Cytomegalovirus Infection in Vascular Diseases and Transplant Rejection

Human cytomegalovirus (HCMV) infects 60-100% of the adult population. It belongs to the Herpesviridae family and establishes latency within its host post primary infection. HCMV reactivation is dependent on inflammation and the virus has evolved numerous mechanisms to sustain an inflammatory process and thus prolong its replication period. This has led to the hypothesis that HCMV may contribute to the pathogenesis of various inflammatory diseases. Our studies herein focus on further elucidating the role of HCMV in vascular diseases and transplant rejection. We found that: I) HCMV is present in a vast majority of abdominal aortic aneurysms where it predominantly infects the intimal smooth muscle cells. The infected cells showed an increased migratory capacity that was in part dependent on basic fibroblast growth factor. Furthermore, in the vascular lesions where HCMV was present there was an induced expression of 5-lipoxygenase, a key enzyme in the synthesis of the potent proinflammatory leukotriene B4. Thus, our study supports previous findings that HCMV is found in abdominal aortic aneurysm, and that it has the potential to contribute to the pathogenesis of abdominal aortic aneurysm. II) Native arteriovenous fistula (AVF) is the preferred form of haemodialysis vascular access however dysfunction due to neointimal hyperplasia, vascular stenosis and thrombosis is a major cause of morbidity in this patient population. In a prospective cohort study we sought to identify novel prognostic factors for failure of native AVF. Numerous biochemical and patient characteristics were analysed just prior to construction of the AVF. We identified white blood cell count, monocyte count and red blood cell distribution width as independent prognostic factors for AVF failure. Red blood cell distribution width is a novel prognostic factor and was also the most optimal. The mechanistic link between high red blood cell distribution width and AVF failure is yet to be elucidated. III) Using the patient cohort described in (II) we investigated the potential role of HCMV in the failure of AVF. In contrary to previous reports, high anti-HCMV IgG levels were not associated with reduced AVF patency in our study. HCMV proteins could be located in the vessels of 46% of patients at the time of AVF construction but presence of HCMV proteins was not associated with reduced AVF patency. Our study does not support the hypothesis that HCMV has a role in the failure of AVF. IV) HCMV has been associated with chronic transplant rejection however the virus has been difficult to detect in the affected organs and thus the effects of HCMV have been defined as indirect. In this retrospective cohort study we evaluated the presence of HCMV in chronic renal allograft dysfunction, in early as well as end-stage biopsies. We found that HCMV is present in a majority of grafts early post transplantation and that the HCMV levels increase as the graft deteriorates. Furthermore, high HCMV intragraft protein expression in the early biopsy is associated with reduced allograft survival. Our study provides further support for a role of HCMV in allograft rejection and suggests that direct effects of the virus are involved in chronic allograft dysfunction. LIST OF PUBLICATIONS I. Sara Gredmark-Russ*, Mensur Dzabic*, Afsar Rahbar, Anders Wanhainen, Martin Björck, Erik Larsson, Jean-Baptiste Michel, Cecilia Söderberg-Nauclér. Active cytomegalovirus infection in aortic smooth muscle cells from patients with abdominal aortic aneurysm. J Mol Med (Berl). 2009 Apr;87(4):347-56. II. Krzysztof Bojakowski*, Mensur Dzabic*, Ewa Kurzejamska, Grzegorz Styczynski, Piotr Andziak, Zbigniew Gaciong, Cecilia Söderberg-Nauclér, Piotr Religa. A high red blood cell distribution width predicts failure of arteriovenous fistula. PLoS ONE. 2012 May;7(5):e36482 III. Mensur Dzabic, Krzysztof Bojakowski, Ewa Kurzejamska, Grzegorz Styczynski, Piotr Andziak, Cecilia Söderberg-Nauclér*, Piotr Religa*. Significance of cytomegalovirus infection in the failure of native arteriovenous fistula. Clin Microbiol Infect. 2012 Jan;18(1):E5-7 IV. Mensur Dzabic, Afsar Rahbar, Koon-Chu Yaiw, Mansour Naghibi, Piotr Religa, Bengt Fellström, Erik Larsson, Cecilia Söderberg-Nauclér. Intragraft cytomegalovirus protein expression is associated with reduced renal allograft survival. Clin Infect Dis. 2011 Nov;53(10):969-76 *These authors contributed equally. RELATED PUBLICATIONS Nathalie Hollink, Mensur Dzabic, Nina Wolmer, Lennart Boström, Afsar Rahbar. High prevalence of an active human cytomegalovirus infection in patients with colonic diverticulitis. J Clin Virol. 2007 Oct;40(2):116-9. Mensur Dzabic, Lennart Boström, Afsar Rahbar. High prevalence of an active human cytomegalovirus infection in the appendix of immunocompetent patients with acute appendicitis. Inflamm Bowel Dis. 2008 Feb;14(2):236-41. Cecilia Söderberg-Nauclér, Mensur Dzabic, Afsar Rahbar. Understanding the molecular mechanisms involved in indirect effects of CMV. Trends in Transplantation. 2008 Jan-Apr;2(1):32-43. Mensur Dzabic, Cecilia Söderberg-Nauclér. Indirect Effects of Cytomegalovirus: A Challenge for Improved Long-Term Outcome in Transplant Recipients. British Journal of Transplantation. 2011 Feb;5(Supplement 2):9-13.