Hepatitis C virus E2 and CD81 interaction may be associated with altered trafficking of dendritic cells in chronic hepatitis C

Nattermann, Jacob; Zimmermann, Henning W.; Iwan, Agathe; Lilienfeld‐Toal, Marie von; Leifeld, Ludger; Nischalke, Hans Dieter; Langhans, Bettina; Sauerbruch, Tilman; Spengler, Ulrich

doi:10.1002/hep.21350

Cited by 80 publications

(99 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…98 Another feasible explanation is that PDCs may be trapped in the liver, as recently suggested by Spengler's group. 99 Our own group indirectly confirmed the findings of Nattermann et al 99 by reporting increased expression of the PDC markers CD123 and BDCA-2 in the livers of patients with chronic HCV compared with normal liver or nonviral hepatitis. 98 PDC enrichment in the liver could explain the discrepancy between the elevated expressions of IFN-␣ genes in the livers of HCVinfected individuals 100,101 that was still associated with their inability to clear the virus.…”

Section: Dendritic Cells In Hcv Infectionsupporting

confidence: 76%

Altered innate immunity in chronic hepatitis C infection: Cause or effect?

2007

View full text Add to dashboard Cite

H epatitis C virus (HCV) is a uniquely successful hepatitis virus in its ability to establish chronic infection in more than two-thirds of those who contract it. The inability of the innate and adaptive immune responses to control HCV invasion and replication contribute to development and persistence of chronic infection. Multiple components have been identified in this process, including pathways by which HCV subverts innate immune recognition and activation, delayed organization of an effective adaptive immune response, the tolerogenic liver environment, and the persistently high levels of viral antigens. We summarize recent findings on the interaction between HCV infection and innate immune responses. Hepatitis C Virus, Immune Responses and Hepatocytes-Brief OverviewA critical role for innate and adaptive immunity has been identified in HCV persistence and liver injury. During acute infection, type I interferon (IFN) is induced in the liver; however, HCV viral load does not decrease, suggesting that HCV interferes with antiviral mechanisms. Innate immune cells, including natural killer cells and dendritic cells shape innate immunity and determine adaptive immune activation. Vigorous, multi-epitopespecific, T helper 1-type and sustained CD4ϩ and CD8ϩ T cell responses were found in resolved acute HCV infections. [1][2][3][4] In contrast, in cases that progress to chronic infection, CD4ϩ T cell responses are weak, short-lived, and targeted to a narrow range of epitopes. 1

show abstract

Section: Dendritic Cells In Hcv Infectionsupporting

confidence: 76%

Altered innate immunity in chronic hepatitis C infection: Cause or effect?

2007

View full text Add to dashboard Cite

show abstract

“…In patients with chronic HCV infection, there is a preferential migration of mDCs to areas of liver inflammation (57,58), coinciding with a reduction in circulating DCs driven by HCV E2 protein-mediated RANTES and MIP-1␣ secretion (58). Subsequently, dysfunctional DCs are trapped inside the liver, unable to migrate to lymph nodes.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, activated pDCs and mDCs may contribute to increased IFN-␣ and IL-12 levels. Each of these factors has some association with virus control but also has well-described mechanisms for hepatocyte death, particularly IFN-␥ (58). This may suggest that in acute hepatitis, DC-and NK cell-mediated inflammation and hepatocyte death are indirect mechanisms via cytokine production.…”

Section: Discussionmentioning

confidence: 99%

Acute Liver Damage Associated with Innate Immune Activation in a Small Nonhuman Primate Model of Hepacivirus Infection

Manickam

Rajakumar

Wachtman

et al. 2016

J Virol

View full text Add to dashboard Cite

Despite its importance in shaping adaptive immune responses, viral clearance, and immune-based inflammation, tissue-specific innate immunity remains poorly characterized for hepatitis C virus (HCV) infection due to the lack of access to acutely infected tissues. In this study, we evaluated the impact of natural killer (NK) cells and myeloid (mDCs) and plasmacytoid (pDCs) dendritic cells on control of virus replication and virus-induced pathology caused by another, more rapidly resolving hepacivirus, GB virus B (GBV-B), in infections of common marmosets. High plasma and liver viral loads and robust hepatitis characterized acute GBV-B infection, and while viremia was generally cleared by 2 to 3 months postinfection, hepatitis and liver fibrosis persisted after clearance. Coinciding with peak viral loads and liver pathology, the levels of NK cells, mDCs, and pDCs in the liver increased up to 3-fold. Although no obvious numerical changes in peripheral innate cells occurred, circulating NK cells exhibited increased perforin and Ki67 expression levels and increased surface expression of CXCR3. These data suggested that increased NK cell arming and proliferation as well as tissue trafficking may be associated with influx into the liver during acute infection. Indeed, NK cell frequencies in the liver positively correlated with plasma (R ‫؍‬ 0.698; P ‫؍‬ 0.015) and liver (R ‫؍‬ 0.567; P ‫؍‬ 0.057) viral loads. Finally, soluble factors associated with NK cells and DCs, including gamma interferon (IFN-␥) and RANTES, were increased in acute infection and also were associated with viral loads and hepatitis. Collectively, the findings showed that mobilization of local and circulating innate immune responses was linked to acute virus-induced hepatitis, and potentially to resolution of GBV-B infection, and our results may provide insight into similar mechanisms in HCV infection. IMPORTANCEHepatitis C virus (HCV) infection has created a global health crisis, and despite new effective antivirals, it is still a leading cause of liver disease and death worldwide. Recent evidence suggests that innate immunity may be a potential therapeutic target for HCV, but it may also be a correlate of increased disease. Due to a lack of access to human tissues with acute HCV infection, in this study we evaluated the role of innate immunity in resolving infection with a hepacivirus, GBV-B, in common marmosets. Collectively, our data suggest that NK cell and DC mobilization in acute hepacivirus infection can dampen virus replication but also regulate acute and chronic liver damage. How these two opposing effects on the host may be modulated in future therapeutic and vaccine approaches warrants further study. H epatitis C virus (HCV) infection has become a global health epidemic, with the virus infecting more than 170 million people worldwide (1) and resulting in 350,000 HCV-related liver disease deaths each year (2). HCV infection results in the following two disparate manifestations: (i) an acute, self-resolving infection and (ii) a chron...

show abstract

“…In fact, Mantegazza and colleagues recently demonstrated the tetraspanin CD63 to slow down migration of DC possibly via interfering with surface expression of integrins. Our group showed that crosslinking of the tetraspanin CD81 also significantly impaired DC motility [19,21]. In addition, Volkov and colleagues demonstrated that triggering CD81 has profound effects on the process of PKC-b translocation to the cytoskeleton subsequently affecting LFA-1-dependent signaling for lymphocyte migration [22].…”

mentioning

confidence: 83%

Regulation of NK cell trafficking by CD81

et al. 2009

Self Cite

View full text Add to dashboard Cite

NK cells, a heterogeneous sub-population of lymphocytes, are critically involved in the regulation of both innate and adaptive immune responses in humans. Besides their participation in the control of tumors and viral infections, they also regulate inflammatory processes, mediating both beneficial and detrimental effects. To effectively fulfil their role in immune surveillance, proper trafficking of NK cells is essential. However, the mechanisms and factors governing NK cell recruitment are only poorly dissected. Here, we describe the functional role of tetraspanins, a family of evolutionary conserved cellsurface proteins, in modulating migration and transmigration of human NK cells. We demonstrate expression of various tetraspanins on NK cells. Furthermore, we show that stimulation of the NK cell-expressed tetraspanin CD81 induces phosphorylation of ezrin/ radixin/moesin proteins and leads to NK cell polarization thereby facilitating NK cell migration toward various chemokines/cytokines. Finally, we provide evidence for a role of CD81 in promoting adhesion of NK cells to components of the extracellular matrix, a prerequisite for extravasation of lymphocytes in inflamed tissues. Thus, our data suggest that the tetraspanin CD81 is importantly involved in the regulation of NK cell recruitment.Key words: Adhesion . Cell migration . Cell trafficking . Chemokines . NK cells Supporting Information available onlineIntroduction NK cells, a heterogeneous sub-population of lymphocytes, are a central part of the innate immune system. Due to their ability to rapidly attack target cells without prior immunization, NK cells can control infection by viruses, and many studies indicate a role for NK cells in the control of tumor development in mice [1]. Moreover, NK cells are also involved in the regulation of adaptive immune responses via secretion of pro-inflammatory cytokines [2] and modulation of interactions between APC and T cells. In addition, NK cells can act as APC themselves [3].In contrast to their beneficial role in the control of malignancies and invading pathogens, NK cells have been shown to also act as mediators of innate immunopathology (reviewed in [1]). Thus, NK cells do not only participate in the control of tumors and viral infections, but also regulate inflammatory processes and influence subsequent adaptive immune responses, mediating both beneficial and detrimental effects.To fulfil their role in immune surveillance, proper trafficking of NK cells is essential. In general, NK cells are found widely Eur. J. Immunol. 2009. 39: 3447-3458 DOI 10.1002 Innate immunity 3447 distributed in the body. Upon inflammation, NK cells are rapidly recruited into various organs such as the lung, liver, or central nervous system following gradients of chemokines and lysolipids, and can then extravasate into the parenchyma or body cavities, resulting in marked NK cell accumulation within inflamed tissues/organs. This requires that NK cells interact with the vessel wall under flow conditions, arrest, and transmigrate. All th...

show abstract

Hepatitis C virus E2 and CD81 interaction may be associated with altered trafficking of dendritic cells in chronic hepatitis C

Cited by 80 publications

References 36 publications

Altered innate immunity in chronic hepatitis C infection: Cause or effect?

Altered innate immunity in chronic hepatitis C infection: Cause or effect?

Acute Liver Damage Associated with Innate Immune Activation in a Small Nonhuman Primate Model of Hepacivirus Infection

Regulation of NK cell trafficking by CD81

Contact Info

Product

Resources

About