Biological importance of cytomegalovirus infection in health and disease : profound effects of infection on monocyte and smooth muscle cell function

Human cytomegalovirus (HCMV) is a herpesvirus. Following a primary infection, HCMV persists in the body in a latent form and most adults are virus carriers. Infection and reactivation of HCMV occur in inummocompromised patients causing severe disease and appear to be the result of inflammatory processes. Since HCMV establishes latency in monocytes, and since monocytes can differentiate into cells with important functions in both innate and adaptive immune responses, I have investigated the effect of HCMV on the differentiation of monocytes into macrophages and dendritic cells (DCs). I have also further examined the potential role of HCMV in the pathogenesis of vascular diseases.

We first investigated the potential role of HCMV in the induction of immunosuppression and establishment of latency in the myeloid cell linage. HCMV infection of monocytes inhibited cytokine-induced differentiation of monocytes into active CD1a positive DCs, as was demonstrated by impaired DC functions, such as endocytosis, migration, phagocytosis and induction of T lymphocyte reactivity. HCMV also blocked cytokine-induced monocyte differentiation into macrophages in vitro. This effect was not dependent on HCMV infection of monocytes, as it could also be mediated solely by binding of HCMV particles to the cell surface receptor CD131 aminopeptidase N, which engaged Ca2+-dependent intracellular signalling pathways. Further studies suggested that the viral protein gB could induce effects similar to whole virus particles. Our findings may contribute to further understand mechanisms of how HCMV establishes latency in host monocytes and can provide deeper insights into the mechanisms that are responsible for the immunosuppression, which clinically often is associated with HCMV infection.

HCMV can infect a number of different cell types including smooth muscle cells (SMC). Differentiation, proliferation, migration, alpha-actin reorganization and synthesis of extracellular matrix in SMC is dependent on signalling by PDGF. Here, we found that HCMV infection may impair these processes in SMC, as the virus downregulates the PDGFR receptor expression. Hence, HCMV infection in SMC may impair cellular processes that are known to be important in cellular development and possibly also in vascular disease development.

Atherosclerosis is today considered to be an inflammatory disease, and HCMV infection is regarded as a risk factor for the development of vascular disease in transplant patients as well as for the development of atherosclerosis. In the present study, we showed that all SMC samples isolated from vascular biopsies obtained from patients with vascular disease expressed HCMV DNA, identifying these cells as a possible site for HCMV latency. Furthermore, in situ hybridization experiments of SMC samples from aortic biopsies showed that a substantial proportion of SMC from the intima, but not from the media were HCMV DNA positive. Finally, a higher frequency of patients with coronary artery disease (CAD) as compared to healthy controls had signs of ongoing HCMV infection. Active HCMV infection was correlated with T cell phenotypic changes in the blood of the patients, with expansion of T cell subsets expressing CD56 and CD57. Our findings further substantiate a role for HCMV as a pathogen that could be responsible for induction and maintenance of the chronic inflammation that is typical of vascular disease.

List of scientific papers

I. Gredmark S, Soderberg-Naucler C (2003). "Human cytomegalovirus inhibits differentiation of monocytes into dendritic cells with the consequence of depressed immunological functions. " J Virol 77(20): 10943-56
https://pubmed.ncbi.nlm.nih.gov/14512544

II. Gredmark S, Tilburgs T, Soderberg-Naucler C (2004). "Human cytomegalovirus inhibits cytokine-induced macrophage differentiation. " J Virol 78(19): 10378-89
https://pubmed.ncbi.nlm.nih.gov/15367604

III. Gredmark S, Britt WB, Xie X, Lindbom L, Soderberg-Naucler C (2004). "Human cytomegalovirus induces inhibition of macrophage differentiation by binding to human aminopeptidase N/CD13. " J Immunol 173(8): 4897-907
https://pubmed.ncbi.nlm.nih.gov/15470031

IV. Gredmark S, Straat K, Homman-Loudiyi M, Kannisto K, Soderberg-Naucler C (2005). "Human cytomegalovirus (HCMV) down regulates the expression of PDGF receptors in smooth muscle cells." (Manuscript)

V. Gredmark S, Rahbar A, Soderberg-Naucler C (2005). "Identification of cytomegalovirus in smooth muscle cells obtained from patients with atherosclerotic disease." (Manuscript)

VI. Gredmark S, Jonasson L, van Gosliga D, Ernerudh J, Soderberg-Naucler C (2005). "Active cytomegalovirus infection in patients with coronary disease." (Manuscript)