Bridging Innate and Adaptive Immunity During Acute HCV Infection

Sanaa Kamal, M.D., Ph.D.

Ain Shams University

Funded in March, 2006: $600000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Bridging Innate and Adaptive Immunity During Acute HCV Infection

This consortium proposes to determine whether strong immune responses early in hepatitis C infection correlate with improved outcomes and to examine whether a specific genetic makeup helps to confer protection. The results are anticipated to provide an essential first step toward development of a preventive vaccine and also may help lead to potential therapies against this potentially deadly infection.

A small percent of people exposed to Hepatitis C (HepC) virus infection spontaneously clear away the virus. Most people, though, develop persistent infection. Chronic HepC infection eventually leads to deadly liver disease, including liver cancer. Consortium researchers plan to compare the evolution and interaction of immune defenses in patients who resolve HepC infection spontaneously and those who develop persistent infection to identify the factors that favor a successful immune response. Specifically, the investigators will examine how the HepC virus interacts with innate immune cells, which initiate a rapid, general response and marshal a highly targeted attack on the virus by adaptive immune T cells. The findings would be the first step toward development of an effective preventive vaccine, or therapy.

Consortium investigators hypothesize that a strong response by innate immune natural killer (NK) cells induces maturation of innate dendritic cells. The mature dendritic cells, in turn, activate adaptive immune T cells to mount a highly effective attack against the HepC virus. Moreover, the consortium investigators hypothesize, the strength of the NK cells' response, and the outcome of infection, is associated with a specific genetic factor that regulates NK cells.

Investigators plan to test these hypotheses by conducting a study of viral-immune cell interactions in health care workers in Egypt, which has the highest prevalence of HepC infection in the world. Ain Shams University researchers will enroll those health care workers (initially free of HepC infection) who subsequently sustain a documented accidental needle stick injury while caring for HepC patients. The Ain Shams investigators will regularly draw blood samples from the workers and follow them over time to determine whether or not they develop HepC infection.

Among workers who become infected, the Ain Shams researchers will determine whether the infection was resolved or became chronic. The Montreal researchers will analyze immune-viral cell interactions in the workers' blood samples taken regularly following exposure, and correlate these analyses with the workers' disease outcomes. University of Southampton investigators will conduct genetic analyses from the blood samples.

Consortium researchers anticipate that good outcomes (brief or no infection) in HepC-exposed workers would be associated with rapid activation of NK cells, leading to maturation of dendritic cells and producing a strong attack by immune T cells. The consortium investigators further anticipate that good outcomes would be correlated with the presence of one of several genetic factors that regulate NK cells.

Significance: Identifying the factors that favor a successful immune response to HepC will provide an essential step toward developing an effective vaccine. Additionally, understanding the nature of the genes that may influence the strength of the immune response could pave the way for development of new therapies for HepC and for preventing liver damage resulting from chronic infection.

ABSTRACT

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Bridging Innate and Adaptive Immunity During Acute HCV Infection

The majority of individuals exposed to hepatitis C virus (HCV) develop persistent infection and chronic liver disease. Early events in the interaction between the virus and the immune system likely determine the outcome of infection. The role of natural killer (NK) cells and innate immune responses during acute HCV infection is unknown. NK cells provide an early defense line against viral infections by killing infected cells and producing cytokines like interferon gamma (IFN-g) that can directly inhibit viral replication and trigger the adaptive immune response. In addition, NK cells interact with dendritic cells (DCs), and this reciprocal interaction results in regulation of both innate and adaptive immune responses. We have recently demonstrated that genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group 1 (HLA-C1) ligand directly influence resolution of HCV infection. These observations suggest that inhibition of NK function during the early phase of HCV leads to viral persistence. However, a correlation between NK cell activity and induction of an efficient T cell-mediated response that results in virus clearance was not established.

We hypothesize that increased NK cell activity during the early phase of HCV infection will prime a highly efficient adaptive immune response and generate terminally differentiated effector CD4+ and CD8+ T cells, resulting in viral clearance. In contrast, a weak NK cell response (i.e. inhibited NK response) will trigger a mediocre or no T cell response and will fail to generate terminally differentiated effector T cells, resulting in viral persistence. The genetic background of HCV-exposed individuals may play a significant role in NK cell activation, determining the outcome to infection, and may even provide sterilizing immunity or lead to subclinical infection, as observed in exposed uninfected individuals.

This collaborative project will study interaction between innate and adaptive immune responses post-HCV exposure, with a focus on exposed uninfected individuals. We will establish a link between the genetic background of the individuals (KIR receptor typing), activation of innate immune mediators (NK cells and DCs) and triggering of the HCV-specific CD4+ and CD8+ T cell response. The aims of this proposal are:
1. To establish a correlation between NK cell activity and the outcome of HCV infection.
2. To establish a correlation between NK cell activity, DC maturation and induction of T cell-mediated immunity.
3. To establish a correlation between KIRs, their MHC class I ligands and protection from HCV infection.

INVESTIGATOR BIOGRAPHIES

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Sanaa Kamal, M.D., Ph.D.

Sanaa M. Kamal, M.D., Ph.D., is currently a professor of medicine at the Department of Gastroenterology and Liver Disease Center, Ain Shams School of Medicine, Cairo, Egypt. She has obtained her M.B, Bch., M.Sc. and M.D. in medicine from Ain Shams University, Cairo, Egypt. She obtained her Ph.D. from the University of Freiburg, Germany, in 1997. She received her postdoctoral training in hepatology and immunology from the Albert-Ludwig Uni-klinik, Freiburg, Germany, sponsored by the prestigious Alexander von Humboldt Grant, Jenner Research Institute, Oxford, UK, and the National Institutes of Health, Bethesda, USA. Here, she studied the characteristics of hepatitis C and Schistosoma mansoni coinfection. This yielded to the establishment of a unique model for viral/parasitic coinfection and a model for accelerated liver fibrosis presented in publication in LIVER, Journal of Hepatology and Journal of Infectious Diseases.

From 2000 to 2001, Dr. Kamal studied the correlates d and impact of HCV-immune responses on the outcome of acute hepatitis C and the progression of liver disease in chronic hepatitis C, sponsored by Fulbright Senior Scholar Research Award and a grant from the International Society of Infectious Diseases. This research was published in top tier journals, including Gastroenterology, Hepatology, Journal of Infectious Diseases, GUT, Journal of Virology, and Journal of Hepatology.

Dr. Kamal is also a visiting professor at Harvard Medical School and is the director of a Fulbright US/Egyptian collaborative program. She is a principle investigator on several NIH, NAID, European, and Egyptian research grants. She is an associate editor for LIVER International and a member in the editorial board of World Journal of Gastroenterology and a reviewer for more than 15 medical journals. She has written several editorials on hepatitis C, HCV-immune responses and viral parasitic interactions, and she is also heading a successful liver transplantation team in Cairo, Egypt. Dr. Kamal is also a member of the continuous medical education committee in Egypt, and supervises Egyptian Infection Control activities.

Naglaa H. Shoukry, B. Pharm., Ph.D., obtained her pharmacy degree from Cairo University (Cairo, Egypt) in 1991 and her Ph.D. in immunology from McGill University (Montreal, Canada) in 2000. During her postdoctoral training at Columbus Children's Research Institute (2000-2004), she demonstrated the essential role of CD4+ and CD8+ T cells in controlling HCV infection in the chimpanzee model. She is the lead author on several publications and review articles in top tier journals, including Annual Reviews, Journal of Experimental Medicine, and Science, and is the recipient of numerous awards from the American Liver Foundation, Canadian Institutes of Heath Research (CIHR) and Fonds de la recherche en santé du Québec (FRSQ).

In January 2005, Dr. Shoukry joined the University of Montreal as an assistant professor at the Department of Medicine. Her laboratory is located within the hepatology axis of the CHUM Research Centre at Saint Luc Hospital, a new, state-of-the-art research center dedicated to the study of hepatitis C. Her research is funded by CIHR, FRSQ and the Dana Foundation, and focuses on understanding the immune response and host-virus interactions during HCV infection. She is a Chercheur boursier junior 1 of the FRSQ, a mentor in the National Canadian Research Training Program on Hepatitis C (NCRTP-HepC), and a member of the INSERM (Unit 743) for research on immunovirology in Montreal.

Salim Khakoo, M.D., MRCP, is currently a Wellcome Trust senior fellow in Clinical Science and Professor of Hepatology at Imperial College, London. He was previously at Southampton University and Southampton General Hospital; he trained in hepatology at The Royal Free Hospital in London and subsequently as a post-doctoral fellow at Stanford University, USA. He combines his clinical interest in hepatology with a basic scientific interest in immunology, and now has an active research program studying the immunology of hepatitis C virus infection. This program encompasses cellular immunology and molecular genetics in order to give a wide perspective on the problem.