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Human cytomegalovirus and dendritic cell interaction : role in immunosupression and autoimmunity

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posted on 2024-09-02, 22:16 authored by Stefania Varani

Human cytomegalovirus (HCMV) infection is a major cause of morbidity and mortality in patients with an impaired immune system. The virus itself can cause transitory but significant immunosuppression in immunocompetent as well as immunocompromised infected individuals. Besides immunosuppression, HCMV infected patients often develop other signs of immune dysfunction, such as autoimmune phenomena.

The aim of this thesis was to analyze the immunological dysfunctions observed in HCMV-infected patients and to further examine the underlying mechanisms of these immunological abnormalities. In our first study, we observed the presence of anti-endothelial cell, anti-smooth muscle cell and anti-nuclear autoantibodies in the sera of 43% of liver transplant recipients undergoing an acute HCMV infection and we found a correlation between the appearance of these autoantibodies and the presence of high amounts of virus in the blood. A strategy that may be effective for the virus in inducing general immunomodulation is subverting the function of cells that play a key role in the generation of both the innate and the adaptive immunity, i.e. dendritic cells (DC). It has been shown that HCMV inhibits DC functions in vitro. We examined the effect of HCMV on DC functions in vitro and in vivo.

We compared myeloid DC (MDC) obtained from heart transplant patients undergoing an acute HCMV infection with MDC from HCMV-negative transplant recipients. We found an impaired immunophenotype in immature MDC and a reduction in the ability of mature MDC to stimulate an allogenic T cell response in cells obtained from patients undergoing an active HCMV infection. Similar results were observed in immunocompetent individuals undergoing a symptomatic HCMV infection (i.e., HCMV mononueleosis), who are not subjected to immunosuppressive therapy. Mature DC obtained from patients with H~ mononucleosis were inefficient in stimulating proliferation of allogenic lymphocytes. We also analyzed the pattern of cyto-chemokines secreted by DC obtained from HCMV-infected patients and observed a proinflammatory profile. We therefore concluded that HCMV impairs the MDC immunophenotype and functions during infection in both immunocompetent and immunocompromised hosts. These strategies may assist the virus to interfere with early functions of the host immune system and may lead to immunosuppression.

The peculiar trafficking properties of DC is a key event in the early host response to pathogens and may also be targeted by the virus to hamper DC functions. We therefore examined the viral effect on DC migration in response to inflammatory chemokines upon HCMV infection in vitro. HCMV inhibited the migration of immature MDC in response to inflammatory chemokines by 95% at 1 day after infection. HCMV infection significantly reduced the cell-surface expression of CCR1 and CCR5, but left expression of the lymphoid chemokine receptor CCR7 unchanged. HCMV infection also induced secretion of the inflammatory chemokines CCL3, CCL4 and CCL5 and neutralizing antibodies specific for these chemokines reduced the effects of HCMV on chemokine receptor expression and DC migration. We therefore suggest that HCMV may downregulate the chemokine receptor expression on DC by inducing the secretion of inflammatory chemokines and thereby hamper DC migration. The interference of HCMV with the migratory ability of DC may prevent DC trafficking in vivo and contribute to immune suppression in infected individuals.

Finally, we examined the effects of HCMV on the recently discovered plasmacytoid DC (PDC) in an in vitro model of infection. Through the production of type I IFN PDC exert a dual role in antiviral responses by directly inhibiting viral replication and by determining the initiation and regulation of downstream B cell and T cell responses. Although HCMV only infected 13% of PDC, we observed viral induced activation of PDC that resulted in secretion of high amounts of IFN-alpha through engagement of TLR9. PDC interaction with HCMV resulted in opposite downstream effects for B cell and T cell subsets. HCMV-activated PDC secreted soluble factors that stimulated B cell activation and proliferation and we suggest that B cell hyperactivation may contribute to the development of humoral autoimmunity, as was observed in the first study of this thesis. Conversely, HCMV inhibited the allostimulatory ability of PDC, leading to depressed proliferation of CD4+ and CD8+ lymphocytes. Subverting the immunostimulatory ability of these potent antigen presenting cells may considerably support a condition of immunosuppression.

In conclusion, a viral attack on cells that are crucial in initiation and orchestration of innate and adaptive immune responses such as the DC, may result as an effective strategy for the virus to escape the host immune response. A side effect of this strategy may be the induction of significant immunosuppression and the generation of autoimmune phenomena in HCMV-infected patients.

List of scientific papers

I. Varani S, Muratori L, De Ruvo N, Vivarelli M, Lazzarotto T, Gabrielli L, Bianchi FB, Bellusci R, Landini MP (2002). Autoantibody appearance in cytomegalovirus-infected liver transplant recipients: correlation with antigenemia. J Med Virol. 66(1): 56-62.
https://doi.org/10.1002/jmv.2111

II. Varani S, Frascaroli G, Gibellini D, Potena L, Lazzarotto T, Lemoli RM, Magelli C, Soderberg-Naucler C, Landini MP (2005). Impaired dendritic cell immunophenotype and function in heart transplant patients undergoing active cytomegalovirus infection. Transplantation. 79(2): 219-27.
https://doi.org/10.1097/01.TP.0000147359.63158.29

III. Varani S, Frascaroli G, Homman-Loudiyi M, Feld S, Landini MP, Soderberg-Naucler C (2005). Human cytomegalovirus inhibits the migration of immature dendritic cells by down-regulating cell-surface CCR1 and CCR5. J Leukoc Biol. 77(2): 219-28.
https://doi.org/10.1189/jlb.0504301

IV. Frascaroli G, Varani S, Mastroianni A, Britton S, Gibelleni D, Rossini G, Landini MP, Soderberg-Naucler C (2005). Dendritic cell function in cytomegalovirus-infected patients with mononucleosis. [Submitted]

V. Varani S, Frederich M, Feld S, Tammik C, Frascaroli G, Landini MP, Soderberg-Naucler C (2005). Human cytomegalovirus differentially controls B-cell and T-cell responses through effects on plasmacytoid dendritic cells. [Manuscript]

History

Defence date

2005-11-25

Department

  • Department of Medicine, Solna

Publication year

2005

Thesis type

  • Doctoral thesis

ISBN-10

91-7140-505-4

Number of supporting papers

5

Language

  • eng

Original publication date

2005-11-04

Author name in thesis

Varani, Stefania

Original department name

Department of Medicine

Place of publication

Stockholm

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