; Färnert, A. Obesity and diabetes as risk factors for severe plasmodium falciparum malaria: Results from a swedish nationwide study. Clin. Infect. Dis., 2017, 65(6), 949-958.
[http://dx.doi.org/10.1093/cid/cix437] [PMID: 28510633]
[116]
Rumjanek, F.D.; Campos, E.G.; Afonso, L.C. Evidence for the occurrence of LDL receptors in extracts of schistosomula of Schistosoma mansoni. Mol. Biochem. Parasitol., 1988, 28(2), 145-152.
[http://dx.doi.org/10.1016/0166-6851(88)90062-X] [PMID: 3367933]

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