Genomic Variability of Monkeypox Virus among Humans, Democratic Republic of the Congo - Volume 20, Number 2—February 2014 - Emerging Infectious Disease journal - CDC
Volume 20, Number 2—February 2014
Genomic Variability of Monkeypox Virus among Humans, Democratic Republic of the Congo
Jeffrey R. Kugelman1, Sara C. Johnston1, Prime M. Mulembakani, Neville Kisalu, Michael S. Lee, Galina Koroleva, Sarah E. McCarthy, Marie C. Gestole, Nathan D. Wolfe, Joseph N. Fair, Bradley S. Schneider, Linda L. Wright, John Huggins, Chris A. Whitehouse, Emile Okitolonda Wemakoy, Jean Jacques Muyembe-Tamfum, Lisa E. Hensley, Gustavo F. Palacios2 , and Anne W. Rimoin2
Author affiliations: United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA (J.R. Kugelman, S.C. Johnston, M.S. Lee, G. Koroleva, S.E. McCarthy, M.C. Gestole, J. Huggins, C.A. Whitehouse, G.F. Palacios);Kinshasa School of Public Health, Kinshasa, Democratic Republic of the Congo (P.M. Mulembakani, E.O. Wemakoy); University of California, Los Angeles, California, USA (N. Kisalu, A.W. Rimoin);Global Viral Forecasting (now known as Metabiota), San Francisco, California, USA (N.D. Wolfe, J.N, Fair, B.S. Schneider); The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA (L.L. Wright); National Institute of Biomedical Research, Kinshasa (J.J. Muyembe-Tamfum); US Food and Drug Administration, Silver Spring, Maryland, USA (L.E. Hensley)
Monkeypox virus is a zoonotic virus endemic to Central Africa. Although active disease surveillance has assessed monkeypox disease prevalence and geographic range, information about virus diversity is lacking. We therefore assessed genome diversity of viruses in 60 samples obtained from humans with primary and secondary cases of infection from 2005 through 2007. We detected 4 distinct lineages and a deletion that resulted in gene loss in 10 (16.7%) samples and that seemed to correlate with human-to-human transmission (p = 0.0544). The data suggest a high frequency of spillover events from the pool of viruses in nonhuman animals, active selection through genomic destabilization and gene loss, and increased disease transmissibility and severity. The potential for accelerated adaptation to humans should be monitored through improved surveillance.
Viruses in the family Poxviridae, genus Orthopoxvirus, consist of numerous pathogens known to infect humans, including variola virus (VARV), monkeypox virus (MPXV), cowpox virus (CPXV), and vaccinia virus (VACV). Genomes of these viruses are ≈200 kb long, have highly conserved central regions coding for replication and assembly machinery, and have more variable terminal ends that contain genes involved in host range determination and pathogenesis (1).
Although orthopoxviruses are antigenically and genetically similar, they have diverse host range and virulence properties (1–6). Comparative genomics studies have shown that the evolution of orthopoxviruses is ongoing and can be driven by selective pressure from a host species (4,7). It has been postulated that progressive gene loss, primarily at the terminal ends of the genome, has been a driving force behind the evolution of these viruses (7). CPXV, which causes only mild infection in humans, contains the largest genome of all sequenced orthopoxviruses (≈220 kb), encodes 223 open reading frames (ORFs), and has a broad host range that includes rodents, humans, felids, bovids, and voles (7–10). Conversely, VARV, the causative agent of smallpox, is highly pathogenic (case-fatality rate ≈30%) (11), has the smallest genome of all naturally occurring orthopoxviruses (≈186 kb), is predicted to encode 20% fewer functional proteins than CPXV, and has a host range restricted to humans (7).
Similar to VARV, MPXV is a virulent orthopoxvirus that causes high levels of illness and death (case-fatality rate ≈10%) (12–15). Unlike natural VARV infections, which were declared eradicated in 1979, MPXV infections occur naturally in MPXV-endemic regions of Africa, such as the Democratic Republic of the Congo (DRC) and Republic of the Congo. Human exposure to animal reservoirs, including squirrels of the genera Funisciurus and Heliosciurus, poses high risk for MPXV infection (16–19). Recent reports suggest that human-to-human transmission of MPXV is increasing (20,21). In 2003 in the DRC, 7 generations of uninterrupted spread among humans were reported (21). Increasing susceptibility coincident with decreasing herd immunity is expected to profoundly increase the introduction and spread of MPXV among humans. In 2003, an outbreak of monkeypox in the midwestern United States revealed the propensity for transmission to MPXV-naive populations (22). The strain of MPXV responsible belonged to the Western African clade; these strains tend to be less pathogenic than the Central African strains that circulate in the DRC (2).
MPXV is a linear DNA genome of ≈197 kb and contains ≈190 nonoverlapping ORFs >180 nt long (1,7,26). Like all orthopoxviruses, the central coding region sequence (CRS) at MPXV nucleotide positions ≈56000–120000 is highly conserved and flanked by variable ends that contain inverted terminal repeats (ITRs) (1). VACV homologs to genes found in the terminal ends of the MPXV genome are predominantly involved in immunomodulation, and most are either predicted or known to influence host range determination and pathogenicity (27). Unlike VARV, which lacks ORFs in the ITR region, MPXV contains at least 4 ORFs in the ITR region (7,26).
The evolution of short-read, high-throughput sequencing technologies has made genomic surveys of large populations readily attainable (23,24). It has been suggested that the progressive loss of genes that were not essential for pathogenesis in humans is the mechanism that led to the emergence of a highly adapted virus that causes serious disease and is capable of efficient and rapid human-to-human transmission (7). A recent study demonstrated that gene copy number variation might be a crucial factor for modulating virus fitness (25). In the study reported here, we investigated the genomic plasticity of MPXV strains obtained from patients in the DRC during active surveillance for monkeypox disease (20).
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