Sequence-Based Classification of Select Agents A Brighter Line (2010) / Chapter Skim
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Appendix I: Botulinum Neurotoxin, B. Anthracis and Variola Virus
Appendix I: Botulinum Neurotoxin, B. Anthracis and Variola Virus
Pages 165-180
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From page 165... ...
Both B anthracis and variola virus encode a large number of virulence genes that are responsible for their capacity to infect and sometimes kill humans.
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From page 166... ...
2005) , who determined the structure of BoNT/E light chain with single amino acid substitutions outside of the canonical active site in regions adjacent to the catalytic residues.
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Virulence Genes Vegetative bacilli produce the two toxins edema factor (EF) and lethal factor (LF)
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Virulence Genes The protein coding regions of the variola virus genome is 96 percent identical at the nucleotide level to other orthopoxviruses. The majority of the sequence diversity occurs in the flanking regions of the genomes, which contain the virulence genes that target host apoptosis and the innate/immune response functions.
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From page 169... ...
Although monkeypox virus differs from variola virus in only 12 virulence genes, it is unable to sustain transmission in human populations after introduction from an animal source. The genetic basis of the difference in transmissibility between monkeypox and variola virus is unknown, and there are no physiologically relevant animal models that could be used to answer the question.
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From page 170... ...
0 BOX I-1 VariolaVirus Virulence Genes Predicted function/location Predicted function/location IMV-MP/Virulen. factor (Cop-A14.5)
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From page 171... ...
In support of that idea, REBOV is not pathogenic in humans. Filoviruses are filamentous, nonsegmented negative-strand RNA viruses that have about a 19-kb RNA genome, have a highly conserved gene order, and are surrounded by a helical nucleocapsid structure and a lipid bilayer that contains several virus glycoprotein spikes.
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From page 172... ...
Virulence Determinants Filovirus virulence determinants include viral proteins that antagonize adaptive and innate immune responses, suggesting a role for inflammation in resistance and disease. Extensive replication of filoviruses in primates is regu lated by two key viral proteins that antagonize host interferon responses.
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Most notably, severe acute respiratory syndrome (SARS) , a human lower respiratory disease that was first reported in late 2002 in Guangdong Province, China, quickly spread worldwide over a period of four
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Protein sequence identity is greater than 95 percent across most of the genome of human epidemic SARS-CoV and bat group2b coronaviruses although the S glycoproteins are only 80-90 percent identical. It has been proposed that bat coronaviruses were the progenitor strains for all group 1 and group 2 coronaviruses and genome homologies range from 43 to >90 percent amino acid identity.
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From page 175... ...
. GD03 is a very early human isolate (Dec 22, 03)
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From page 176... ...
Only two or three mutations are needed for to promote efficient replication in human airway cells, yet animal strains whose S RBD recognize hACE2 receptors are only weakly pathogenic and require extensive adaptation in S and elsewhere in the genome. Current proposals to include "SARS-CoV" as a potential select agent are unclear regarding the disposition of the closely related but human host range-restricted, civet and raccoon dog SARS-like strains, sporadic hu man strains identified in 2004 that are mostly zoonotic in origin, as well as bat SARS-CoV-like strains in this classification scheme.
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From page 177... ...
, nsp7 and nsp15 all encode strong interferon antagonist activities that either block type 1 interferon and/or NFκB sensing/signaling pathways. These four non-structural proteins are encoded in all coronavirus genomes but are highly variable in primary amino acid sequence making it difficult to predict whether similar in nate immune antagonism activities are universally encoded in all Coronaviridae genomes.
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From page 178... ...
In addition to the non-structural proteins encoded in ORF1, antagonist activities are also encoded in ORF3b, ORF6 and the N protein, which either block type 1 interferon sensing and/or signaling by targeting novel cellular components essential for signal transduction. Except for ORF6 from the closely related Bt-SARS-CoV HKU3, it is not clear whether closely related group2b homologs also encode similar IFN antagonist activities.
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From page 179... ...
The clear association of SARS-CoV ORF6 and Ebola VP24 with the host nuclear import pathway identifies nuclear import as a key site by which highly pathogenic viruses regu late the intracellular environment. By modulating the kinetics of nuclear import during infection, the virus controls innate immune, adaptive immune, apoptotic and cell stress signaling networks.
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