Virulence differences between monkeypox virus isolates from West Africa and the Congo basin

Abstract

Studies indicate that West African and Congo basin isolates of monkeypox virus (MPXV) are genetically distinct. Here, we show Congo basin MPXV-ZAI-V79 is more virulent for cynomolgus monkeys as compared to presumed West African MPXV-COP-58. This finding may explain the lack of case-fatalities in the U.S. 2003 monkeypox outbreak, which was caused by a West African virus. Virulence differences between West African and Congo basin MPXV are further supported by epidemiological analyses that observed a similar prevalence of antibodies in non-vaccinated humans in both regions, while >90% of reported cases occurred in the Congo basin, and no fatal cases were observed outside of this region. To determine the basis for this difference in virulence, we sequenced the genomes of one human West African isolate, and two presumed West African isolates and compared the sequences to Congo basin MPXV-ZAI-96-I-16. The analysis identified D10L, D14L, B10R, B14R, and B19R as possible virulence genes, with D14L (ortholog of vaccinia complement protein) as a leading candidate.

Ecology and Geography of Human Monkeypox Case Occurrences Across Africa

“…that is similar to other known orthopoxviruses in Uganda (Goldberg et al, 2008). A geographic break in the potential distribution of human monkeypox, located along the border of eastern Nigeria and western Cameroon in an area characterized by a chain of mountain ranges and volcanoes known as the Cameroon Range, was noted in both studies and may correspond to the distributional gap between the two major monkeypox clades (Chen et al, 2005;Likos et al, 2005).…”

“…In the Congo Basin, monkeypox is associated with higher case numbers and increased morbidity, mortality, viremia, and transmission via human-to-human contact when compared with cases in West Africa (Chen et al, 2005;Likos et al, 2005). Initial molecular genetic studies and whole-genome analyses of monkeypox isolates indicate the presence of two distinct strains (Mackett and Archard, 1979;Esposito and Knight, 1985;Likos et al, 2005).…”

A chemokine-binding domain in the tumor necrosis factor receptor from variola (smallpox) virus

“…Here we demonstrate anti-TNF and antichemokine activities in the TNFR homologue CrmB encoded by VaV, define a protein domain (SECRET domain) that binds chemokines and uncover a previously undescribed family of secreted CrmB is the only predicted vTNFR active in VaV major and minor strains, which cause different fatality rates (1,(22)(23)(24), and in the four sequenced strains of monkeypox virus, which causes a smallpox-like disease in humans (22,25,26). Our demonstration that VaV CrmB is a potent inhibitor of TNF is consistent with previous evidence of down-regulation of TNF responses in an experimental macaque model of human smallpox (29).…”

“…VV Western Reserve and the strains used as smallpox vaccines Copenhagen, DryVax (Wyeth), and Tian-Tan, do not encode vTNFRs, but CrmC and CrmE are encoded by the vaccine strains Lister, USSR, and Evans (20,21). VaV and monkeypox virus, which causes a smallpox-like disease in humans, encode CrmB only (22)(23)(24)(25)(26). The reasons for the variety of vTNFRs are not understood.…”

The Vaccinia Virus Complement Control Protein Modulates Adaptive Immune Responses during Infection

“…Both VARV and MPXV express orthologs of VCP that have been shown to regulate complement activation in vitro (30-32, 46, 48). The MPXV homolog of VCP (known as MoPICE) is thought to contribute to virulence because it is expressed by the more virulent Central African strain of this virus but is not found in the less pathogenic West African strain (6,29). Additionally, complement-deficient mice succumb to infection with ECTV (40), demonstrating the importance of complement in protection against pathogenic poxvirus infection.…”