Author(s): Ceri A Fielding [*]
cytokines; IFNs; immune evasion; inflammation; ILs; TNF superfamily; virokines; viruses
Cytokines are low molecular weight proteins, which are secreted, conveying signals from their site of production to other cells expressing specific cognate cell surface cytokine receptors [1-5 ]. They have many roles but are especially important in the functioning of the immune system. Many cytokines play critical roles in host immune defense from pathogens, but also contribute to immune-mediated pathology occurring in autoimmune disease, for example, TNF-[alpha] and rheumatoid arthritis. There are a number of cytokine families, defined either on the basis of shared functional characteristics or structural homology for example, IFNs, ILs, TNF superfamily, chemokines [1-5 ].
Viruses have evolved to be 'master immunologists', manipulating the host's immune response to prevent their elimination in the initial stages of virus entry and infection and throughout their long-term persistence. Virus immune evasion mechanisms covers aspects of the antiviral immune response, such as innate immune pathways, such as pattern recognition receptors (e.g., Toll-like receptors and nucleic acid sensors) [6 ], antiviral restriction factors [7 ], the IFN pathway [8 ], complement [9 ] and NK cells [10 ] and acquired immune pathways, such as T-cell and B-cell responses [ 11,12 ].
Cytokine pathways represent an attractive target for viruses for modulation to prevent antiviral immune responses and allow their long-term persistence. Cytokines have multiple roles in the host immune system, including being directly antiviral (IFNs), pro-apoptotic or pro-survival (TNFs, ILs), pro- or anti-inflammatory (TNFs, ILs) and in driving the recruitment of immune cells to sites of infection (chemokines) [1-5 ]. Therefore, cytokine-mediated effects are of great relevance to the outcome of virus infection and viral persistence.
Viruses have acquired mechanisms to modulate or suppress the function of cytokines in their favor enhancing pro-viral and inhibiting antiviral effects to allow viral replication and persistence. This modulation can involve suppressing cytokine production by interfering with innate immune sensing of virus infection, encoding cytokine-binding receptor or cytokine receptor mimics, promoting or suppressing cytokine-induced signaling and encoding cytokine mimics themselves. Viruses encode gene products, which are able either to mimic or inhibit cytokine activity. These properties are especially true for viruses with large DNA genomes, for example, the herpesvirus family, which have the coding capacity to encode additional accessory immunomodulatory functions, which although not essential for replication in vitro , enable persistence in vivo [13 ].
There are eight members of the herpesvirus family (Table 1). Although they have different cellular tropisms, they all establish a life-long persistent infection within the host, following the initial acute infection. Herpesviruses have evolved mechanisms to allow their co-existence with the host immune system, including modulating cytokine pathways in a number of ways: encoding viral cytokine and chemokine mimics, encoding viral cytokine and chemokine receptor mimics and encoding inhibitors of cytokine pathways (Table 2).
* HCMV & EBV viral IL-10 (vIL-10)
ILs are produced by and act on a variety of cell types, including both stromal/tissue and hematopoietic cells. They fall into a number of different...