We aim to understand the generation of dysfunctional adaptive immune cells in chronic hepatitis B virus (HBV) infection and develop new strategies to reprogram them into functional cells endowed with potent antiviral activity. Taking advantage of unique mouse models of HBV pathogenesis, and well-characterized cohorts of patients, we plan to dissect and target dysregulated pathways that characterize adaptive immune cell dysfunction during chronic hepatitis B. State-of-the-art static and dynamic imaging are used to analyze the behavior of adaptive immune cells ultimately differentiating into dysfunctional cells in the liver at an unprecedented level of spatial and temporal resolution. In parallel, high-dimensional flow cytometry and single-cell sequencing performed in mouse models of HBV pathogenesis and in chronically infected patients are revealing the proteogenomic landscape and heterogeneity underlying adaptive immune cell dysfunction. Immune-regulatory mechanisms that have been already identified from preliminary work or that are emerging from the abovementioned analyses will be targeted both in vitro and in vivo. In addition to fostering new concepts in adaptive immunity and viral pathogenesis, we are confident that results emerging from this research will have the potential to instruct the design of novel, rational strategies that direct the immune system to terminate chronic HBV infection and its attendant costs and complications.

Finally, in collaboration with Luca Guidotti, Romano Di Fabio and Raffaele De Francesco, we are developing the next-generation of ultrapotent capsid assembly modulators for the treatment of chronic hepatitis B virus infection. 

Immunobiology, pathogenesis and treatment of HBV infection

#HBV #HepatitisB #liver #infection #pathogenesis #adaptiveresponses #imaging #mousemodels #treatment #CD8 #CD4 #Bcells

We are developing novel animal models and platforms to better understand the determinants of COVID-19 severity. Moreover, we aim to dissect the pathogenesis of anosmia and of the long-term consequences of infection. Finally, in collaboration with Luca Guidotti, Vincenzo Summa and Raffaele De Francesco we are generating and characterizing novel protease inhibitors as antiviral agents against COVID-19 and future coronavirus pandemics. All the work is done in our BSL-3 animal facility that features state-of-the-art multiphoton intravital microscopes, FACS sorters and a whole-body plethysmograph for the real-time assessment of lung physiology.

Pathogenesis and treatment of SARS-CoV-2 infection

#SARSCov2 #covid19 #mousemodels #pathogenesis #infection #anosmia #treatment

This line of research aims at dissecting the heterogeneity of B cell responses in different pathological contexts. We use ad hoc animal models and approaches to understand where and when B cells are activated in response to different viral infections. Besides focusing on B cells, we take a comprehensive approach in understanding the interacting partners of B cells, both those that support and those that suppress B cell activation and humoral responses. For example, we have found that T cell help to B cells is dependent on cellular and molecular mechanisms that differ to a great extent within different viral infections. In addition, we have described that myeloid cells recruited upon some infection contexts can directly suppress humoral responses by inducing B cell apoptosis. 

B cell dynamics in viral infections

#Bcells #infection #mousemodels #pathogenesis #interactions #humoralresponses #adaptiveresponses #antibodies #Tcells

CD8+ T cells have a key role in eliminating tumors that affect the liver. The protective capacity of these cells relies on their ability to migrate to and traffic within the liver, recognize tumor-derived antigens, get activated and deploy effector functions. While some of the rules that characterize CD8+ T cell behavior in the cancerous liver have been characterized at the population level, we have only limited knowledge of the precise dynamics of intrahepatic CD8+ T cell conduct at the single-cell level. We have developed several advanced imaging techniques that allow us to dissect the interactive behavior of CD8+ T cells within the mouse liver at an unprecedented level of spatial and temporal resolution. We predict that the time- and space-resolved visualization of hepatic CD8+ T cell behavior, combined with mouse models of primary and secondary liver tumors, will generate novel mechanistic insights into the cellular and molecular mechanisms that govern the capacity of CD8+ T cells to home and function in the tumor-bearing liver.

Our hypothesis is that the anatomic, hemodynamic, and environmental cues that tumors acquire as a function of growth render tumor cells progressively less sensitive to CD8+ T cell-mediated elimination.

We will provide the first in vivo imaging survey of CD8+ T cells within liver tumors and we will identify cellular and molecular mechanisms that govern intratumoral CD8+ T cell behavior and function.

Determinants of immune cell behavior and function within liver tumors 

#tumor #cancer #liver #HCC #mousemodels #pathogenesis #Tcells #CD8 #imaging