Cytokine determinants of viral tropism

Abstract

The specificity of a given virus for a cell type, tissue or species - collectively known as viral tropism - is an important factor in determining the outcome of viral infection in any particular host. Owing to the increased prevalence of zoonotic infections and the threat of emerging and re-emerging pathogens, gaining a better understanding of the factors that determine viral tropism has become particularly important. In this Review, we summarize our current understanding of the central role of antiviral and pro-inflammatory cytokines, particularly the interferons and tumour necrosis factor, in dictating viral tropism and how these cytokine pathways can be exploited therapeutically for cancer treatment and to better counter future threats from emerging zoonotic pathogens.

Figure 1. Levels of viral tropism.

Viral tropism can be divided into three distinct categories depending on the physiological level at which it is measured. Tropism in which the virus replicates in one cell type but not another is known as cellular tropism , tropism in which the virus replicates in a particular tissue or organ but not another is known as tissue tropism, and tropism in which the virus replicates in one host species but not another is known as host tropism.

Figure 2. Cytokine-mediated regulation of viral tropism.

a |All viral replication cycles begin with the binding of an infectious virion to the cell surface. Frequently this step is mediated by a specific host cell surface receptor that the virus hijacks for attachment and/or entry. b | After binding, the virion is internalized into the cell and disassembles into its genome and associated proteins. c | The virus then uses a combination of viral and host proteins to transcribe and translate its own genes and replicate its genome. d | After replication, the newly synthesized genomes are packaged into nascent virus particles which then mature and traffic to the cell surface. e | Finally, the virus particles are released as infectious virus. It is important to note that this simplified life cycle is extremely general and that many viruses will deviate from this outline to some extent. Tumour necrosis factor (TNF) and interferons (IFNs) can inhibit this replication cycle by inducing the expression of proteins with antiviral properties. The important points in this replication cycle at which TNF and the IFNs can manipulate viral tropism, and the antiviral proteins that are involved, are indicated. APOBEC, apolipoprotein B mRNA editing enzyme, catalytic polypeptide; BST2, bone marrow stromal cell antigen 2; IFNAR, interferon-α/β receptor; INDO, indoleamine 2,3-dioxygenase; ISG: interferon-stimulated gene; JAK1, Janus family kinase 1; MAPK3, mitogen-activated protein kinase 3; MXA, myxovirus resistance protein A; NF-κB, nuclear factor-κB; OAS1, 2′-5′ oligoadenylate synthase 1; PKR, dsRNA-dependent protein kinase; RIP1, receptor-interacting protein 1; STAT, signal transducer and activator of transcription; TNFR1, tumour necrosis factor receptor 1; TRADD, TNFR1-associated via death domain; TRAF2, TNFR-associated factor 2; TRIM22, tripartite motif-containing 22; TYK2, tyrosine-protein kinase 2.

Figure 3. Cytokine-mediated viral tropism in tumour tissues.

In a normal tissue, the host innate immune defences respond to infection of a single cell (shown in green) by releasing pro-inflammatory and antiviral cytokines (such as interferons (IFNs) and tumour necrosis factor (TNF)). These cytokines not only affect immune responses but also induce an antiviral state (shown in yellow) in normal tissue, such that the virus cannot productively infect neighbouring cells and the spread of infection is stopped or impeded. However, in a tumour, although the immune sentinel cells in the host might still initiate a potent innate immune response, including the release of the same antiviral cytokines, the tumour cells are frequently unable to respond to these secreted cytokines and so fail to establish an antiviral state. This can favour virus spread within the tumour tissue (and lysis of tumour cells) but not into neighbouring normal tissues, in which the antiviral state has been established.