The current status and future directions of myxoma virus, a master in immune evasion

Abstract

Myxoma virus (MYXV) gained importance throughout the twentieth century because of the use of the highly virulent Standard Laboratory Strain (SLS) by the Australian government in the attempt to control the feral Australian population of Oryctolagus cuniculus (European rabbit) and the subsequent illegal release of MYXV in Europe. In the European rabbit, MYXV causes a disease with an exceedingly high mortality rate, named myxomatosis, which is passively transmitted by biting arthropod vectors. MYXV still has a great impact on European rabbit populations around the world. In contrast, only a single cutaneous lesion, restricted to the point of inoculation, is seen in its natural long-term host, the South-American Sylvilagus brasiliensis and the North-American S. Bachmani. Apart from being detrimental for European rabbits, however, MYXV has also become of interest in human medicine in the last two decades for two reasons. Firstly, due to the strong immune suppressing effects of certain MYXV proteins, several secreted virus-encoded immunomodulators (e.g. Serp-1) are being developed to treat systemic inflammatory syndromes such as cardiovascular disease in humans. Secondly, due to the inherent ability of MYXV to infect a broad spectrum of human cancer cells, the live virus is also being developed as an oncolytic virotherapeutic to treat human cancer. In this review, an update will be given on the current status of MYXV in rabbits as well as its potential in human medicine in the twenty-first century.Table of contentsAbstract1. The virus2. History3. Pathogenesis and disease symptoms4. Immunomodulatory proteins of MYXV4.1. MYXV proteins with anti-apoptotic functions4.1.1. Inhibition of pro-apoptotic molecules4.1.2. Inhibition by protein-protein interactions by ankyrin repeat viral proteins4.1.3. Inhibition of apoptosis by enhancing the degradation of cellular proteins4.1.4. Inhibition of apoptosis by blocking host Protein Kinase R (PKR)4.2. MYXV proteins interfering with leukocyte chemotaxis4.3. MYXV serpins that inhibit cellular pro-inflammatory or pro-apoptotic proteases4.4. MYXV proteins that interfere with leukocyte activation4.5. MYXV proteins with sequence similarity to HIV proteins4.6. MYXV proteins with unknown immune function5. Vaccination strategies against myxomatosis5.1. Current MYXV vaccines5.2. Vaccination campaigns to protect European rabbits in the wild6. Applications of myxoma virus for human medicine6.1. MYXV proteins as therapeutics for allograft vasculopathy and atherosclerosis6.2. Applications for MYXV as a live oncolytic virus to treat cancer7. Discussion and Conclusions8. List of AbbreviationsReferencesAuthor DetailsAuthors' contributionsCompeting interestsFigure LegendsAcknowledgements

Decrease in C-reactive protein levels in rabbits after vaccination with a live attenuated myxoma virus vaccine

“…Watzinger et al (2011) reported the increase in CR protein levels observed after injection of antigens (Complete Freund's Adjuvant, typhoid vaccine, saline solutions) to rabbits, what is in contrast with our study with MXT vaccination. On the other hand our results are in agreement with the literature, in which myxoma virus has shown an inherent ability to infect and cause immunosuppression in rabbits after infection (Jeklova et al 2008;Spiesschaert et al 2011). *P < 0.05, **P < 0.01, ***P < 0.001…”

Comparative Analysis of the Complete Genome Sequence of the California MSW Strain of Myxoma Virus Reveals Potential Host Adaptations

“…Both the Lu and RFV genomes encode multiple proteins involved in host range determination and suppression or evasion of host innate and adaptive immune responses (3,4). In their natural hosts, these proteins are presumed to be essential for virus persistence at high titers and enable sufficient time for vector transmission; persistence in RFV can be more than 9 months, allowing overwintering in the absence of vectors.…”

“…In its native hosts, MYXV induces an innocuous cutaneous fibroma at the site of infection; virus is passively transmitted on the mouthparts of biting arthropods, such as mosquitoes or fleas, probing through the virus-rich epidermis of the fibroma for a blood meal. However, in the European rabbit, which is not native to the Americas, both types of MYXV induce the lethal generalized disease myxomatosis, characterized by a profound suppression of innate and adaptive host immune responses (3,4). A third leporipoxvirus, called Rabbit fibroma virus (RFV; also called Shope fibroma virus), is found in Sylvilagus floridanus (eastern cottontail) in the eastern and central states of the United States and Ontario, Canada.…”

Adaptive Gene Loss? Tracing Back the Pseudogenization of the Rabbit CCL8 Chemokine

“…It is noteworthy that NWL species are resistant to Myxoma virus (MYXV) and at least two Sylvilagus species are natural hosts of the virus and known to serve as reservoirs. In contrast, in naïve European rabbit, this large DNA virus causes a systemic immune deficiency with a fatal outcome (reviewed in Abrantes et al 2012;Spiesschaert et al 2011). Numerous studies have documented the crucial role played by CCL8 and its posttranslational byproducts in CCR5-dependent signal transduction (Hellier et al 2003;Loetscher et al 1994;Struyf et al 2009), more in particular in Human during infection by HIV (Moser et al 2004;Proost et al 1998a, b).…”