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Living in the liver: hepatic infections

Nature Reviews Immunology volume 12, pages 201–213 (2012)Cite this article

Subjects

Key Points

  • The liver serves as an important filter organ to remove circulating pathogens from the blood. However, certain pathogens — such as hepatitis B virus, hepatitis C virus and malaria-inducing Plasmodium spp. parasites — efficiently target the liver and can establish persistent infections in hepatocytes.

  • Despite the function of the liver in skewing immune responses towards tolerance, hepatic cells are equipped with innate immune sensory receptors to detect infectious microorganisms and mount inflammatory responses.

  • Most infectious microorganisms are cleared from the liver through the combination of innate and adaptive immune defence, despite pathogen-specific immune escape strategies. However, our knowledge on the decisive molecular mechanisms that discriminate acute, resolving infections from chronic infections is still incomplete.

  • Persistent infection of hepatocytes is perpetuated by the immunoregulatory liver microenvironment, the predominant co-inhibitory over co-stimulatory signalling by hepatic antigen-presenting cells and the exhaustion of pathogen-specific T cells.

  • Novel therapeutic strategies to overcome chronic viral infection of hepatocytes will combine measures to lower the level of viral antigens in combination with measures to increase the number of virus-specific T cells and their efficiency to locally exert their effector function in the liver.

Abstract

The liver has vital metabolic and clearance functions that involve the uptake of nutrients, waste products and pathogens from the blood. In addition, its unique immunoregulatory functions mediated by local expression of co-inhibitory receptors and immunosuppressive mediators help to prevent inadvertent organ damage. However, these tolerogenic properties render the liver an attractive target site for pathogens. Although most pathogens that reach the liver via the blood are eliminated or controlled by local innate and adaptive immune responses, some pathogens (such as hepatitis viruses) can escape immune control and persist in hepatocytes, causing substantial morbidity and mortality worldwide. Here, we review our current knowledge of the mechanisms of liver targeting by pathogens and describe the interplay between pathogens and host factors that promote pathogen elimination and maintain organ integrity or that allow pathogen persistence.

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Figure 1: Liver microanatomy.
Figure 2: Host mechanisms involved in the clearance of pathogens in the liver.
Figure 3: Host mechanisms that promote the persistence of liver infection.

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Acknowledgements

We acknowledge financial support by the German Research Foundation (DFG; SFB 704, SFB 670, SFB 576, SFB TR57), the Helmholtz Alliance on Immunotherapy of Cancer and the UK Medical Research Council (G0801213). We apologize to all colleagues whose excellent work could not be cited owing to space restrictions.

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Authors and Affiliations

  1. Institute of Virology, Technische Universität München and Helmholtz Zentrum München, Munich, 81675, Germany

    Ulrike Protzer

  2. Division of Infection and Immunity, University College London, London, WC1E 6JF, UK

    Mala K. Maini

  3. Institutes of Molecular Medicine and Experimental Immunology, Friedrich-Wilhelms-Universität Bonn, Bonn, D-53105, Germany

    Percy A. Knolle

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  1. Ulrike Protzer
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Glossary

Liver sinusoidal endothelial cells

(LSECs). Cells that line the hepatic sinusoids and take up molecules from the blood. LSECs function as liver-resident antigen-presenting cells and contribute to the induction of local tolerance.

Kupffer cells

Specialized macrophages in the liver that line the sinusoidal vessels. They present antigens, regulate local immune responses and remove microbial particles, endotoxins and other noxious substances that are present in portal venous blood.

Hepatic stellate cells

A perisinusoidal cell population within the space of Dissé that controls sinusoidal diameter and hepatic blood flow. Stellate cells are the main reservoir of retinol in the liver and contribute to the development of liver fibrosis following inflammation. They have antigen-presenting cell function and contribute to local hepatic immune tolerance.

Space of Dissé

The space between liver sinusoidal endothelial cells (LSECs) and hepatocytes that is filled with extracellular matrix and is populated by hepatic stellate cells. Access to the space of Dissé is provided through fenestrae in LSECs or following transcytotic transport through LSECs.

Granulomas

Structures that are orchestrated by macrophages at different stages of activation and are usually surrounded by a layer of lymphocytes. These macrophages resemble epithelial cells and often include multinucleated giant cells. Granuloma formation is a chronic inflammatory response that can be initiated by various infectious and non-infectious agents.

Pattern-recognition receptors

Immune sensory receptors — such as membrane-bound Toll-like receptors or cytosolic RIG-I-like helicases — that recognize conserved structures of pathogens.

LPS tolerance

A state of hyporesponsiveness to various pro-inflammatory stimuli that results from continuous exposure to low-level lipopolysaccharide derived from the gut. It was described first for Kupffer cells.

Unfolded protein response

A response that increases the ability of the endoplasmic reticulum to fold and translocate proteins, decreases the synthesis of proteins and causes cell cycle arrest and apoptosis.

Autophagy

An evolutionarily conserved process, in which acidic double-membrane vacuoles sequester intracellular contents (such as damaged organelles and macromolecules) and target them for degradation and recycling, through fusion with lysosomes.

Damage-associated molecular pattern

(DAMP). A molecule that is produced by or released from host cells following cellular stress, damage or non-physiological cell death. DAMPs are thought to be responsible for the initiation and perpetuation of inflammatory responses and tissue repair under non-infectious conditions. Examples include: hyaluronan (which is released from the degraded stroma); HMGB1 (which is released from the nucleus); and ATP, uric acid, S100 calcium-binding proteins and heat-shock proteins (which are released from the cytosol). They can induce tolerogenic or immunogenic myeloid dendritic cells, depending on the nature of other signals that are present.

Pathogen-associated molecular pattern

(PAMP). A conserved microbial structure that is not found in mammalian cells and is recognized by non-variable pattern-recognition receptors. PAMPs include microbial components such as bacterial lipopolysaccharide, hypomethylated DNA, flagellin, double-stranded RNA and other cytosolic nucleic acids.

Suicidal emperipolesis

A recently described process during which CD8+ T cells invade hepatocytes, leading to CD8+ T cell death.

Ribavirin

A drug that interferes with RNA metabolism and blocks viral replication. Ribavirin is used in combination with interferon-α to treat hepatitis C.

IFNλ

(Interferon-λ; also known as type III IFNs). There are three IFNλ cytokines, interleukin-28A (IL-28A), IL-28B and IL-29, which can be produced by almost every cell type after infection and bind to a heterodimeric receptor (comprised of the IL-10 receptor β-chain and the IL-28 receptor α-chain) that is expressed mainly by epithelial cells. They have direct antiviral properties, induce IFN-responsive gene expression and increase antigen presentation.

Chimeric antigen receptor

An artificial T cell receptor construct that consists of an extracellular single-chain antibody fragment that functions as the antigen-binding domain, together with transmembrane and intracellular signalling domains from the T cell receptor CD3ζ chain and/or from a co-stimulatory molecule such as CD28.

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Protzer, U., Maini, M. & Knolle, P. Living in the liver: hepatic infections. Nat Rev Immunol 12, 201–213 (2012). https://doi.org/10.1038/nri3169

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