Marburgvirus genomics and association with a large hemorrhagic fever outbreak in Angola - PubMed
. 2006 Jul;80(13):6497-516.
doi: 10.1128/JVI.00069-06.
Marina L Khristova, Tara K Sealy, Martin J Vincent, Bobbie R Erickson, Darcy A Bawiec, Amy L Hartman, James A Comer, Sherif R Zaki, Ute Ströher, Filomena Gomes da Silva, Fernando del Castillo, Pierre E Rollin, Thomas G Ksiazek, Stuart T Nichol
Affiliations
- PMID: 16775337
- PMCID: PMC1488971
- DOI: 10.1128/JVI.00069-06
Marburgvirus genomics and association with a large hemorrhagic fever outbreak in Angola
Jonathan S Towner et al. J Virol. 2006 Jul.
Abstract
In March 2005, the Centers for Disease Control and Prevention (CDC) investigated a large hemorrhagic fever (HF) outbreak in Uige Province in northern Angola, West Africa. In total, 15 initial specimens were sent to CDC, Atlanta, Ga., for testing for viruses associated with viral HFs known to be present in West Africa, including ebolavirus. Marburgvirus was also included despite the fact that the origins of all earlier outbreaks were linked directly to East Africa. Surprisingly, marburgvirus was confirmed (12 of 15 specimens) as the cause of the outbreak. The outbreak likely began in October 2004 and ended in July 2005, and it included 252 cases and 227 (90%) fatalities (report from the Ministry of Health, Republic of Angola, 2005), making it the largest Marburg HF outbreak on record. A real-time quantitative reverse transcription-PCR assay utilized and adapted during the outbreak proved to be highly sensitive and sufficiently robust for field use. Partial marburgvirus RNA sequence analysis revealed up to 21% nucleotide divergence among the previously characterized East African strains, with the most distinct being Ravn from Kenya (1987). The Angolan strain was less different ( approximately 7%) from the main group of East African marburgviruses than one might expect given the large geographic separation. To more precisely analyze the virus genetic differences between outbreaks and among viruses within the Angola outbreak itself, a total of 16 complete virus genomes were determined, including those of the virus isolates Ravn (Kenya, 1987) and 05DRC, 07DRC, and 09DRC (Democratic Republic of Congo, 1998) and the reference Angolan virus isolate (Ang1379v). In addition, complete genome sequences were obtained from RNAs extracted from 10 clinical specimens reflecting various stages of the disease and locations within the Angolan outbreak. While the marburgviruses exhibit high overall genetic diversity (up to 22%), only 6.8% nucleotide difference was found between the West African Angolan viruses and the majority of East African viruses, suggesting that the virus reservoir species in these regions are not substantially distinct. Remarkably few nucleotide differences were found among the Angolan clinical specimens (0 to 0.07%), consistent with an outbreak scenario in which a single (or rare) introduction of virus from the reservoir species into the human population was followed by person-to-person transmission with little accumulation of mutations. This is in contrast to the 1998 to 2000 marburgvirus outbreak, where evidence of several virus genetic lineages (with up to 21% divergence) and multiple virus introductions into the human population was found.
Figures
![FIG. 1.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e960/1488971/d24b4e61345f/zjv0130679050001.gif)
(A) Map of Angola, with Uige Province highlighted in burgundy. (B) Expansion of the inset in panel A to show the local municipalities from which individual cases were analyzed. The majority of cases (∼90%) in the outbreak were in the Uige municipality located within Uige Province.
![FIG. 2.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e960/1488971/1cdfad6ef16b/zjv0130679050002.gif)
(A) Maximum-likelihood analysis of full-length genomes with indicated bootstrap values. *, reference specimen. (B) Nucleotide diversity, comparing full-length genome sequences of the indicated filoviruses. The Angola marburgvirus sequence was represented by that determined from the reference specimen 1379c.
![FIG. 3.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e960/1488971/0985070c32bf/zjv0130679050003.gif)
Summary of single-nucleotide (nt) changes among the 11 indicated marburgvirus sequences from the Angola outbreak. Beneath the position descriptions of each change are the RT-PCR fragment(s) used to generate the sequence.
![FIG. 4.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e960/1488971/c0b3f16a4453/zjv0130679050004.gif)
Similarity plot of an alignment of eight marburgvirus sequences (Ang, Pop, Mus, Ozo, Rav, 05DRC, 07DRC, and 09DRC), using a sliding window of 50 nucleotides. The Angola marburgvirus sequence was represented by that determined from the reference specimen 1379c.
![FIG. 5.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e960/1488971/bd37372d1b7f/zjv0130679050005.gif)
Alignment of the transcription start and stop signals, IR sequences, and lengths of the 5′ and 3′ untranslated regions (UTRs) for each marburgvirus sequences. Shown in red are nucleotides (nt) or UTR lengths that are different from the consensus. The Angola marburgvirus sequence was represented by that determined from the reference specimen 1379c.
![FIG.6.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e960/1488971/77712d1893d8/zjv013067905006a.gif)
Percent nucleotide (nt) (A) or amino acid (B) differences for each of the seven marburgvirus gene products. The Angola marburgvirus sequence was represented by that determined from the reference specimen 1379c.
![FIG.6.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e960/1488971/77712d1893d8/zjv013067905006a.gif)
Percent nucleotide (nt) (A) or amino acid (B) differences for each of the seven marburgvirus gene products. The Angola marburgvirus sequence was represented by that determined from the reference specimen 1379c.
![FIG.7.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e960/1488971/076a8431672a/zjv013067905007a.gif)
Comparative amino acid alignments for each of the seven marburgvirus gene products. The Angola marburgvirus sequence was represented by that determined from the reference specimen 1379c. (A) NP. Shown are conserved cysteines (underlined and in boldface) and serine/threonine phosphorylation motifs (boxed) residing in domains previously defined (28) (gray) when queried with the Angola marburgvirus NP amino acid sequences for the kinase substrates casein kinase II (S/TxxD/E), protein kinase C (S/TxK/R), protein kinase A (RxS/T), glycogen synthase kinase 3 (S/TxxxS/T), casein kinase I (SxxS/T), and mitogen-activated protein kinase (S/TP). (B) VP35. Shown are the predicted oligomerization domain (35) (gray) with hydrophobic residues in the first and forth positions of the heptad repeats (+), type I IFN antagonism domain (boxed) with critical basic residues (asterisks), and conserved cysteines (underlined and in boldface). (C) VP40. Shown are the L domain (PPxY) (boxed) and conserved cysteines (underlined and in boldface). (D) GP. Shown are conserved cysteines (underlined and in boldface); N-glycosylation sites (N x T/S), conserved (boxed in gray) and nonconserved (boxed only); furin cleavage sites (R x K/RR) (double underlined); fusion domain (+); immunosuppressive domain (asterisks); and transmembrane domain (parentheses). (E) VP30. Shown are phosphorylated serine residues (34) (asterisks), conserved cysteines (underlined and in boldface), Cys3-His residues of the zinc binding motif (+), and tetraleucine motif for VP30 oligomerization (boxed). (F) VP24. Shown are conserved cysteines (underlined and in boldface). (G) Polymerase. Shown are conserved cysteines (underlined and in boldface, with the double-cysteine motif [36] double underlined and in boldface), ATP binding motifs (asterisks), D-D diresidue motifs (boxed), MGDNQ motif (+), box A* to C* regions (36) (light gray and labeled), domains of higher variability (light gray and labeled), and motifs A** to C** (53) (dark gray).
![FIG.7.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e960/1488971/076a8431672a/zjv013067905007a.gif)
Comparative amino acid alignments for each of the seven marburgvirus gene products. The Angola marburgvirus sequence was represented by that determined from the reference specimen 1379c. (A) NP. Shown are conserved cysteines (underlined and in boldface) and serine/threonine phosphorylation motifs (boxed) residing in domains previously defined (28) (gray) when queried with the Angola marburgvirus NP amino acid sequences for the kinase substrates casein kinase II (S/TxxD/E), protein kinase C (S/TxK/R), protein kinase A (RxS/T), glycogen synthase kinase 3 (S/TxxxS/T), casein kinase I (SxxS/T), and mitogen-activated protein kinase (S/TP). (B) VP35. Shown are the predicted oligomerization domain (35) (gray) with hydrophobic residues in the first and forth positions of the heptad repeats (+), type I IFN antagonism domain (boxed) with critical basic residues (asterisks), and conserved cysteines (underlined and in boldface). (C) VP40. Shown are the L domain (PPxY) (boxed) and conserved cysteines (underlined and in boldface). (D) GP. Shown are conserved cysteines (underlined and in boldface); N-glycosylation sites (N x T/S), conserved (boxed in gray) and nonconserved (boxed only); furin cleavage sites (R x K/RR) (double underlined); fusion domain (+); immunosuppressive domain (asterisks); and transmembrane domain (parentheses). (E) VP30. Shown are phosphorylated serine residues (34) (asterisks), conserved cysteines (underlined and in boldface), Cys3-His residues of the zinc binding motif (+), and tetraleucine motif for VP30 oligomerization (boxed). (F) VP24. Shown are conserved cysteines (underlined and in boldface). (G) Polymerase. Shown are conserved cysteines (underlined and in boldface, with the double-cysteine motif [36] double underlined and in boldface), ATP binding motifs (asterisks), D-D diresidue motifs (boxed), MGDNQ motif (+), box A* to C* regions (36) (light gray and labeled), domains of higher variability (light gray and labeled), and motifs A** to C** (53) (dark gray).
![FIG.7.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e960/1488971/076a8431672a/zjv013067905007a.gif)
Comparative amino acid alignments for each of the seven marburgvirus gene products. The Angola marburgvirus sequence was represented by that determined from the reference specimen 1379c. (A) NP. Shown are conserved cysteines (underlined and in boldface) and serine/threonine phosphorylation motifs (boxed) residing in domains previously defined (28) (gray) when queried with the Angola marburgvirus NP amino acid sequences for the kinase substrates casein kinase II (S/TxxD/E), protein kinase C (S/TxK/R), protein kinase A (RxS/T), glycogen synthase kinase 3 (S/TxxxS/T), casein kinase I (SxxS/T), and mitogen-activated protein kinase (S/TP). (B) VP35. Shown are the predicted oligomerization domain (35) (gray) with hydrophobic residues in the first and forth positions of the heptad repeats (+), type I IFN antagonism domain (boxed) with critical basic residues (asterisks), and conserved cysteines (underlined and in boldface). (C) VP40. Shown are the L domain (PPxY) (boxed) and conserved cysteines (underlined and in boldface). (D) GP. Shown are conserved cysteines (underlined and in boldface); N-glycosylation sites (N x T/S), conserved (boxed in gray) and nonconserved (boxed only); furin cleavage sites (R x K/RR) (double underlined); fusion domain (+); immunosuppressive domain (asterisks); and transmembrane domain (parentheses). (E) VP30. Shown are phosphorylated serine residues (34) (asterisks), conserved cysteines (underlined and in boldface), Cys3-His residues of the zinc binding motif (+), and tetraleucine motif for VP30 oligomerization (boxed). (F) VP24. Shown are conserved cysteines (underlined and in boldface). (G) Polymerase. Shown are conserved cysteines (underlined and in boldface, with the double-cysteine motif [36] double underlined and in boldface), ATP binding motifs (asterisks), D-D diresidue motifs (boxed), MGDNQ motif (+), box A* to C* regions (36) (light gray and labeled), domains of higher variability (light gray and labeled), and motifs A** to C** (53) (dark gray).
![FIG.7.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e960/1488971/076a8431672a/zjv013067905007a.gif)
Comparative amino acid alignments for each of the seven marburgvirus gene products. The Angola marburgvirus sequence was represented by that determined from the reference specimen 1379c. (A) NP. Shown are conserved cysteines (underlined and in boldface) and serine/threonine phosphorylation motifs (boxed) residing in domains previously defined (28) (gray) when queried with the Angola marburgvirus NP amino acid sequences for the kinase substrates casein kinase II (S/TxxD/E), protein kinase C (S/TxK/R), protein kinase A (RxS/T), glycogen synthase kinase 3 (S/TxxxS/T), casein kinase I (SxxS/T), and mitogen-activated protein kinase (S/TP). (B) VP35. Shown are the predicted oligomerization domain (35) (gray) with hydrophobic residues in the first and forth positions of the heptad repeats (+), type I IFN antagonism domain (boxed) with critical basic residues (asterisks), and conserved cysteines (underlined and in boldface). (C) VP40. Shown are the L domain (PPxY) (boxed) and conserved cysteines (underlined and in boldface). (D) GP. Shown are conserved cysteines (underlined and in boldface); N-glycosylation sites (N x T/S), conserved (boxed in gray) and nonconserved (boxed only); furin cleavage sites (R x K/RR) (double underlined); fusion domain (+); immunosuppressive domain (asterisks); and transmembrane domain (parentheses). (E) VP30. Shown are phosphorylated serine residues (34) (asterisks), conserved cysteines (underlined and in boldface), Cys3-His residues of the zinc binding motif (+), and tetraleucine motif for VP30 oligomerization (boxed). (F) VP24. Shown are conserved cysteines (underlined and in boldface). (G) Polymerase. Shown are conserved cysteines (underlined and in boldface, with the double-cysteine motif [36] double underlined and in boldface), ATP binding motifs (asterisks), D-D diresidue motifs (boxed), MGDNQ motif (+), box A* to C* regions (36) (light gray and labeled), domains of higher variability (light gray and labeled), and motifs A** to C** (53) (dark gray).
![FIG.7.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e960/1488971/076a8431672a/zjv013067905007a.gif)
Comparative amino acid alignments for each of the seven marburgvirus gene products. The Angola marburgvirus sequence was represented by that determined from the reference specimen 1379c. (A) NP. Shown are conserved cysteines (underlined and in boldface) and serine/threonine phosphorylation motifs (boxed) residing in domains previously defined (28) (gray) when queried with the Angola marburgvirus NP amino acid sequences for the kinase substrates casein kinase II (S/TxxD/E), protein kinase C (S/TxK/R), protein kinase A (RxS/T), glycogen synthase kinase 3 (S/TxxxS/T), casein kinase I (SxxS/T), and mitogen-activated protein kinase (S/TP). (B) VP35. Shown are the predicted oligomerization domain (35) (gray) with hydrophobic residues in the first and forth positions of the heptad repeats (+), type I IFN antagonism domain (boxed) with critical basic residues (asterisks), and conserved cysteines (underlined and in boldface). (C) VP40. Shown are the L domain (PPxY) (boxed) and conserved cysteines (underlined and in boldface). (D) GP. Shown are conserved cysteines (underlined and in boldface); N-glycosylation sites (N x T/S), conserved (boxed in gray) and nonconserved (boxed only); furin cleavage sites (R x K/RR) (double underlined); fusion domain (+); immunosuppressive domain (asterisks); and transmembrane domain (parentheses). (E) VP30. Shown are phosphorylated serine residues (34) (asterisks), conserved cysteines (underlined and in boldface), Cys3-His residues of the zinc binding motif (+), and tetraleucine motif for VP30 oligomerization (boxed). (F) VP24. Shown are conserved cysteines (underlined and in boldface). (G) Polymerase. Shown are conserved cysteines (underlined and in boldface, with the double-cysteine motif [36] double underlined and in boldface), ATP binding motifs (asterisks), D-D diresidue motifs (boxed), MGDNQ motif (+), box A* to C* regions (36) (light gray and labeled), domains of higher variability (light gray and labeled), and motifs A** to C** (53) (dark gray).
![FIG.7.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e960/1488971/076a8431672a/zjv013067905007a.gif)
Comparative amino acid alignments for each of the seven marburgvirus gene products. The Angola marburgvirus sequence was represented by that determined from the reference specimen 1379c. (A) NP. Shown are conserved cysteines (underlined and in boldface) and serine/threonine phosphorylation motifs (boxed) residing in domains previously defined (28) (gray) when queried with the Angola marburgvirus NP amino acid sequences for the kinase substrates casein kinase II (S/TxxD/E), protein kinase C (S/TxK/R), protein kinase A (RxS/T), glycogen synthase kinase 3 (S/TxxxS/T), casein kinase I (SxxS/T), and mitogen-activated protein kinase (S/TP). (B) VP35. Shown are the predicted oligomerization domain (35) (gray) with hydrophobic residues in the first and forth positions of the heptad repeats (+), type I IFN antagonism domain (boxed) with critical basic residues (asterisks), and conserved cysteines (underlined and in boldface). (C) VP40. Shown are the L domain (PPxY) (boxed) and conserved cysteines (underlined and in boldface). (D) GP. Shown are conserved cysteines (underlined and in boldface); N-glycosylation sites (N x T/S), conserved (boxed in gray) and nonconserved (boxed only); furin cleavage sites (R x K/RR) (double underlined); fusion domain (+); immunosuppressive domain (asterisks); and transmembrane domain (parentheses). (E) VP30. Shown are phosphorylated serine residues (34) (asterisks), conserved cysteines (underlined and in boldface), Cys3-His residues of the zinc binding motif (+), and tetraleucine motif for VP30 oligomerization (boxed). (F) VP24. Shown are conserved cysteines (underlined and in boldface). (G) Polymerase. Shown are conserved cysteines (underlined and in boldface, with the double-cysteine motif [36] double underlined and in boldface), ATP binding motifs (asterisks), D-D diresidue motifs (boxed), MGDNQ motif (+), box A* to C* regions (36) (light gray and labeled), domains of higher variability (light gray and labeled), and motifs A** to C** (53) (dark gray).
![FIG.7.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e960/1488971/076a8431672a/zjv013067905007a.gif)
Comparative amino acid alignments for each of the seven marburgvirus gene products. The Angola marburgvirus sequence was represented by that determined from the reference specimen 1379c. (A) NP. Shown are conserved cysteines (underlined and in boldface) and serine/threonine phosphorylation motifs (boxed) residing in domains previously defined (28) (gray) when queried with the Angola marburgvirus NP amino acid sequences for the kinase substrates casein kinase II (S/TxxD/E), protein kinase C (S/TxK/R), protein kinase A (RxS/T), glycogen synthase kinase 3 (S/TxxxS/T), casein kinase I (SxxS/T), and mitogen-activated protein kinase (S/TP). (B) VP35. Shown are the predicted oligomerization domain (35) (gray) with hydrophobic residues in the first and forth positions of the heptad repeats (+), type I IFN antagonism domain (boxed) with critical basic residues (asterisks), and conserved cysteines (underlined and in boldface). (C) VP40. Shown are the L domain (PPxY) (boxed) and conserved cysteines (underlined and in boldface). (D) GP. Shown are conserved cysteines (underlined and in boldface); N-glycosylation sites (N x T/S), conserved (boxed in gray) and nonconserved (boxed only); furin cleavage sites (R x K/RR) (double underlined); fusion domain (+); immunosuppressive domain (asterisks); and transmembrane domain (parentheses). (E) VP30. Shown are phosphorylated serine residues (34) (asterisks), conserved cysteines (underlined and in boldface), Cys3-His residues of the zinc binding motif (+), and tetraleucine motif for VP30 oligomerization (boxed). (F) VP24. Shown are conserved cysteines (underlined and in boldface). (G) Polymerase. Shown are conserved cysteines (underlined and in boldface, with the double-cysteine motif [36] double underlined and in boldface), ATP binding motifs (asterisks), D-D diresidue motifs (boxed), MGDNQ motif (+), box A* to C* regions (36) (light gray and labeled), domains of higher variability (light gray and labeled), and motifs A** to C** (53) (dark gray).
![FIG.7.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e960/1488971/076a8431672a/zjv013067905007a.gif)
Comparative amino acid alignments for each of the seven marburgvirus gene products. The Angola marburgvirus sequence was represented by that determined from the reference specimen 1379c. (A) NP. Shown are conserved cysteines (underlined and in boldface) and serine/threonine phosphorylation motifs (boxed) residing in domains previously defined (28) (gray) when queried with the Angola marburgvirus NP amino acid sequences for the kinase substrates casein kinase II (S/TxxD/E), protein kinase C (S/TxK/R), protein kinase A (RxS/T), glycogen synthase kinase 3 (S/TxxxS/T), casein kinase I (SxxS/T), and mitogen-activated protein kinase (S/TP). (B) VP35. Shown are the predicted oligomerization domain (35) (gray) with hydrophobic residues in the first and forth positions of the heptad repeats (+), type I IFN antagonism domain (boxed) with critical basic residues (asterisks), and conserved cysteines (underlined and in boldface). (C) VP40. Shown are the L domain (PPxY) (boxed) and conserved cysteines (underlined and in boldface). (D) GP. Shown are conserved cysteines (underlined and in boldface); N-glycosylation sites (N x T/S), conserved (boxed in gray) and nonconserved (boxed only); furin cleavage sites (R x K/RR) (double underlined); fusion domain (+); immunosuppressive domain (asterisks); and transmembrane domain (parentheses). (E) VP30. Shown are phosphorylated serine residues (34) (asterisks), conserved cysteines (underlined and in boldface), Cys3-His residues of the zinc binding motif (+), and tetraleucine motif for VP30 oligomerization (boxed). (F) VP24. Shown are conserved cysteines (underlined and in boldface). (G) Polymerase. Shown are conserved cysteines (underlined and in boldface, with the double-cysteine motif [36] double underlined and in boldface), ATP binding motifs (asterisks), D-D diresidue motifs (boxed), MGDNQ motif (+), box A* to C* regions (36) (light gray and labeled), domains of higher variability (light gray and labeled), and motifs A** to C** (53) (dark gray).
![FIG.7.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e960/1488971/076a8431672a/zjv013067905007a.gif)
Comparative amino acid alignments for each of the seven marburgvirus gene products. The Angola marburgvirus sequence was represented by that determined from the reference specimen 1379c. (A) NP. Shown are conserved cysteines (underlined and in boldface) and serine/threonine phosphorylation motifs (boxed) residing in domains previously defined (28) (gray) when queried with the Angola marburgvirus NP amino acid sequences for the kinase substrates casein kinase II (S/TxxD/E), protein kinase C (S/TxK/R), protein kinase A (RxS/T), glycogen synthase kinase 3 (S/TxxxS/T), casein kinase I (SxxS/T), and mitogen-activated protein kinase (S/TP). (B) VP35. Shown are the predicted oligomerization domain (35) (gray) with hydrophobic residues in the first and forth positions of the heptad repeats (+), type I IFN antagonism domain (boxed) with critical basic residues (asterisks), and conserved cysteines (underlined and in boldface). (C) VP40. Shown are the L domain (PPxY) (boxed) and conserved cysteines (underlined and in boldface). (D) GP. Shown are conserved cysteines (underlined and in boldface); N-glycosylation sites (N x T/S), conserved (boxed in gray) and nonconserved (boxed only); furin cleavage sites (R x K/RR) (double underlined); fusion domain (+); immunosuppressive domain (asterisks); and transmembrane domain (parentheses). (E) VP30. Shown are phosphorylated serine residues (34) (asterisks), conserved cysteines (underlined and in boldface), Cys3-His residues of the zinc binding motif (+), and tetraleucine motif for VP30 oligomerization (boxed). (F) VP24. Shown are conserved cysteines (underlined and in boldface). (G) Polymerase. Shown are conserved cysteines (underlined and in boldface, with the double-cysteine motif [36] double underlined and in boldface), ATP binding motifs (asterisks), D-D diresidue motifs (boxed), MGDNQ motif (+), box A* to C* regions (36) (light gray and labeled), domains of higher variability (light gray and labeled), and motifs A** to C** (53) (dark gray).
![FIG.7.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e960/1488971/076a8431672a/zjv013067905007a.gif)
Comparative amino acid alignments for each of the seven marburgvirus gene products. The Angola marburgvirus sequence was represented by that determined from the reference specimen 1379c. (A) NP. Shown are conserved cysteines (underlined and in boldface) and serine/threonine phosphorylation motifs (boxed) residing in domains previously defined (28) (gray) when queried with the Angola marburgvirus NP amino acid sequences for the kinase substrates casein kinase II (S/TxxD/E), protein kinase C (S/TxK/R), protein kinase A (RxS/T), glycogen synthase kinase 3 (S/TxxxS/T), casein kinase I (SxxS/T), and mitogen-activated protein kinase (S/TP). (B) VP35. Shown are the predicted oligomerization domain (35) (gray) with hydrophobic residues in the first and forth positions of the heptad repeats (+), type I IFN antagonism domain (boxed) with critical basic residues (asterisks), and conserved cysteines (underlined and in boldface). (C) VP40. Shown are the L domain (PPxY) (boxed) and conserved cysteines (underlined and in boldface). (D) GP. Shown are conserved cysteines (underlined and in boldface); N-glycosylation sites (N x T/S), conserved (boxed in gray) and nonconserved (boxed only); furin cleavage sites (R x K/RR) (double underlined); fusion domain (+); immunosuppressive domain (asterisks); and transmembrane domain (parentheses). (E) VP30. Shown are phosphorylated serine residues (34) (asterisks), conserved cysteines (underlined and in boldface), Cys3-His residues of the zinc binding motif (+), and tetraleucine motif for VP30 oligomerization (boxed). (F) VP24. Shown are conserved cysteines (underlined and in boldface). (G) Polymerase. Shown are conserved cysteines (underlined and in boldface, with the double-cysteine motif [36] double underlined and in boldface), ATP binding motifs (asterisks), D-D diresidue motifs (boxed), MGDNQ motif (+), box A* to C* regions (36) (light gray and labeled), domains of higher variability (light gray and labeled), and motifs A** to C** (53) (dark gray).
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