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)
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.
. Emerging concepts in immunity to hepatitis C
J Clin Invest. 2013 Oct
Golden-Mason L, Rosen HR
Natural killer cells: multifaceted players with key roles in hepatitis C
Immunol Rev. 2013
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
Liver Transpl. 2009
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.
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
, 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.
, 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.
One. 2010 Mar 4;5(3):e9504.
, McMahan RH, Strong M, Reisdorph R, Mahaffey
S, Palmer BE, Cheng L, Kulesza C, Hirashima M, Niki T, Rosen HR
functionally impairs natural killer cells in humans and mice. J Virol. 2013
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
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
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
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.
, 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.
, 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
, 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
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
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.
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.
, 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
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.
, 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.
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
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
The ultimate goal is to
use the knowledge obtained from these studies to define new therapeutic and
diagnostic opportunities for patients with NAFLD.
, 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.