Deletion of the Monkeypox Virus Inhibitor of Complement Enzymes Locus Impacts the Adaptive Immune Response to Monkeypox Virus in a Nonhuman Primate Model of Infection

Estep, Ryan D.; Messaoudi, Ilhem; O’Connor, Megan A.; Li, Hai; Sprague, Jerald; Barron, Alex; Engelmann, Flora; Yen, Bonnie; Powers, Michael F.; Jones, J. M.; Robinson, Bridget A.; Orzechowska, Beata; Manoharan, Minsha; Legasse, Alfred W.; Planer, Shannon L.; Wilk, Jennifer; Axthelm, Michael K.; Wong, Scott W.

doi:10.1128/jvi.00199-11

Cited by 61 publications

(45 citation statements)

References 37 publications

(46 reference statements)

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“…These studies have shown that deletion of individual genes can either reduce (Johnston and McFadden, 2004; Senkevich et al, 1994) or enhance (Estep et al, 2011; Ng et al., 2001) replication and virulence. Previous studies that investigated differences in virulence of MPXV strains have predominantly focused on the function and characterization of individual genes, for example, the inhibitor of complement-binding protein (MOPICE), an important anti-inflammatory factor of OPXV (Estep et al, 2011; Hudson et al, 2012). The gene that codes for these enzymes (D14R) is absent in the less virulent west African MPXV strains and has been considered a major virulence factor in Central African MPXV clade infection (Chen et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…These genes have evolved specifically to simultaneously inhibit diverse processes such as pattern-recognition receptor signaling, apoptosis, chemokine and cytokine function, and lymphocyte and antibody activity (Fernandez de Marco Mdel et al, 2010; Hammarlund et al., 2008; Kindrachuk et al, 2012; Weaver and Isaacs, 2008). Whereas previous evaluations of MPXV virulence factors have predominantly focused on the function and characterization of individual viral genes, these studies demonstrated that individual genes were not solely responsible for the observed differences in pathogenicity between MPXV clades (Estep et al, 2011; Hudson et al, 2012). In contrast, we evaluated the effect of deletions of large genomic regions in MPXV that contain several host range and IMM genes to facilitate selection of candidate virulence factors involved in pathogenesis.…”

Section: Introductionmentioning

confidence: 98%

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Attenuation of monkeypox virus by deletion of genomic regions

et al. 2015

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Monkeypox virus (MPXV) is an emerging pathogen from Africa that causes disease similar to smallpox. Two clades with different geographic distributions and virulence have been described. Here, we utilized bioinformatic tools to identify genomic regions in MPXV containing multiple virulence genes and explored their roles in pathogenicity; two selected regions were then deleted singularly or in combination. In vitro and in vivo studies indicated that these regions play a significant role in MPXV replication, tissue spread, and mortality in mice. Interestingly, while deletion of either region led to decreased virulence in mice, one region had no effect on in vitro replication. Deletion of both regions simultaneously also reduced cell culture replication and significantly increased the attenuation in vivo over either single deletion. Attenuated MPXV with genomic deletions present a safe and efficacious tool in the study of MPX pathogenesis and in the identification of genetic factors associated with virulence.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Attenuation of monkeypox virus by deletion of genomic regions

et al. 2015

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“…Although there are differences, this is a conclusion also reached by another group when testing a CCP knockout monkeypox virus recombinant in the non-human primate model [36]. Homologues to several other virulence factors such as the myxoma virus M-T4, anti-apoptosis protein and B14R, interleukin-1 binding protein are also missing from the West African clade genomes and are inferred to be involved in determining disease pathogenesis and virulence [5].…”

Section: Discussionmentioning

confidence: 86%

Elucidating the Role of the Complement Control Protein in Monkeypox Pathogenicity

et al. 2012

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Monkeypox virus (MPXV) causes a smallpox-like disease in humans. Clinical and epidemiological studies provide evidence of pathogenicity differences between two geographically distinct monkeypox virus clades: the West African and Congo Basin. Genomic analysis of strains from both clades identified a ∼10 kbp deletion in the less virulent West African isolates sequenced to date. One absent open reading frame encodes the monkeypox virus homologue of the complement control protein (CCP). This modulatory protein prevents the initiation of both the classical and alternative pathways of complement activation. In monkeypox virus, CCP, also known as MOPICE, is a ∼24 kDa secretory protein with sequence homology to this superfamily of proteins. Here we investigate CCP expression and its role in monkeypox virulence and pathogenesis. CCP was incorporated into the West African strain and removed from the Congo Basin strain by homologous recombination. CCP expression phenotypes were confirmed for both wild type and recombinant monkeypox viruses and CCP activity was confirmed using a C4b binding assay. To characterize the disease, prairie dogs were intranasally infected and disease progression was monitored for 30 days. Removal of CCP from the Congo Basin strain reduced monkeypox disease morbidity and mortality, but did not significantly decrease viral load. The inclusion of CCP in the West African strain produced changes in disease manifestation, but had no apparent effect on disease-associated mortality. This study identifies CCP as an important immuno-modulatory protein in monkeypox pathogenesis but not solely responsible for the increased virulence seen within the Congo Basin clade of monkeypox virus.

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“…Thus, a well-defined animal model using monkeypox virus should mimic the natural course of smallpox disease. Macaques have been used at various stages of smallpox vaccine and antiviral research (16,(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36), and in each case the route of infection, dose, and choice of challenge strain have been key factors in determining whether the macaque model of monkeypox resembles human clinical variola virus infection.…”

Section: Discussionmentioning

confidence: 99%

Assessment of the Protective Effect of Imvamune and Acam2000 Vaccines against Aerosolized Monkeypox Virus in Cynomolgus Macaques

Hatch

Graham

Bewley

et al. 2013

J Virol

113

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To support the licensure of a new and safer vaccine to protect people against smallpox, a monkeypox model of infection in cynomolgus macaques, which simulates smallpox in humans, was used to evaluate two vaccines, Acam2000 and Imvamune, for protection against disease. Animals vaccinated with a single immunization of Imvamune were not protected completely from severe and/or lethal infection, whereas those receiving either a prime and boost of Imvamune or a single immunization with Acam2000 were protected completely. Additional parameters, including clinical observations, radiographs, viral load in blood, throat swabs, and selected tissues, vaccinia virus-specific antibody responses, immunophenotyping, extracellular cytokine levels, and histopathology were assessed. There was no significant difference (P > 0.05) between the levels of neutralizing antibody in animals vaccinated with a single immunization of Acam2000 (132 U/ml) and the prime-boost Imvamune regime (69 U/ml) prior to challenge with monkeypox virus. After challenge, there was evidence of viral excretion from the throats of 2 of 6 animals in the prime-boost Imvamune group, whereas there was no confirmation of excreted live virus in the Acam2000 group. This evaluation of different human smallpox vaccines in cynomolgus macaques helps to provide information about optimal vaccine strategies in the absence of human challenge studies.

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Deletion of the Monkeypox Virus Inhibitor of Complement Enzymes Locus Impacts the Adaptive Immune Response to Monkeypox Virus in a Nonhuman Primate Model of Infection

Abstract: Monkeypox virus (MPXV) is an orthopoxvirus closely related to variola virus

Cited by 61 publications

References 37 publications

Attenuation of monkeypox virus by deletion of genomic regions

Attenuation of monkeypox virus by deletion of genomic regions

Elucidating the Role of the Complement Control Protein in Monkeypox Pathogenicity

Assessment of the Protective Effect of Imvamune and Acam2000 Vaccines against Aerosolized Monkeypox Virus in Cynomolgus Macaques

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