Parapox and molluscum infections are relatively painless and cause very little constitutional disturbance. Human cowpox is very painful, particularly in young children, usually causes pyrexia and marked lymphadenopathy; patients often require hospitalization. Rare encephalitic complications of cowpox have been reported, and erythema multiforme is a complication of parapox infections. Infection in immunocompromised or eczematous individuals is more severe and usually results in generalized illness, and in cowpox has caused deaths.
Smallpox vaccination has been associated with serious complications. However, routine use of smallpox vaccine has been discontinued, and any future use of recombinant vaccinia virus vaccines will involve attenuated strains, thus reducing the chances of complications. Although human monkeypox is rare and geographically localized, it is a serious generalized infection, which clinically resembles mild smallpox Figs.
A febrile prodrome precedes the development of a vesicular or pustular rash, typically centrifugal in distribution. Detailed examination of more than cases in Zaire showed an overall mortality of 10 percent, reaching 15 to 20 percent in unvaccinated children. Respiratory complications were seen in about 12 percent of unvaccinated patients.
Poxvirus virions are large and brick shaped. Orthopoxviruses are approximately nm by nm, with short surface tubules 10 nm wide. Parapoxviruses are narrower nm and have one long tubule that winds around the virion; in electron micrographs, superimposition of the top and bottom surfaces gives a characteristic criss-cross appearance Fig Virions extracted artificially from infected cells are infectious and are generally used in studies on poxviruses. However, virions released naturally from infected cells acquire an additional envelope, which is easily lost during manipulation Fig.
These naturally released virions possess extra antibody neutralization sites not present on the artificially extracted forms Fig. Internally, virions have a dumbbell-shaped core and two lateral bodies Fig. The genome consists of one molecule of double-stranded DNA, from kb parapox to kb fowlpox , and the core contains enzymes for virus uncoating and genome replication.
Linear maps of the genomes of various poxviruses have been prepared, and the entire genome of a strain of vaccinia virus has been sequenced. Electron micrographs of negatively stained, naturally released virions of A vaccinia virus and B parapoxvirus. The outer envelope is particularly obvious in A.
Thin section of intracellular vaccinia virus showing the core or nucleoid N , lateral bodies LB , inner membrane IM , and outer membrane OM. The outer element of OM is lost as the virion is released naturally from the cell.
Poxviruses are assigned to genera on the basis of close genetic and serologic relationships Table The viruses are antigenically complex. Surface and soluble antigens show extensive cross-reaction between species in a genus but not between genera.
This means that antigenic typing, as used for other virus groups, is not appropriate. Poxviruses have traditionally been assigned to species on the basis of biologic criteria. Genome analysis is now used and has generally confirmed biologic work, although some strains e.
Isolates of molluscum virus can be typed by DNA restriction enzyme analysis. Poxvirus replication takes place in cytoplasmic inclusions. Infecting virions are partly uncoated by cellular enzymes and then fully uncoated by viral enzymes released from the virion core. The replication cycle can be divided into functions controlled by early prereplicative gene products and those controlled by late postreplicative gene products. Most virions 80 to 90 percent remain within cells and therefore lack the outer envelope found on naturally released virions Fig.
Knowledge of the molecular biology of poxvirus replication has led to the development of recombinant vaccinia virus strains that code for the products of foreign genes inserted into the vaccinia virus genome Fig. Such recombinants are infectious and are being widely used to study gene expression, as candidate vaccines e. An extension of these studies has led to the development of canarypox recombinants which express foreign genes in mammals without causing productive infection.
The use of such non-replicating vectors may overcome objections to the use of vaccinia virus as a vector. Strategy for the production of recombinant vaccinia virus strains. The pathogenesis of localized poxvirus infections is simple. Virus invades through broken skin, replicates at the site of inoculation, and causes dermal hyperplasia and leukocyte infiltration.
With cowpox, and to a lesser extent with parapox, there is limited lymphatic spread; this causes lymphadenopathy and elicits an immune response. The lesion of molluscum is circumscribed by a connective tissue capsule, and the dermis, although distorted, is not usually broken.
Some poxviruses express an epidermal growth factor and host range genes which play a role in pathogenesis and cell tropism. Human monkeypox is usually acquired via the respiratory tract, and during a day incubation period viremia distributes infection to internal organs, which are damaged by virus infection.
Spread to the skin initiates the clinical phase, and the lesions progress through the classic stages of macule to papule to vesicle to pustule to crust. Lymphadenopathy, usually involving the cervical and inguinal areas, is often marked.
With the exception of human monkeypox, which is usually acquired via the respiratory route, human poxvirus infections are acquired by inoculation into the skin or contact with broken skin Fig. Consequently, unbroken skin presents the first line of defense. Copyright notice. The publisher's final edited version of this article is available at Immunol Rev. See other articles in PMC that cite the published article.
Summary Monkeypox is a disease that is endemic in Central and Western Africa. Keywords: monkeypox virus, immune evasion, immune modulatory. Introduction Monkeypox virus is a member of the family Poxviridae , genus Orthopoxvirus. Clinical features of monkeypox infection The clinical features of monkeypox are very similar to those of smallpox. Open in a separate window.
Monkeypox rash African woman with classical rash of monkeypox virus infection with deep seeded lesions on face, arms, and palms. Laboratory diagnosis of monkeypox Because the clinical features of smallpox and monkeypox are similar, laboratory diagnosis is of great importance, and newer methods that exploit differences in the host immune responses to orthopoxviruses are under development. Two strains of monkeypox: Central African and West African Before the outbreak of monkeypox in the United States 3 , all previous cases of monkeypox had been only in Africa and mainly in Central and West African countries.
Phylogenetic tree of different orthopoxvirus species, strain, or isolate based on nucleic acid sequence alignment The circled portion of the tree represents the comparison of the genomes between three isolates of the West African strain and one isolate of the Central African strain of monkeypox virus MPXV. Table 1 Comparison of the genomes of a central African strain of monkeypox virus Zaire and a west African strain of monkeypox USA Gene nomenclature used in this review The naming of genes in the orthopoxviruses has been evolving ever since whole viral genomes began to be routinely sequenced.
BR virulence protein The protein encoded by BR is believed to have a role in avoiding apoptosis of infected lymphocytes 23 , COP-C3L: complement control protein The vaccinia virus COP-C3L gene encodes a aa secreted protein that inhibits early steps of the host complement cascade and has been named the vaccinia virus complement control protein VCP 30 - Differences in non-virulence genes In addition to differences found in the virulence gene ortholog family, there were also differences found in genes involved in the viral life cycle that influence replication and transcription, which also could contribute to the difference in pathogenicity between the Central and West African strains.
Genomic differences between monkeypox and variola viruses To help understand the potential differences in the disease resulting from infection with monkeypox versus variola viruses as well as the potential of monkeypox virus to become a more efficient human pathogen, it is useful to understand major genetic differences between monkeypox and variola viruses.
Table 2 Comparison of monkeypox virus and variola virus genomes A. Additional genomic differences There are additional genomic differences between monkeypox and variola viruses. Prior smallpox vaccination affects severity of monkeypox infection Similar to the protection from smallpox conferred by vaccination, vaccinia vaccination protects against monkeypox. Genomic differences between monkeypox and vaccinia viruses While smallpox vaccination confers immunity from monkeypox disease, it is useful to think about the differences between monkeypox and vaccinia viruses.
Table 3 Comparison of monkeypox virus and vaccinia virus genomes A. Person-to-person transmission of monkeypox and models for an epidemic Although monkeypox and variola viruses generate similar clinical diseases, they differ in their resulting mortality and their transmissibility from person-to-person.
Orthopoxvirus seroprevalence and its relation to monkeypox virus infections It is speculated that most individuals become infected with monkeypox through the hunting, skinning, and eating of infected animals 8. Summary and conclusions Because of the continuous outbreaks of human monkeypox in Africa and the recent accidental importation of monkeypox virus resulting in cases in the US in , it is of great importance that this orthopoxvirus remains at the forefront of potential emerging infectious diseases.
Acknowledgments S. References 1. Smallpox and its eradication. Geneva: World Health Organization; Poxvirus dilemmas--monkeypox, smallpox. N Engl J Med. Reed KD, et al. The detection of monkeypox in humans in the Western Hemisphere. Immunity and immunological memory following smallpox vaccination. A human infection caused by monkeypox virus in Basankusu Territory, Democratic Republic of the Congo. Bull World Health Organ.
Isolation and properties of the causal agent of a new variola-like disease monkeypox in man. Khodakevich L, et al. The role of squirrels in sustaining monkeypox virus transmission. Trop Geogr Med. Monkeypox virus in relation to the ecological features surrounding human settlements in Bumba zone, Zaire. Hutin YJ, et al. Outbreak of human monkeypox, democratic republic of congo, to Emerg Infect Dis. Hutson CL, et al. Monkeypox zoonotic associations: insights from laboratory evaluation of animals associated with the multi-state US outbreak.
Am J Trop Med Hyg. Hammarlund E, et al. Multiple diagnostic techniques identify previously vaccinated individuals with protective immunity against monkeypox. Nat Med. Human monkeypox: an emerging zoonosis. Lancet Infect Dis. Reemergence of monkeypox: prevalence, diagnostics, and countermeasures. Clin Infect Dis. Detection of monkeypox virus with real-time PCR assays. J Clin Virol.
Karem KL, et al. Clin Diagn Lab Immunol. Shchelkunov SN, et al. Analysis of the monkeypox virus genome. Human monkeypox, Jezek Z, Fenner F. Human monkeypox. Monographs Virol. Chen N, et al. Virulence differences between monkeypox virus isolates from West Africa and the Congo basin.
Likos AM, et al. A tale of two clades: monkeypox viruses. J Gen Virol. The complete DNA sequence of vaccinia virus. An update on the vaccinia virus genome. The myxoma virus M-T4 gene encodes a novel RDEL-containing protein that is retained within the endoplasmic reticulum and is important for the productive infection of lymphocytes.
Hnatiuk S, et al. Alcami A, Smith GL. Spriggs MK, et al. Vaccinia and cowpox viruses encode a novel secreted InterleukinBinding protein. Dinarello CA. Biologic basis for interleukin-1 in disease. Vaccinia virus immune evasion. A mechanism for the inhibition of fever by a virus. Kotwal GJ, Moss B. Vaccinia virus encodes a secretory polypeptide structurally related to complement control proteins.
Inhibition of the complement cascade by the major secretory protein of vaccinia virus. Vaccinia virus complement-control protein prevents antibody-dependent complement-enhanced neutralization of infectivity and contributes to virulence. Liszewski MK, et al. Structure and regulatory profile of the monkeypox inhibitor of complement: comparison to homologs in vaccinia and variola and evidence for dimer formation.
J Immunol. Variola virus immune evasion design: expression of a highly efficient inhibitor of human complement. The relevance of complement to virus biology. Control of the complement system. Adv Immunol. Regulation of complement activity by vaccinia virus complement-control protein. J Infect Dis. Interaction of vaccinia virus complement control protein with human complement proteins: factor I-mediated degradation of C3b to iC3b1 inactivates the alternative complement pathway.
Rosengard AM, et al. Functional characterization of soluble and membrane-bound forms of vaccinia virus complement control protein VCP Mol Immunol. Smith SA, et al. Mapping of regions within the vaccinia virus complement control protein involved in dose-dependent binding to key complement components and heparin using surface plasmon resonance.
Biochim Biophys Acta. Kinetic analysis of the interactions between vaccinia virus complement control protein and human complement proteins C3b and C4b. J Virol. Electrostatic modeling predicts the activities of orthopoxvirus complement control proteins. Identification of hot spots in the variola virus complement inhibitor SPICE for human complement regulation.
Species-specific differences in the structure of orthopoxvirus complement-binding protein. Virus Res. Cell surface expression of the vaccinia virus complement control protein is mediated by interaction with the viral a56 protein and protects infected cells from complement attack. Carroll MC. The complement system in regulation of adaptive immunity. Nat Immunol. Kemper C, Atkinson JP. T-cell regulation: with complements from innate immunity.
Nat Rev Immunol. Human monkeypox and smallpox viruses: genomic comparison. FEBS Lett. Massung RF, et al. Analysis of the complete genome of smallpox variola major virus strain Bangladesh Viral entry may also occur via the respiratory tract in the rare cases of person-to-person transmission.
Like smallpox, monkeypox virus replicates in lymphoid tissue, although it has a greater degree of lymphadenopathy. The virus first localizes in mononuclear phagocytic cells, is released into the bloodstream, and then localizes again in skin cells.
For more detailed information, please refer to the pathogenesis section of smallpox virus. Prevention and Management. Vaccination with smallpox vaccine immunizes against monkeypox, but it is not justified since the disease is so rare. In the United States, vaccinia vaccination is recommended for laboratory workers who directly handle cultures or animals infected with monkeypox virus. Links with this icon indicate that you are leaving the CDC website.
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