Inducible Hepatic-Associated Lymphoid Tissue (iHALT): generating and maintaining long-lived plasma cells

About This Grant

It has long been evasive why strictly hepatotropic viruses, such as hepatitis C virus (HCV), have been associated with the generation of delayed antibody responses that are of relatively poor quality to other, more systemic infections. Studies to date investigating antiviral adaptive immune priming within the liver have been hindered by lack of a natural, biologically relevant small animal model of viral infection exclusively restricted to hepatocytes. In this proposal, we will accordingly use the HGV-related rodent hepacivirus (RHV) recently discovered by our team, which possesses several similarities to its genetic relative, including strict liver tropism, conserved replication dependence on miR-122 interaction with the viral 5' UTR, identical genomic organizational structure and polyprotein cleavage pattern, and the propensity to cause chronic infection with fibrosis and hepatocellular carcinoma tumorigenesis. Our preliminary identification of robust antibody-secreting cell (ASC) responses, both total lgG and those targeting the envelope glycoprotein E2, almost exclusively arising within the liver during both human HCV and murine RHV infection, served as the rational impetus for further investigation of how, when, and where such responses are generated. The secondary lymphoid organ (SLO) dormancy accompanying such strong ASC responses within the liver alongside their durable maintenance therein by putative cognate anchoring pairs, many of which are also critical for tethering of long-lived plasma cells (LLPCs) to stromal niches in bone marrow, collectively suggest that the liver may serve as a site conducive to both the local generation and perpetual maintenance thereafter of LLPCs during strictly hepatotropic viral infection. As our recently published findings demonstrate that viral-specific lgG is critical for viral resolution, the development of chronic infection and HCC tumors in its absence suggests that generation of plausibly locally generated humoral responses within the liver at sites of virus-induced tertiary lymphoid structures, hereafter denoted as inducible Hepatic-Associated Lymphoid Tissue (iHALT), likely serve an important functional role. The survival of LLPCs residing in the liver 1.5 years post-clearance in these mice represents a unique scenario in which the liver may also provide a suitable niche for these cells, contrary to the canonical paradigm in which the bone marrow or select SLO circumstances are exclusively capable of fostering such an environment. We propose to mechanistically determine the signaling prerequisites responsible for driving this local, successful antiviral antibody response within the liver (Aim 1) as well as the cues instructing putatively locally derived progenies to be retained directly adjacent to their generative origins (Aim 2). Understanding these processes would significantly enhance our understanding of the relationship between hepatotropic viruses capable of suppressing SLOs in a state of functional dormancy with humoral responses plausibly being housed ectopically at extra lymphoid sites. Further, these studies would likely yield important insights capable of influencing the current paradigm of durable antibody responses in antigen free settings, specifically exploring a potentially novel niche site conducive to LLPC survival within the liver.