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28 July World Hepatitis Day: Understanding Hepatitis with single cell RNA-seq

28 July World Hepatitis Day: Understanding Hepatitis with single cell RNA-seq

28 July is World Hepatitis Day. It is one of WHO’s seven officially mandated global public health days to raise awareness of the global burden of viral hepatitis and to encourage the stepping up of international efforts on preventing and treating hepatitis.

Hepatitis is an inflammation of the liver, most commonly caused by a viral infection. There are five main hepatitis viruses, referred to as types A, B, C, D and E. These five types are of greatest concern because of the burden of illness and death they cause and the potential for outbreaks and epidemic spread. This blogpost summarises a few recent research utilizing single cell RNA-seq to study the mechanism of hepatitis viral infection and pathogenesis.

Liver-resident T cells may be causing harm

In chronic hepatitis B (CHB), accumulation of activated immune cells results in nonspecific hepatocyte killing, leading to scarring of the liver, a condition known as cirrhosis. Nkongolo and colleagues performed single cell RNA-seq of CHB patients with active liver damage and found a distinct liver-resident, polyclonal CD8+ T cell population that was enriched at baseline and displayed a highly activated immune signature during liver damage (1). Treatment by a combination of cytokines identified by computational prediction of ligand-receptor interaction induced the activated phenotype in healthy liver CD8+ T cells, resulting in nonspecific Fas ligand–mediated killing of target cells in vitro experiments. These results indicate a CD8+ T cell population in the human liver that can drive nonspecific hepatocyte killing via a key pathway.

Immune status of alcoholic and
hepatitis B virus-related liver cirrhosis is different

Apart from viral infection, hepatitis can also be caused by excess alcoholic consumption. Both viral and alcoholic hepatitis may progress to cirrhosis. Zhang and colleagues performed single cell RNA-seq and found the immune status of alcoholic (ALC) and hepatitis B virus (HBV)-related liver cirrhosis differed significantly (2). The ALC group had a higher proportion of intrahepatic monocyte/macrophages and a lower proportion of T cells and B. The B cells in ALC group also exhibited a dysregulated mitochondrial oxidative phosphorylation system. Ligand receptor interaction analysis showed that expression of Galectin-9 on Kupffer cells, a subset of macrophage, may be responsible for T cell exhaustion and inhibiting humoral immunity.

Characteristics of T cells in different disease phases of hepatitis B infection are different

Zhang and colleagues performed single cell RNA-seq on liver and blood samples of individuals undergoing different phases of HBV infection and recovery (3). They found that both immune active (the later stage in chronic hepatitis B marked by liver inflammation) and acute recovery (recovering from acute hepatitis B) patients showed high levels of intrahepatic exhausted CD8+ T cells (Tex), but these Tex derived from different T cell subtypes for the 2 types of patients as found by tracking TCR clones. In immune active but not acute recovery patients, significant cell–cell interactions were observed between Tex cells and regulatory CD4+ T cells, as well as between Tex and FCGR3A+ macrophages. They also found that the proportions of certain T cell subtypes can act as markers for the different disease stages of HBV infection.

The granularity of single cell RNA-seq technique employed in these recent studies revealed some details of the pathogenesis of hepatitis that may be useful for designing diagnostic and treatment strategies down the road.


  1. (1) Nkongolo S, Mahamed D, Kuipery A, Sanchez Vasquez JD, Kim SC, Mehrotra A, Patel A, Hu C, McGilvray I, Feld JJ, Fung S, Chen D, Wallin JJ, Gaggar A, Janssen H, Gehring AJ. Longitudinal liver sampling in patients with chronic hepatitis B starting antiviral therapy reveals hepatotoxic CD8+ T cells. J Clin Invest. 2023 Jan 3;133(1):e158903. doi: 10.1172/JCI158903. PMID: 36594467; PMCID: PMC9797343.
  1. (2) Zhang P, Li H, Peng B, Zhang Y, Liu K, Cheng K, Ming Y. Single-cell RNA transcriptomics reveals differences in the immune status of alcoholic and hepatitis B virus-related liver cirrhosis. Front Endocrinol (Lausanne). 2023 Feb 2;14:1132085. doi: 10.3389/fendo.2023.1132085. PMID: 36817578; PMCID: PMC9932584.

  2. (3) Zhang C, Li J, Cheng Y, Meng F, Song JW, Fan X, Fan H, Li J, Fu YL, Zhou MJ, Hu W, Wang SY, Fu YJ, Zhang JY, Xu RN, Shi M, Hu X, Zhang Z, Ren X, Wang FS. Single-cell RNA sequencing reveals intrahepatic and peripheral immune characteristics related to disease phases in HBV-infected patients. Gut. 2023 Jan;72(1):153-167. doi: 10.1136/gutjnl-2021-325915. Epub 2022 Mar 31. PMID: 35361683; PMCID: PMC9763233.

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