Top

Published in:

01-02-2013 | Original Investigation

Induction of a broad spectrum of inflammation-related genes by Coxsackievirus B3 requires Interleukin-1 signaling

Authors: Fabienne Rehren, Barbara Ritter, Oliver Dittrich-Breiholz, Andreas Henke, Elena Lam, Semra Kati, Michael Kracht, Albert Heim

Published in: Medical Microbiology and Immunology | Issue 1/2013

Abstract

Coxsackievirus B3 (CVB3) is a major cause of acute and chronic forms of myocarditis. Previously, direct viral injury and post-infectious autoimmune response were suspected as main pathogenetic mechanisms. However, induction of pro-inflammatory cytokines may be crucial for pathogenesis in spite of host protein shut off caused by CVB3 replication. We investigated the global expression profile of pro-inflammatory genes induced by acute and persistent (carrier state) CVB3 infection in human fibroblast cell cultures with DNA microarrays, quantitative RT-PCR and ELISA. Rapid induction of a typical spectrum of about 30 inflammation-related genes (e.g., PTGS2, CCL2, IL-1β, IL-6, IL-8, CSF2, MMP-1, MMP-3, and MMP-15) suggested an essential, autocrine role of IL-1. This hypothesis was confirmed by over-expression of IL-1RI, which resulted in a cytokine response upon CVB3 infection in HEK 293 cells otherwise refractory to CVB3-caused gene expression. Blocking IL-1 receptor type I (IL-1RI)-signaling during CVB3 infection with an IL-1 receptor antagonist (IL-1ra) as well as knockdown of IL-1RI using siRNA abrogated cytokine response in human fibroblasts. Both IL-1α and IL-1β are relevant for the induction of inflammation-related genes during CVB3 infection as shown by neutralization experiments. Paracrine effects of IL-1 on the subset of non-infected cells in carrier state infected fibroblast cultures enhanced induction of inflammation-related genes. Conclusions: A broad spectrum of inflammatory cytokines was induced by CVB3 replication via a pathway that requires IL-1 signaling. Our results suggest that IL-1ra may be used as a therapeutic agent to limit inflammation and tissue destruction in myocarditis.

Available only for authorised users

Feldman AM, McNamara D (2000) Myocarditis. N Engl J Med 343(19):1388–1398PubMedCrossRef

Taylor DO, Stehlik J, Edwards LB, Aurora P, Christie JD, Dobbels F, Kirk R, Kucheryavaya AY, Rahmel AO, Hertz MI (2009) Registry of the international society for heart and lung transplantation: twenty-sixth official adult heart transplant report-2009. J Heart Lung Transplant 28(10):1007–1022PubMedCrossRef

Kawai C (1999) From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death: learning from the past for the future. Circulation 99(8):1091–1100PubMedCrossRef

Knowlton KU (2008) CVB infection and mechanisms of viral cardiomyopathy. Curr Top Microbiol Immunol 323:315–335PubMedCrossRef

Leslie K, Blay R, Haisch C, Lodge A, Weller A, Huber S (1989) Clinical and experimental aspects of viral myocarditis. Clin Microbiol Rev 2(2):191–203PubMed

Neumann DA, Burek CL, Baughman KL, Rose NR, Herskowitz A (1990) Circulating heart-reactive antibodies in patients with myocarditis or cardiomyopathy. J Am Coll Cardiol 16(6):839–846PubMedCrossRef

Schwimmbeck PL, Bigalke B, Schulze K, Pauschinger M, Kuhl U, Schultheiss HP (2004) The humoral immune response in viral heart disease: characterization and pathophysiological significance of antibodies. Med Microbiol Immunol 193(2–3):115–119PubMed

Kishimoto C, Thorp KA, Abelmann WH (1990) Immunosuppression with high doses of cyclophosphamide reduces the severity of myocarditis but increases the mortality in murine Coxsackievirus B3 myocarditis. Circulation 82(3):982–989PubMedCrossRef

Latham RD, Mulrow JP, Virmani R, Robinowitz M, Moody JM (1989) Recently diagnosed idiopathic dilated cardiomyopathy: incidence of myocarditis and efficacy of prednisone therapy. Am Heart J 117(4):876–882PubMedCrossRef

10.

Mason JW, O’Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME, Moon TE (1995) A clinical trial of immunosuppressive therapy for myocarditis. The myocarditis treatment trial investigators. N Engl J Med 333(5):269–275PubMedCrossRef

11.

Parrillo JE, Cunnion RE, Epstein SE, Parker MM, Suffredini AF, Brenner M, Schaer GL, Palmeri ST, Cannon RO III, Alling D et al (1989) A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy. N Engl J Med 321(16):1061–1068PubMedCrossRef

12.

Chapman NM, Kim KS (2008) Persistent coxsackievirus infection: enterovirus persistence in chronic myocarditis and dilated cardiomyopathy. Curr Top Microbiol Immunol 323:275–292PubMedCrossRef

13.

McManus BM, Chow LH, Wilson JE, Anderson DR, Gulizia JM, Gauntt CJ, Klingel KE, Beisel KW, Kandolf R (1993) Direct myocardial injury by enterovirus: a central role in the evolution of murine myocarditis. Clin Immunol Immunopathol 68(2):159–169PubMedCrossRef

14.

Yuan J, Cheung PK, Zhang H, Chau D, Yanagawa B, Cheung C, Luo H, Wang Y, Suarez A, McManus BM, Yang D (2004) A phosphorothioate antisense oligodeoxynucleotide specifically inhibits coxsackievirus B3 replication in cardiomyocytes and mouse hearts. Lab Invest 84(6):703–714PubMedCrossRef

15.

Fairweather D, Frisancho-Kiss S, Yusung SA, Barrett MA, Davis SE, Gatewood SJ, Njoku DB, Rose NR (2004) Interferon-gamma protects against chronic viral myocarditis by reducing mast cell degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-beta 1, interleukin-1 beta, and interleukin-4 in the heart. Am J Pathol 165(6):1883–1894PubMedCrossRef

16.

Figulla HR, Stille-Siegener M, Mall G, Heim A, Kreuzer H (1995) Myocardial enterovirus infection with left ventricular dysfunction: a benign disease compared with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 25(5):1170–1175PubMedCrossRef

17.

Heim A, Stille-Seigener M, Pring-Akerblom P, Grumbach I, Brehm C, Kreuzer H, Figulla HR (1996) Recombinant Interferons beta and gamma have a higher antiviral activity than interferon-alpha in coxsackievirus B3-infected carrier state cultures of human myocardial fibroblasts. J Interferon Cytokine Res 16(4):283–287PubMedCrossRef

18.

Heim A, Weiss S (2004) Interferons in enteroviral heart disease: modulation of cytokine expression and antiviral activity. Med Microbiol Immunol (Berl) 193(2–3):149–154CrossRef

19.

Kuhl U, Pauschinger M, Schwimmbeck PL, Seeberg B, Lober C, Noutsias M, Poller W, Schultheiss HP (2003) Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 107(22):2793–2798PubMedCrossRef

20.

Matsumori A, Tomioka N, Kawai C (1988) Protective effect of recombinant alpha interferon on coxsackievirus B3 myocarditis in mice. Am Heart J 115(6):1229–1232PubMedCrossRef

21.

Klingel K, Rieger P, Mall G, Selinka HC, Huber M, Kandolf R (1998) Visualization of enteroviral replication in myocardial tissue by ultrastructural in situ hybridization: identification of target cells and cytopathic effects. Lab Invest 78(10):1227–1237PubMed

22.

Koide H, Kitaura Y, Deguchi H, Ukimura A, Kawamura K, Hirai K (1992) Genomic detection of enteroviruses in the myocardium–studies on animal hearts with coxsackievirus B3 myocarditis and endomyocardial biopsies from patients with myocarditis and dilated cardiomyopathy. Jpn Circ J 56(10):1081–1093PubMedCrossRef

23.

Eghbali M, Czaja MJ, Zeydel M, Weiner FR, Zern MA, Seifter S, Blumenfeld OO (1988) Collagen chain mRNAs in isolated heart cells from young and adult rats. J Mol Cell Cardiol 20(3):267–276PubMedCrossRef

24.

Heim A, Brehm C, Stille-Siegener M, Muller G, Hake S, Kandolf R, Figulla HR (1995) Cultured human myocardial fibroblasts of pediatric origin: natural human interferon-alpha is more effective than recombinant interferon-alpha 2a in carrier-state coxsackievirus B3 replication. J Mol Cell Cardiol 27(10):2199–2208PubMedCrossRef

25.

Kandolf R, Canu A, Hofschneider PH (1985) Coxsackie B3 virus can replicate in cultured human foetal heart cells and is inhibited by interferon. J Mol Cell Cardiol 17(2):167–181PubMedCrossRef

26.

Bedard KM, Semler BL (2004) Regulation of picornavirus gene expression. Microbes Infect 6(7):702–713PubMedCrossRef

27.

Heim A, Zeuke S, Weiss S, Ruschewski W, Grumbach IM (2000) Transient induction of cytokine production in human myocardial fibroblasts by coxsackievirus B3. Circ Res 86(7):753–759PubMedCrossRef

28.

Henke A, Mohr C, Sprenger H, Graebner C, Stelzner A, Nain M, Gemsa D (1992) Coxsackievirus B3-induced production of tumor necrosis factor-alpha, IL-1 beta, and IL-6 in human monocytes. J Immunol 148(7):2270–2277PubMed

29.

Garmaroudi FS, Marchant D, Si X, Khalili A, Bashashati A, Wong BW, Tabet A, Ng RT, Murphy K, Luo H, Janes KA, McManus BM (2010) Pairwise network mechanisms in the host signaling response to coxsackievirus B3 infection. Proc Natl Acad Sci USA 107(39):17053–17058PubMedCrossRef

30.

Shen Y, Xu W, Chu YW, Wang Y, Liu QS, Xiong SD (2004) Coxsackievirus group B type 3 infection upregulates expression of monocyte chemoattractant protein 1 in cardiac myocytes, which leads to enhanced migration of mononuclear cells in viral myocarditis. J Virol 78(22):12548–12556PubMedCrossRef

31.

Gluck B, Schmidtke M, Merkle I, Stelzner A, Gemsa D (2001) Persistent expression of cytokines in the chronic stage of CVB3-induced myocarditis in NMRI mice. J Mol Cell Cardiol 33(9):1615–1626PubMedCrossRef

32.

Kishimoto C, Kuroki Y, Hiraoka Y, Ochiai H, Kurokawa M, Sasayama S (1994) Cytokine and murine coxsackievirus B3 myocarditis. Interleukin-2 suppressed myocarditis in the acute stage but enhanced the condition in the subsequent stage. Circulation 89(6):2836–2842PubMedCrossRef

33.

Lane JR, Neumann DA, Lafond-Walker A, Herskowitz A, Rose NR (1992) Interleukin 1 or tumor necrosis factor can promote Coxsackie B3-induced myocarditis in resistant B10.A mice. J Exp Med 175(4):1123–1129PubMedCrossRef

34.

Lane JR, Neumann DA, Lafond-Walker A, Herskowitz A, Rose NR (1993) Role of IL-1 and tumor necrosis factor in coxsackie virus-induced autoimmune myocarditis. J Immunol 151(3):1682–1690PubMed

35.

Schmidtke M, Selinka HC, Heim A, Jahn B, Tonew M, Kandolf R, Stelzner A, Zell R (2000) Attachment of coxsackievirus B3 variants to various cell lines: mapping of phenotypic differences to capsid protein VP1. Virology 275(1):77–88PubMedCrossRef

36.

Zautner AE, Korner U, Henke A, Badorff C, Schmidtke M (2003) Heparan sulfates and coxsackievirus-adenovirus receptor: each one mediates coxsackievirus B3 PD infection. J Virol 77(18):10071–10077PubMedCrossRef

37.

Zautner AE, Jahn B, Hammerschmidt E, Wutzler P, Schmidtke M (2006) N- and 6-O-sulfated heparan sulfates mediate internalization of coxsackievirus B3 variant PD into CHO-K1 cells. J Virol 80(13):6629–6636PubMedCrossRef

38.

Harms W, Rothamel T, Miller K, Harste G, Grassmann M, Heim A (2001) Characterization of human myocardial fibroblasts immortalized by HPV16 E6–E7 genes. Exp Cell Res 268(2):252–261PubMedCrossRef

39.

Reed L, Muench, HA (1938) A simple method of estimating fifty per cent endpoints. Am J Hyg (27)

40.

Dierssen U, Rehren F, Henke-Gendo C, Harste G, Heim A (2008) Rapid routine detection of enterovirus RNA in cerebrospinal fluid by a one-step real-time RT-PCR assay. J Clin Virol 42(1):58–64PubMedCrossRef

41.

Dittrich-Breiholz O, Schneider H, Wehmeier L, Resch K, Kracht M (2003) Entwicklung und Evaluierung eines DNA Mikroarrays für entzündungsrelevante Gene. Biospketrum 1/03:88–92

42.

Kettner-Buhrow D, Dittrich-Breiholz O, Schneider H, Wolter S, Resch K, Kracht M (2006) Small interfering RNAs generated by recombinant dicer induce inflammatory gene expression independent from the TAK1-NFkappaB-MAPK signaling pathways. Biochem Biophys Res Commun 347(3):566–573PubMedCrossRef

43.

Wolf K, Schulz C, Riegger GA, Pfeifer M (2002) Tumour necrosis factor-alpha induced CD70 and interleukin-7R mRNA expression in BEAS-2B cells. Eur Respir J 20(2):369–375PubMedCrossRef

44.

Birkenkamp-Demtroder K, Christensen LL, Olesen SH, Frederiksen CM, Laiho P, Aaltonen LA, Laurberg S, Sorensen FB, Hagemann R, TF OR (2002) Gene expression in colorectal cancer. Cancer Res 62(15):4352–4363

45.

Houliston RA, Keogh RJ, Sugden D, Dudhia J, Carter TD, Wheeler-Jones CP (2002) Protease-activated receptors upregulate cyclooxygenase-2 expression in human endothelial cells. Thromb Haemost 88(2):321–328PubMed

46.

Elliott SF, Coon CI, Hays E, Stadheim TA, Vincenti MP (2002) Bcl-3 is an interleukin-1-responsive gene in chondrocytes and synovial fibroblasts that activates transcription of the matrix metalloproteinase 1 gene. Arthritis Rheum 46(12):3230–3239PubMedCrossRef

47.

Nagaeva O, Jonsson L, Mincheva-Nilsson L (2002) Dominant IL-10 and TGF-beta mRNA expression in gammadeltaT cells of human early pregnancy decidua suggests immunoregulatory potential. Am J Reprod Immunol 48(1):9–17PubMedCrossRef

48.

Jung M, Romer A, Keyszer G, Lein M, Kristiansen G, Schnorr D, Loening SA, Jung K (2003) mRNA expression of the five membrane-type matrix metalloproteinases MT1-MT5 in human prostatic cell lines and their down-regulation in human malignant prostatic tissue. Prostate 55(2):89–98PubMedCrossRef

49.

Zarember KA, Godowski PJ (2002) Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 168(2):554–561PubMed

50.

Pfaffl MW, Horgan GW, Dempfle L (2002) Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30(9):e36PubMedCrossRef

51.

Henke A, Jarasch N, Martin U, Zell R, Wutzler P (2008) Characterization of the protective capability of a recombinant coxsackievirus B3 variant expressing interferon-gamma. Viral Immunol 21(1):38–48PubMedCrossRef

52.

Tonew M, Wagner B, Wagner M, Schmidtke M, Stelzner A (1996) Permissiveness of human embryonal fibroblasts for coxsackieviruses B3. Investigations on virus genetic markers in vitro and localization of virus receptor distribution by immunogold replica technique. Zentralbl Bakteriol 284(2–3):443–456PubMedCrossRef

53.

O’Neill LA, Dinarello CA (2000) The IL-1 receptor/toll-like receptor superfamily: crucial receptors for inflammation and host defense. Immunol Today 21(5):206–209PubMedCrossRef

54.

Triantafilou K, Orthopoulos G, Vakakis E, Ahmed MA, Golenbock DT, Lepper PM, Triantafilou M (2005) Human cardiac inflammatory responses triggered by Coxsackie B viruses are mainly Toll-like receptor (TLR) 8-dependent. Cell Microbiol 7(8):1117–1126PubMedCrossRef

55.

Liu P, Aitken K, Kong YY, Opavsky MA, Martino T, Dawood F, Wen WH, Kozieradzki I, Bachmaier K, Straus D, Mak TW, Penninger JM (2000) The tyrosine kinase p56lck is essential in coxsackievirus B3-mediated heart disease. Nat Med 6(4):429–434PubMedCrossRef

56.

Luo H, Yanagawa B, Zhang J, Luo Z, Zhang M, Esfandiarei M, Carthy C, Wilson JE, Yang D, McManus BM (2002) Coxsackievirus B3 replication is reduced by inhibition of the extracellular signal-regulated kinase (ERK) signaling pathway. J Virol 76(7):3365–3373PubMedCrossRef

57.

Esfandiarei M, Luo H, Yanagawa B, Suarez A, Dabiri D, Zhang J, McManus BM (2004) Protein kinase B/Akt regulates coxsackievirus B3 replication through a mechanism which is not caspase dependent. J Virol 78(8):4289–4298PubMedCrossRef

58.

Kishimoto C, Kawamata H, Sakai S, Shinohara H, Ochiai H (2000) Role of MIP-2 in coxsackievirus B3 myocarditis. J Mol Cell Cardiol 32(4):631–638PubMedCrossRef

59.

Yuan H, Ito S, Senga T, Hyodo T, Kiyono T, Kikkawa F, Hamaguchi M (2009) Human papillomavirus type 16 oncoprotein E7 suppresses cadherin-mediated cell adhesion via ERK and AP-1 signaling. Int J Oncol 35(2):309–314PubMed

60.

Claycomb WC, Lanson NA Jr, Stallworth BS, Egeland DB, Delcarpio JB, Bahinski A, Izzo NJ Jr (1998) HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proc Natl Acad Sci USA 95(6):2979–2984PubMedCrossRef

61.

Lim BK, Choe SC, Shin JO, Ho SH, Kim JM, Yu SS, Kim S, Jeon ES (2002) Local expression of interleukin-1 receptor antagonist by plasmid DNA improves mortality and decreases myocardial inflammation in experimental coxsackieviral myocarditis. Circulation 105(11):1278–1281PubMed

62.

Weinstock-Guttman B, Ramanathan M, Zivadinov R (2008) Interferon-beta treatment for relapsing multiple sclerosis. Exp Opin Biol Ther 8(9):1435–1447CrossRef

63.

Walther EU, Hohlfeld R (1999) Multiple sclerosis: side effects of interferon beta therapy and their management. Neurology 53(8):1622–1627PubMedCrossRef

64.

Nuki G, Bresnihan B, Bear MB, McCabe D (2002) Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 46(11):2838–2846PubMedCrossRef

65.

Heymans S, Pauschinger M, De Palma A, Kallwellis-Opara A, Rutschow S, Swinnen M, Vanhoutte D, Gao F, Torpai R, Baker AH, Padalko E, Neyts J, Schultheiss HP, Van de Werf F, Carmeliet P, Pinto YM (2006) Inhibition of urokinase-type plasminogen activator or matrix metalloproteinases prevents cardiac injury and dysfunction during viral myocarditis. Circulation 114(6):565–573PubMedCrossRef

66.

Tanaka T, Kanda T, McManus BM, Kanai H, Akiyama H, Sekiguchi K, Yokoyama T, Kurabayashi M (2001) Overexpression of interleukin-6 aggravates viral myocarditis: impaired increase in tumor necrosis factor-alpha. J Mol Cell Cardiol 33(9):1627–1635PubMedCrossRef

67.

Huber SA, Polgar J, Schultheiss P, Schwimmbeck P (1994) Augmentation of pathogenesis of coxsackievirus B3 infections in mice by exogenous administration of interleukin-1 and interleukin-2. J Virol 68(1):195–206PubMed

68.

Horai R, Saijo S, Tanioka H, Nakae S, Sudo K, Okahara A, Ikuse T, Asano M, Iwakura Y (2000) Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J Exp Med 191(2):313–320PubMedCrossRef

69.

Nicklin MJ, Hughes DE, Barton JL, Ure JM, Duff GW (2000) Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene. J Exp Med 191(2):303–312PubMedCrossRef

70.

Westphal E, Rohrbach S, Buerke M, Behr H, Darmer D, Silber RE, Werdan K, Loppnow H (2008) Altered interleukin-1 receptor antagonist and interleukin-18 mRNA expression in myocardial tissues of patients with dilatated cardiomyopathy. Mol Med 14(1–2):55–63

71.

Apte RN, Voronov E (2008) Is interleukin-1 a good or bad ‘guy’ in tumor immunobiology and immunotherapy? Immunol Rev 222:222–241PubMedCrossRef

72.

Crossman DC, Morton AC, Gunn JP, Greenwood JP, Hall AS, Fox KA, Lucking AJ, Flather MD, Lees B, Foley CE (2008) Investigation of the effect of Interleukin-1 receptor antagonist (IL-1ra) on markers of inflammation in non-ST elevation acute coronary syndromes (The MRC-ILA-HEART Study). Trials 9:8PubMedCrossRef

73.

Ikonomidis I, Lekakis JP, Nikolaou M, Paraskevaidis I, Andreadou I, Kaplanoglou T, Katsimbri P, Skarantavos G, Soucacos PN, Kremastinos DT (2008) Inhibition of interleukin-1 by anakinra improves vascular and left ventricular function in patients with rheumatoid arthritis. Circulation 117(20):2662–2669PubMedCrossRef

Title: Induction of a broad spectrum of inflammation-related genes by Coxsackievirus B3 requires Interleukin-1 signaling
Authors: Fabienne Rehren
Barbara Ritter
Oliver Dittrich-Breiholz
Andreas Henke
Elena Lam
Semra Kati
Michael Kracht
Albert Heim
Publication date: 01-02-2013
Publisher: Springer-Verlag
Published in: Medical Microbiology and Immunology / Issue 1/2013
Print ISSN: 0300-8584
Electronic ISSN: 1432-1831
DOI: https://doi.org/10.1007/s00430-012-0245-2

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 1/2013

Performance evaluation of a new fourth-generation HIV combination antigen–antibody assay

Antibody prevalence to the 2009 pandemic influenza A (H1N1) virus in Germany: geographically variable immunity in winter 2010/2011

IFNγ expression by an attenuated strain of Salmonella enterica serovar Typhimurium improves vaccine efficacy in susceptible TLR4-defective C3H/HeJ mice

Poor immunity status against poliomyelitis in medical students: a semi-anonymous study

Comparison of HIV-1 viral load assay performance in immunological stable patients with low or undetectable viremia

Infection of neutrophil granulocytes with Leishmania major activates ERK 1/2 and modulates multiple apoptotic pathways to inhibit apoptosis

Keynote webinar | Spotlight on medication adherence

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

At a glance: The STEP trials