Interruption of cytokine networks by poxviruses: lessons from myxoma virus

Abstract

Myxoma virus is an infectious poxvirus pathogen that induces a virulent systemic disease called myxomatosis in European rabbits. The disease is rapidly and uniformly fatal to susceptible rabbits and is characterized by generalized dysfunction of cellular immunity and multiple interruptions of the host cytokine network. A number of virus genes are classified as virulence factors because virus constructs bearing targeted gene disruptions induce attenuated disease symptoms. Many of these genes encode proteins that interact directly with effector elements of the host immune system. Included among these immunosubversive viral proteins are secreted mimics of host ligands or regulators (virokines) and homologues of cellular cytokine receptors (viroceptors). Five examples of these immune modulator proteins encoded by myxoma virus are reviewed: (1) myxoma growth factor, a member of the epidermal growth factor ligand superfamily; (2) SERP-1, a secreted serine proteinase inhibitor; (3) M11L, a receptor-like surface protein; (4) T2, a tumor necrosis factor receptor homologue; and (5) T7, an interferon-gamma receptor homologue. The origin of viral strategies designed to subvert immune regulation by host cytokines is considered in the context of the biology of myxoma virus within immunocompetent hosts.

Viral Vascular Endothelial Growth Factor Plays a Critical Role in Orf Virus Infection

“…Nor is there any evidence of VEGF-like activity encoded by any virus other than parapoxviruses. However, virus-encoded EGF and VEGF are both examples of a growing family of factors which are expressed by poxviruses and other large DNA viruses, which are often nonessential for viral replication, but which play important roles in modulating the host environment during infection (25,28,36).…”

Myxoma virus in the European rabbit: interactions between the virus and its susceptible host

“…One particular mechanism conceived by MV to subvert the host immune response is carried out by two related sets of immunomodulatory proteins described as virokines and viroreceptors [74,87]. These virus-encoded proteins target specific pathways of the host immune system used to coordinate antiviral and early inflammatory responses directed against viral infection [64,74]. Viroreceptors closely resemble cellular receptors and are often secreted or expressed on the surface of virus infected cells [65].…”

“…They functionally bind and inhibit extracellular host ligands which are intended to induce an inflammatory or antiviral response following virus infection [42]. On the contrary, virokines are normally secreted and are often similar to host immune ligands such as cytokines, or chemokines, but usually the viral versions are smaller or have alternative biological properties compared to the host ligands [54,64,90]. Examples of myxoma encoded secreted immunomodulatory proteins include the following: (1) M-T1, an inhibitor of CC-chemokines; (2) M-T2, a tumor necrosis factor receptor homolog; (3) M-T7, a homolog of the interferongamma receptor; (4) Serp-1, a secreted serine proteinase inhibitor; (5) myxoma growth factor, ligand for the erbB family of EGF receptors.…”

“…There are many extensive and excellent reviews on the immunomodulatory proteins of poxviruses [42,50,64,69,74,75,87,91,106]. This review will focus primarily on the interactions of MV and its susceptible host, the European rabbit in vitro and in vivo.…”

Caspase inhibitors

“…1 As crmA was discovered before the role of caspases in apoptosis had been established, it was hypothesized that viruses used CrmA to bind to active Caspase 1 to reduce the defensive inflammatory response triggered by IL-1b. 2 While this is indeed true, with the identification of caspases as the key mediators of apoptosis it also became clear that CrmA could be used to prevent defensive suicide of infected cells, thereby allowing more time for viral replication. 3 These observations also highlighted the close association between inflammation and defensive apoptosis.…”