Hepatitis B virus (HBV) is a partially double-stranded DNA virus that causes acute and hepatitis in humans. The risk of developing a chronic infection varies depending on the age at the time of exposure with a predisposition to chronic disease outcome when one is infected as an infant or child. Over 90% of infants exposed to HBV will become chronically infected with the virus. Of the 400 million individuals chronically infected with HBV, 25% will experience liver disease, cirrhosis and hepatocellular carcinoma. Alternatively, 95% of adults infected with HBV experience a self-limiting disease and life-long immunity. The steps that lead to the divergent responses are largely unknown. We have recently developed a transgenic mouse model of primary HBV infection that mimics key differences in HBV clearance and persistence in humans, including the age-related dichotomy in human HBV infection outcome. Data recently generated from our model, supported by our preliminary studies in humans, strongly implicate the relative maturity of immune priming within the liver microenvironment as a pivotal factor that guides HBV-specific immune responses. Using this model, we will investigate the key age- dependent cellular and molecular immune mechanisms in the liver that are responsible for the divergent disease outcomes. One difference we have identified is in the expression of the lymphocyte organizational molecule, CXCL13, on liver resident macrophages. We have already defined a role for this molecule and its receptor in HBV disease outcome. We will now identify the role of this molecule in priming and organizing lymphocytes and initiating immune responses in the liver by using mice with mutation in CXCL13 and mice treated with clodronate, a drug known to kill macrophages Another identified difference in adult and young mouse liver is the expression of many genes associated with microbial defenses. It is known that upon weaning, the commensal bacteria in the intestines changes dramatically in both young mice and infants. Additionally, blood from the mesenteric veins flows directly to the liver via the portal vein, allowing for the liver to be directly expose to bacterial products and potentially bacteria. Preliminary data from our model shows that manipulation of adult commensal bacteria by administering broad-spectrum antibiotic in the water of mice results in a change in HBV disease outcome from one of clearance to one of persistence. We now will identify if alterations of GI microbiota influences the liver priming environment and HBV disease outcome with a series of depletion and supplementation experiments. We will also identify age-related differences in presence or abundance of distinct species of bacteria that might direct the HBV response or alter the immune priming environment in the liver. We also will identify if changes in commensal bacteria or exposure to bacterial products affects the expression of CXCL13 or other molecules associated with maturation, on macrophages in the liver.

Public Health Relevance

Currently, hepatitis B and C viruses chronically infect 600 million people and malaria infects more than 400 million each year. Within the liver, immune responses to liver pathogens are influenced by many factors, including age at the time of infection, and are poorly understood. Understanding factors, such as influences of commensal bacteria resident in the digestive system, on the initiation of proper immune responses to these hepatotropic pathogens would allow us to develop new, possibly low cost, therapies to influence disease outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK099405-02
Application #
8686835
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2013-07-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
$143,014
Indirect Cost
$10,594
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143