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Dr.Rosen's Research Lab

Research Team  

Hugo R. Rosen, MD (PI) 
Lucy Golden-Mason, PhD (Associate Professor Research) 
Rachel H. McMahan, PhD (Assistant Professor Research) 
Silvia Giugliano, PhD (Post-Doctoral Fellow) 
Michael Kriss, MD (Post-Doctoral Fellow) 
Melissa Sheiko, MD (Post-Doctoral Fellow) 
Matthew Burchill, PhD (Post-Doctoral Fellow) 
Angela M. Mitchell, MS (Graduate Student) 
Linling Cheng, BS (Professional Research Assistant) 
Cara Porche, BS (Professional Research Assistant) 
Leah VanderMeer, BS (Professional Research Assistant) 
  
Overview: 
 
Our laboratory is interested in the immune response to hepatitis C virus (HCV), particularly understanding the mechanisms associated with spontaneous or therapeutic-induced clearance versus viral persistence. In addition to examining the role of antigen-specific T cells and regulatory T cells, we are also characterizing the potential role of innate immune cells including, dendritic, liver endothelial, monocytes and natural killer cells. The central theme of our studies is to define why HCV causes diverse outcomes in exposed individuals and characterize the division of labor, i.e., role played by different components of the immune system. The complexity of the hepatic immune response to HCV is illustrated in Figure 1.  
 
  
Figure 1: The hepatic immune response to HCV (Rosen, HR. JClin Invest. 2013)
 
  
Recent Reviews:
  
Rosen HR. Emerging concepts in immunity to hepatitis C infection.  J Clin Invest. 2013 Oct 1;123(10):4121-4130.
 
Golden-Mason L, Rosen HR.  Natural killer cells: multifaceted players with key roles in hepatitis C immunity.  Immunol Rev. 2013 Sep;255(1):68-81.
 
Rosen HR.  Clinical practice. Chronic hepatitis C infection.  N Engl J Med. 2011 Jun 23;364(25):2429-38.
 
Hughes MG Jr, Rosen HR.  Human liver transplantation as a model to study hepatitis C virus pathogenesis.  Liver Transpl. 2009 Nov;15(11):1395-411.
 
 
Challenges in Studying HCV: 
 
The study of HCV infection is challenging because of the lack of a readily available animal model to study the causal relationship between the host immune response and the virus. Thus, a number of very well characterized, prospective human cohorts form the basis of our laboratory’s studies. These cohorts include patients with acute HCV infection, subjects with spontaneously resolved infection, patients undergoing antiviral therapy and chronic HCV liver transplant recipients as well as HCV-infected mother baby dyads. Thus, the experimental systems used in the majority of our studies employ "natural" host-pathogen interactions with an experimental emphasis on identification, characterization; isolation and manipulation of specific immune cells.
 
 
Representative Projects:  
 
While our primary area of interest is in understanding the immune response to HCV infection our findings have implications for other viral infections and liver diseases including non- alcoholic fatty liver disease (NASH) and hepatocellular carcinoma (HCC).
  
 
Co-stimulatory Molecules and Ligands:
 
A number of inhibitory co-receptors and ligands have been implicated in mediating immune cell dysfunction characteristic of chronic viral infection. We have demonstrated a significant role for T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) and its ligand Galectin-9 in the inhibition of adaptive (Golden-Mason L et al., J Virol 2009) and innate immune cells (Mengshol JA et al., PLoS One 2010; Golden-Mason L et al., J Virol 2013).  Furthermore co-expression of multiple inhibitory molecules tracks with defective T cell responses, which suggests their manipulation may represent a rational target for novel immunotherapeutic approaches (McMahan RH et al., J Clin Invest. 2010). We are currently involved in an exciting collaborative study with Dr. Michael Nishimura (University of Chicago) to assess the therapeutic potential of HCV-specific T cell receptor (TCR) transduced cells (Zhang Y et al., PLoS Pathog 2010) to eliminate HCV infection in a novel mouse model engrafted with human liver (Yecuris).
 
Golden-Mason L, Palmer BE, Kassam N, Townshend-Bulson L, Livingston S, McMahon BJ, Castelblanco N, Kuchroo V, Gretch DR, Rosen HR.  Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells.  J Virol. 2009 Sep;83(18):9122-30.
 
Mengshol JA, Golden-Mason L, Arikawa T, Smith M, Niki T, McWilliams R, Randall JA, McMahan R, Zimmerman MA, Rangachari M, Dobrinskikh E, Busson P, Polyak SJ, Hirashima M, Rosen HR.  A crucial role for Kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection.  PLoS One. 2010 Mar 4;5(3):e9504.
 
Golden-Mason L, McMahan RH, Strong M, Reisdorph R, Mahaffey S, Palmer BE, Cheng L, Kulesza C, Hirashima M, Niki T, Rosen HR. Galectin-9 functionally impairs natural killer cells in humans and mice. J Virol. 2013 May;87(9):4835-45.
 
McMahan RH, Golden-Mason L, Nishimura MI, McMahon BJ, Kemper M, Allen TM, Gretch DR, Rosen HR.  Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity.  J Clin Invest. 2010 Dec;120(12):4546-57
 
Zhang Y, Liu Y, Moxley KM, Golden-Mason L, Hughes MG, Liu T, Heemskerk MH, Rosen HR, Nishimura MI.  Transduction of human T cells with a novel T-cell receptor confers anti-HCV reactivity.  PLoS Pathog. 2010 Jul 29;6(7):e1001018
  
 
Natural Killer Cells (NKs):  
 
Natural killer (NK) cells are considered the principal innate effectors representing the first line of defense in the control of viral infections.  We have demonstrated important roles for NK cells in every stage of HCV infection; from protection against infection in injection drug users (Golden-Mason L et al., Hepatology 2010) to prediction of antiviral success or failure with IFN-based therapies (Golden-MasonL et al., Hepatology 2011). Lack of constitutive inhibition and activation via natural cytotoxicity receptors (Golden-Mason L et al., Hepatology 2012) are likely important in these processes (Figure 2).  We still have much to learn, in particular how liver-derived NKs influence the outcome of HCV infection.  The demonstration of NK cell anti-viral memory and the possibility that NKRs may recognize HCV-specific components opens up challenging but exciting avenues of investigation for the future. 

Figure 2: The activation status of NK cells is controlled by the balance of signals initiated through activating and inhibitory cell surface receptors
(Golden-Mason L, Rosen HR. Immunol Rev 2013)
 
Golden-Mason L, Cox AL, Randall JA, Cheng L, Rosen HR.  Increased natural killer cell cytotoxicity and NKp30 expression protects against hepatitis C virus infection in high-risk individuals and inhibits replication in vitro.  Hepatology. 2010 Nov;52(5):1581-9.
 
Golden-Mason L, Bambha KM, Cheng L, Howell CD, Taylor MW, Clark PJ, Afdhal N, Rosen HR; Virahep-C Study Group. Natural killer inhibitory receptor expression associated with treatment failure and interleukin-28B genotype in patients with chronic hepatitis C.  Hepatology. 2011 Nov;54(5):1559-69
 
Golden-Mason L, Stone AE, Bambha KM, Cheng L, Rosen HR.  Race- and gender-related variation in natural killer p46 expression associated with differential anti-hepatitis C virus immunity.  Hepatology. 2012 Oct;56(4):1214-22.
 
  
Liver Sinusoidal Endothelial Cells (LSECs): 
 
LSECS have been evolutionarily conserved to clear waste molecules entering the circulation, and have been implicated as central to induction of tolerance in the liver.  Their functional role in viral hepatitis has not previously been explored. In collaboration with Dr. Vijay Shah (Mayo Clinic, Rochester) we are studying the interactions between HCV and human LSECs.  These studies will shed insight into important innate antiviral responses mediated by LSECs that might be exploited for new immunotherapeutic approaches.
 
  
Plasmacytoid Dendritic Cells (pDCs): 
 
Our recent study has demonstrated that pDCs sense the HCV pathogen-associated molecular pattern (PAMP) (Dr. Michael Gale Jr., University of Washington) RNA to produce type I and type III interferons (IFNs) and control in vitro virus replication.  The HCV- PAMP is recognized through the cytosolic Retinoic Acid-Inducible Gene 1(RIG-I) pattern recognition receptor in conjunction with the Toll-Like-Receptors (TLRs) in order to initiate an IFN response (Stone AE etal., PLoS Pathog. 2013 9:e1003316). This observation challenges the current dogma that RLRs are dispensable in viral recognition by pDCs.  Studies are ongoing to elucidate the mechanisms whereby HCV inhibits or evades pDC anti-viral responses.
   
Stone AE, Giugliano S, Schnell G, Cheng L, Leahy KF, Golden-Mason L, Gale M Jr, Rosen HR
Hepatitis C virus pathogen associated molecular pattern (PAMP) triggers production of lambda-interferons by human plasmacytoid dendritic cells.  PLoS Pathog. 2013 Apr;9(4):e1003316.
 
 
Vertical Transmission:
  
HCV infection has recently been identified as an independent risk factor for pre-term delivery, perinatal mortality, intrauterine growth restriction, and other complications.  However, the rate of HCV transmission to the fetus is <5%, suggesting potent antiviral responses within the maternal-fetal interface.  We have described the diverse immune cell populations found at the maternal-fetal interface (MFI) and have shown that placenta acts not only as a physical barrier but as an active immune organ (HurtadoCW. Et al., PLoS One. 2010) . In collaboration with Dr. Virginia Winn (Obstetrics & Gynecology, UC Denver) we are currently examining how trophoblasts and placental derived immune cells contribute to the low rate of fetal transmission and the associated risk of placental damage and preterm labor. 
  
Hurtado CW, Golden-Mason L, Brocato M, Krull M, Narkewicz MR, Rosen HR.  Innate immune function in placenta and cord blood of hepatitis C-seropositive mother-infant dyads.  PLoS One. 2010 Aug 30;5(8):e12232. 
 
 
Non-alcoholic fatty liver disease (NAFLD): 
 
Obesity can lead to number of clinically relevant health problems including NAFLD.  NAFLD occurs when there is an increase in fat within the liver leading to liver inflammation, scar tissue accumulation and eventual loss of liver function.  Activation of innate immune cells, including monocytes and macrophages, is critical for both development and resolution of NAFLD.  Recent studies have shown that signaling pathways involved in metabolism also have immunoregulatory effects. Specifically, we have shown that activation of the bile acid receptors, FXR and TGR5, can alter the phenotype of macrophages and inhibit the inflammation associated with NAFLD (McMahan RH et al., J Biol Chem. 2013).  Dr. Rachel McMahan’s studies aim to further clarify the role of these metabolic pathways in immune cell function and liver inflammation.  The ultimate goal is to use the knowledge obtained from these studies to define new therapeutic and diagnostic opportunities for patients with NAFLD. 
 
McMahan RH, Wang XX, Cheng LL, Krisko T, Smith M, El Kasmi K, Pruzanski M, Adorini L, Golden-Mason L, Levi M, Rosen HR.  Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease.  J Biol Chem. 2013 Apr 26;288(17):11761-70.