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Journal of Virology logoLink to Journal of Virology
. 2001 Aug;75(15):7122–7130. doi: 10.1128/JVI.75.15.7122-7130.2001

Genome of Lumpy Skin Disease Virus

E R Tulman 1, C L Afonso 1, Z Lu 1, L Zsak 1, G F Kutish 1, D L Rock 1,*
PMCID: PMC114441  PMID: 11435593

Abstract

Lumpy skin disease virus (LSDV), a member of the capripoxvirus genus of the Poxviridae, is the etiologic agent of an important disease of cattle in Africa. Here we report the genomic sequence of LSDV. The 151-kbp LSDV genome consists of a central coding region bounded by identical 2.4 kbp-inverted terminal repeats and contains 156 putative genes. Comparison of LSDV with chordopoxviruses of other genera reveals 146 conserved genes which encode proteins involved in transcription and mRNA biogenesis, nucleotide metabolism, DNA replication, protein processing, virion structure and assembly, and viral virulence and host range. In the central genomic region, LSDV genes share a high degree of colinearity and amino acid identity (average of 65%) with genes of other known mammalian poxviruses, particularly suipoxvirus, yatapoxvirus, and leporipoxviruses. In the terminal regions, colinearity is disrupted and poxvirus homologues are either absent or share a lower percentage of amino acid identity (average of 43%). Most of these differences involve genes and gene families with likely functions involving viral virulence and host range. Although LSDV resembles leporipoxviruses in gene content and organization, it also contains homologues of interleukin-10 (IL-10), IL-1 binding proteins, G protein-coupled CC chemokine receptor, and epidermal growth factor-like protein which are found in other poxvirus genera. These data show that although LSDV is closely related to other members of the Chordopoxvirinae, it contains a unique complement of genes responsible for viral host range and virulence.

Capripoxviruses (CaPVs) represent one of eight genera within the chordopoxvirus (ChPV) subfamily of the Poxviridae. The capripoxvirus genus is currently comprised of lumpy skin disease virus (LSDV), sheeppox virus (ShPV), and goatpox virus (GPV). These viruses are responsible for some of the most economically significant diseases of domestic ruminants in Africa and Asia (18). CaPV infections are generally host specific and they have specific geographic distributions (10, 14, 15). CaPVs are, however, serologically indistinguishable from each other, able to induce heterologous cross-protection, and able in some instances to experimentally cross-infect (8, 10, 15, 16). Restriction fragment analysis and limited DNA sequence data support a close relationship between CaPVs (5, 25, 26, 33). The molecular basis of CaPV host range restriction and virulence remains to be elucidated.

LSD is a subacute to acute cattle disease in Africa. It is characterized by extensive cutaneous lesions and signs typical of generalized poxvirus diseases (14, 15). Transmission of LSD between cattle is inefficient, and arthropod-vectored transmission may be significant in epizootic outbreaks and in the spread of LSD into nonenzootic regions (4, 10–12, 15, 36, 54). Attenuated LSDV strains and ShPV have been successfully used as LSD vaccines in enzootic and outbreak areas; however, vaccine failure and restrictions on the use of live virus vaccines create the need for a safe and effective, live attenuated vaccine (4, 13, 15, 53).

Current molecular data on the LSDV genome consists of restriction endonuclease analysis, cross-hybridization studies, and limited transcriptional and DNA sequence analysis (5, 19, 20, 26, 27, 33). Given the economic significance of LSD, its potential for spread into nonenzootic regions, and the interest in developing more effective LSDV-based vaccines and expression vectors, we have sequenced and analyzed the genome of a pathogenic LSDV. These data provide the first view of a CaPV genome, and they define the gene complement that underlies LSDV virulence and host range.

MATERIALS AND METHODS

LSDV DNA isolation, cloning, sequencing, and sequence analysis.

LSDV genomic DNA was extracted from primary lamb testicle (LT) cells infected with LSDV Neethling type strain 2490 (9). The virus was originally isolated in Kenya in 1958, passed 16 times in LT cells, and subsequently reisolated in 1987 from lesions of an experimentally infected cow (U.S. Department of Agriculture Animal Plant Health Inspection Service, Greenport, N.Y.). Random DNA fragments were obtained by incomplete enzymatic digestion with Tsp509 I endonuclease (New England Biolabs, Beverly, Mass.), and DNA fragments of 1.0 to 6.0 kbp were cloned and used in dideoxy sequencing reactions as previously described (2). Reaction products were run on a Applied Biosystems PRISM 3700 automated DNA sequencer (PE Biosystems, Foster City, Calif.). Sequence data were assembled, and gaps were closed as described previously (1) with confirmatory assemblies performed using CAP3 (30). The final DNA consensus sequence represented on average eightfold redundancy at each base position.

Genome DNA composition, structure, repeats and restriction enzyme patterns were analyzed as previously described (1) using the GCG v.10 software package (17). Open reading frames (ORFs) longer than 30 codons were evaluated for coding potential as previously described (2). All potentially coding ORFs and ORFs greater than 60 codons were subjected to homology searches as previously described (1, 2). Based on these criteria, 156 ORFs were annotated as potential genes. Gene families and promoter regions were analyzed and annotated as previously described (1, 2) and with additional use of Geanfammer (44) and GCG MEME programs. Vaccinia virus (VV) A52R-like protein family was clustered from a nonredundant peptide database of all known poxvirus sequences using the CLUS program (34) and BLASTP2 scores greater than 110. Phylogenetic comparisons were done with the PHYLO_WIN software package (23).

Nucleotide sequence accession number.

The LSDV genome sequence has been deposited in GenBank under accession no. AF325528.

RESULTS AND DISCUSSION

Organization of the LSDV genome.

LSDV genome sequences were assembled into a contiguous sequence of 150,773 bp which is in accordance with previous size estimates of 145 to 152 kbp (19, 26, 27). Because the hairpin loops were not sequenced, the leftmost nucleotide was arbitrarily designated base 1. The nucleotide composition is 73% A+T and is uniformly distributed. As seen for other poxviruses, the LSDV genome contains a central coding region bounded by two identical inverted terminal repeat (ITR) regions which contain at least 2,418 bp at both termini (Fig. 1). The most terminal 241 nucleotides of the assembled sequence contain 7.5 copies of a 24-bp imperfect tandem repeat and four copies of a 15-bp imperfect tandem repeat and are similar to those described in ShPV (25). Comparison with published restriction fragment analysis of the genome indicates there may be additional terminal sequences of less than 200 bp present (27, 33).

FIG. 1.

FIG. 1

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Linear map of the LSDV genome. ORFs are numbered from left to right based on the position of the methionine initiation codon. ORFs transcribed to the right are located above the horizontal line; ORFs transcribed to the left are below. Genes with similar functions and members of gene families are colored according to the figure key. ITRs are represented as black bars below the ORF map.

LSDV contains 156 ORFs which have been annotated here as putative genes. These genes represent a 95% coding density and encode proteins of 53 to 2,025 amino acids (Fig. 1, Table 1). Similar to other poxviruses, many of the 41 putative early genes are members of gene families and/or putative host range genes, while the 46 genes containing the VV late promoter sequence (TAAATG) at the ATG codon (41) include many of the conserved virion-associated poxviral genes (Table 1).

TABLE 1.

LSDV ORFs

ORF Position (length in codons) CaPV accession no.a Best match
Predicted structure and/or functiond Promoter typee MYX
VV
Speciesb Accession no. BlastP2 score % Identity Length (aa)c ORFf % Identity ORFg % Identity
LSDV001 713–237 (159) P18387 RFV P25949 308 46 143 A52R-like family protein, SP M003.1 42 B15R 34
LSDV002 1179–787 (131) P18388 MYX AJ012282 242 43 131 M003.2 43
LSDV003 2151–1432 (240) P18386 MYX AF002684 378 37 231 ER-localized apoptosis regulator, SP, TM E M004 37 B9R 37
LSDV004 2394–2224 (57) SPV P32230 125 47 57 M004.1 41
LSDV005 2446–2955 (170) Ovis aries U11421 357 43 174 IL-10, SP, TM
LSDV006 3664–2972 (231) Mus musculus P27931 179 33 144 IL-1 receptor, SP B16R 26
LSDV007 4753–3689 (355) Yaba-like DV AJ293568 552 35 355 IFN-γ C10L 34
LSDV008 5664–4840 (275) SPV P32226 435 37 257 family receptor, SP L M007 26 B8R 31
LSDV009 6389–5700 (230) Yaba-like DV AJ293568 342 36 233 α-amanitin-sensitive protein. A52R-like protein E MI39R 27 N2L 25
LSDV010 6929–6444 (162) SPV P32225 310 36 150 LAP/PHD-finger protein, TM E M153R 38
LSDV011 8118–6976 (381) S78201 Homo sapiens AY016370 683 43 311 G protein-coupled CC chemokine receptor, TM E
LSDV012 8860–8228 (211) S78201 Yaba-like DV AJ293568 436 40 210 Ankyrin repeat protein E M149R 25 B4R 28
LSDV013 9924–8902 (341) S78201 Equus caballus AB033415 200 27 340 IL-1 receptor, SP E B16R 24
LSDV014 10253–9987 (89) SPV P32224 248 49 85 IF2α-like PKR inhibitor M156R 34 K3L 42
LSDV015 10725–10243 (161) SPV P32223 308 44 129 IL-18 binding protein
LSDV016 11031–10765 (89) Yaba-like DV AJ293568 129 50 48 EGF-like growth factor M010L 32 C11R 50
LSDV017 11552–11025 (176) Yaba-like DV AJ293568 173 34 173 Integral membrane protein, apoptosis regulator, TM E M011L 29
LSDV018 12034–11597 (146) SPV P32208 499 68 141 dUTPase E M012L 63 F2L 63
LSDV019 13790–12084 (569) SPV P32206 1022 40 535 Kelch-like protein, TM M014L 32 F3L 25
LSDV020 14820–13858 (321) Yaba-like DV AJ293568 1361 79 320 Ribonucleotide reductase, small subunit, TM E M015L 76 F4L 75
LSDV021 15121–14864 (86) SPV P32220 179 38 86 TM E,L M016L 34
LSDV022 15500–15165 (112) E
LSDV023 15949–15734 (72) MYX AF170726 169 51 72 E M018L 51 F8L 42
LSDV024 16676–16029 (216) SPV P32207 754 64 216 TM L M019L 50 F9L 46
LSDV025 17997–16657 (447) SPV P32216 1996 80 435 Ser/Thr protein kinase; virus assembly L M020L 77 F10L 72
LSDV026 18941–18036 (302) VV P21052 241 28 293 F11L 28
LSDV027 20866–18953 (638) Yaba-like DV AJ293568 1298 45 626 EEV maturation, TM M021L 39 F12L 38
LSDV028 21985–20876 (370) AF199595 Yaba-like DV AJ293568 1515 77 370 Palmitylated EEV envelope protein L M022L 73 F13L 57
LSDV029 22624–22190 (145) Yaba-like DV AJ293568 518 68 148 E M024L 54 F15L 56
LSDV030 23360–22704 (219) Yaba-like DV AJ293568 391 39 215 E M025L 35 F16L 34
LSDV031 23434–23745 (104) Yaba-like DV AJ293568 410 74 105 DNA-binding virion core phosphoprotein L M026L 75 F17L 61
LSDV032 25176–23755 (474) RFV AF170722 1813 75 474 Poly(A) polymerase PAPL E M027L 74 E1L 66
LSDV033 27380–25176 (735) MYX AF170726 1839 46 728 TM M028L 46 E2L 39
LSDV034 27925–27395 (177) Yaba-like DV AJ293568 464 48 183 PKR inhibitor, host range E M029L 40 E3L 36
LSDV035 28590–29795 (402) RFV AF170722 667 39 379 M031R 39 E5R 27
LSDV036 28591–27989 (201) Yaba-like DV AJ293568 738 69 181 RNA polymerase subunit RPO30 E M030L 68 E4L 62
LSDV037 29807–31504 (566) MYX AF170726 2190 70 566 M032R 70 E6R 62
LSDV038 31514–32311 (266) Yaba-like DV AJ293568 1144 79 263 TM M033R 79 E8R 68
LSDV039 35343–32314 (1010) MYX AF170726 4061 74 1010 DNA polymerase M034L 74 E9L 66
LSDV040 35377–35661 (95) RFV AF170722 418 77 95 Potential redox protein, virus assembly M035R 73 E10R 69
LSDV041 36053–35664 (130) Yaba-like DV AJ293568 375 54 130 Virion core protein L E11L 46
LSDV042 38094–36043 (684) Yaba-like DV AJ293568 1448 43 678 M036L 41 O1L 35
LSDV043 39144–38203 (314) MYX AF170726 1221 75 309 DNA-binding virion core protein, virus assembly L M038L 75 I1L 66
LSDV044 39369–39154 (72) MYX AF170726 191 50 72 TM L M039L 50 12L 44
LSDV045 40200–39373 (276) Yaba-like DV AJ293568 848 62 266 DNA-binding phosphoprotein E M040L 59 I3L 49
LSDV046 40482–40249 (78) Yaba-like DV AJ293568 263 68 76 IMV membrane protein, SP, TM L M041L 50 I5L 35
LSDV047 41684–40503 (394) RFV AF170722 1140 53 394 TM M042L 53 I6L 51
LSDV048 42978–41680 (433) Yaba-like DV AJ293568 1779 75 433 Virion core protein L M043L 75 I7L 66
LSDV049 42984–45011 (676) Yaba-like DV AJ293568 2359 65 676 NPH-II, RNA helicase M044R 60 I8R 59
LSDV050 46801–45014 (596) RFV AF170722 1976 62 595 Metalloprotease, virion morphogenesis L M045L 61 G1L 55
LSDV051 47124–47789 (222) MYX AF170726 737 62 225 Putative transcriptional elongation factor M047R 62 G2R 50
LSDV052 47130–46801 (110) RFV AF170722 332 59 105 TM L M046L 58 G3L 48
LSDV053 48136–47759 (126) MYX AF170726 527 77 123 Glutaredoxin 2, virion morphogenesis, SP L M048L 77 G4L 49
LSDV054 48139–49449 (437) Yaba-like DV AJ293568 1144 52 438 M049R 49 G5R 47
LSDV055 49453–49641 (63) Yaba-like DV AJ293568 286 85 63 RNA polymerase subunit RPO7 E,L M050R 85 G5.5R 79
LSDV056 49644–50165 (174) RFV AF170722 541 58 172 M051R 58 G6R 44
LSDV057 51303–50185 (373) Yaba-like DV AJ293568 1128 60 374 Virion core protein, TM L M052L 60 G7L 55
LSDV058 51333–52112 (260) Yaba MTV AB015885 1214 86 260 Late transcription factor VLTF-1, TM I M053R 85 G8R 87
LSDV059 52142–53149 (336) Yaba-like DV AJ293568 1125 61 336 Myristylated protein M054R 52 G9R 46
LSDV060 53153–53887 (245) Yaba-like DV AJ293568 1069 81 244 Myristylated IMV envelope protein, TM L M055R 76 L1R 66
LSDV061 53928–54203 (92) Yaba MTV AB015885 187 48 75 E M056R 33 L2R 35
LSDV062 55172–54219 (318) Yaba-like DV AJ293568 1170 67 318 L M057L 61 L3L 55
LSDV063 55197–55955 (253) RFV AF170722 1075 82 253 DNA-binding virion core protein VP8 L M058R 81 L4R 61
LSDV064 55974–56366 (131) Yaba-like DV AJ293568 393 59 127 TM L M059R 55 L5R 51
LSDV065 56326–56766 (147) P19746 Yaba-like DV AJ293568 505 67 146 L M060R 61 J1R 55
LSDV066 56797–57327 (177) P16600 SPV P23335 640 68 175 Thymidine kinase M061R 70 J2R 66
LSDV067 57402–57995 (198) A06139 SPV P23333 467 48 186 Host range protein E M062R 41 C7L 33
LSDV068 58056–59054 (333) MYX P18628 1451 81 333 Poly(A) polymerase PAPs M065R 81 J3R 72
LSDV069 58972–59526 (185) Yaba-like DV AJ293568 756 76 185 RNA polymerase subunit RPO22 M066R 73 J4R 68
LSDV070 59936–59538 (133) MYX AF170726 536 67 132 M067L 67 J5L 59
LSDV071 60022–63876 (1285) RFV AF170722 5838 86 1286 RNA polymerase subunit RPO147 E M068R 85 J6R 80
LSDV072 64399–63887 (171) AF124517 MYX L31960 715 76 171 Protein-tyrosine phosphatase, virus assembly L M069L 76 H1L 63
LSDV073 64415–64984 (190) AF124517 RFV AF170722 764 70 190 TM M070R 69 H2R 65
LSDV074 65952–64987 (322) AF124516 MYX AF170726 986 54 319 IMV envelope protein p35, TM M071L 54 H3L 38
LSDV075 68378–65985 (798) Yaba-like DV AJ293568 3289 78 798 RNA polymerase-associated protein RAP94 L M072L 77 H4L 70
LSDV076 68522–69190 (223) Yaba MTV AB015885 419 46 223 Late transcription factor VLTF-4 E M073R 44 H5R 37
LSDV077 69235–70185 (317) Yaba-like DV AJ293568 1171 68 317 DNA topoisomerase M074R 70 H6R 65
LSDV078 70208–70648 (147) MYX AF170726 482 60 146 L M075R 60 H7R 43
LSDV079 70682–73207 (842) Yaba-like DV AJ293568 3258 72 842 mRNA capping enzyme, large subunit E M076R 68 D1R 64
LSDV080 73639–73175 (155) Yaba-like DV AJ293568 269 38 151 Virion protein M077L 21 D2L 41
LSDV081 73641–74375 (245) Yaba MTV AB015885 477 39 245 Virion protein M078R 33 D3R 34
LSDV082 74375–75028 (218) RFV P32941 926 74 218 Uracil DNA glycosylase M079R 74 D4R 66
LSDV083 75074–77431 (786) Yaba-like DV AJ293568 3394 78 786 NTPase; DNA replication M080R 76 D5R 67
LSDV084 77431–79335 (635) Yaba MTV AB015885 2944 88 635 Early transcription factor VETFa+ TM L M081R 88 D6R 81
LSDV085 79363–79851 (163) Yaba-like DV AJ293568 725 80 160 RNA polymerase subunit RPO18 M082R 80 D7R 68
LSDV086 79895–80533 (213) Yaba-like DV AJ293568 742 68 211 mut T motif E M084R 61 D9R 57
LSDV087 80536–81294 (253) Yaba-like DV AJ293568 776 64 237 mut T motif; gene expression regulator M085R 57 D10R 5
LSDV088 83210–81306 (635) Yaba-like DV AJ293568 2559 75 632 NPH-I; transcription termination factor M086L 74 D11L 71
LSDV089 84100–83240 (287) SPV Q08512 1259 80 287 mRNA capping enzyme, small subunit; VITF E,L M087L 77 D12L 74
LSDV090 85789–84143 (549) Yaba-like DV AJ293568 2400 80 549 Rifampin resistance protein, IMV assembly M088L 76 D13L 69
LSDV091 86268–85819 (150) Yaba-like DV AJ293568 563 67 150 Late transcription factor VLTF-2 I,L M089L 67 A1L 63
LSDV092 86996–86301 (232) RFV AF170722 1049 88 225 Late transcription factor VLTF-3 I M090L 88 A2L 84
LSDV093 87220–86996 (75) MYX AF170726 297 72 74 L M091L 72 8.9kd 52
LSDV094 89214–87232 (661) MYX AF170726 2597 73 661 Virion core protein P4b, TM L M092L 73 A3L 65
LSDV095 89824–89342 (161) Yaba-like DV AJ293568 245 39 158 Virion core protein, virion morphogenesis M093L 35 A4L 29
LSDV096 89865–90374 (170) Yaba-like DV AJ293568 537 62 170 RNA polymerase subunit RPO19 M094R 62 A5R 62
LSDV097 91501–90377 (375) MYX AF170726 1434 75 371 L M095L 75 A6L 56
LSDV098 93666–91525 (714) MYX AF170726 3131 82 712 Early transcription factor VETFL L M096L 82 A7L 71
LSDV099 93723–94592 (290) U95121 MYX AF170726 1090 72 288 Intermediate transcription factor VITF-3 E M097R 72 A8R 62
LSDV100 94855–94622 (78) RFV AF170722 323 75 78 IMV membrane protein, SP, TM L M098L 73 A9L 68
LSDV101 97570–94859 (904) Yaba-like DV AJ293568 3193 67 904 Virion core protein P4a L M099L 65 A10L 50
LSDV102 97585–98535 (317) MYX AF170726 1222 73 317 TM L M100R 73 A11R 53
LSDV103 99107–98538 (190) Yaba-like DV AJ293568 446 56 189 Virion core protein M101L 56 A12L 51
LSDV104 99375–99175 (67) RFV AF170722 223 65 67 IMV membrane protein, TM M102L 60 A13L 39
LSDV105 99744–99460 (95) Yaba-like DV AJ293568 391 78 95 IMV membrane protein, SP, TM L M103L 66 A14L 55
LSDV106 99922–99764 (53) Yaba-like DV AJ293568 223 79 53 Virulence factor L M104L 79 A14.5 58
LSDV107 100199–99915 (95) Yaba MTV AB015885 297 57 95 E,L M105L 49 A15L 47
LSDV108 101316–100186 (377) Yaba-like DV AJ293568 1367 62 381 Myristylated protein, TM L M106L 61 A16L 51
LSDV109 101922–101335 (196) Yaba-like DV AJ293568 606 62 196 Phosphorylated IMV membrane protein, TM L M107L 55 A17L 42
LSDV110 101937–103376 (480) RFV AF170722 1516 59 479 DNA helicase; transcriptional elongation M108R 59 A18R 55
LSDV111 103584–103363 (74) RFV AF170722 315 81 74 L M109L 81 A19L 62
LSDV112 103931–105220 (430) MYX AF170726 1140 50 426 DNA polymerase processivity factor E M111R 50 A20R 46
LSDV113 103932–103588 (115) MYX AF170726 374 58 115 SP, TM M110L 58 A21L 55
LSDV114 105192–105695 (168) Yaba-like DV AJ293568 578 69 156 M112R 55 A22R 62
LSDV115 105723–106877 (385) MYX AF170726 1291 64 384 Intermediate transcription factor VITF-3 E M113R 64 A23R 60
LSDV116 106911–110378 (1156) Yaba-like DV AJ293568 5476 87 1156 RNA polymerase subunit RPO132 E M114R 88 A24R 83
LSDV117 110841–110398 (148) P16717 Yaba MTV AB018404 323 46 145 Fusion protein, virus assembly L M115L 48 A27L 33
LSDV118 111264–110845 (140) P16718 RFV AF170722 520 66 139 TM L M116L 65 A28L 52
LSDV119 112173–111268 (302) MYX AF170726 1059 63 300 RNA polymerase subunit RPO35 E M117L 63 A29L 60
LSDV120 112366–112145 (74) Yaba MTV AB018404 228 61 75 L M118L 60 A30L 49
LSDV121 113309–112548 (254) MYX AF170726 1168 86 252 DNA packaging, virus assembly M120L 86 A32L 60
LSDV122 113441–114028 (196) Yaba-like DV AJ293568 364 42 193 EEV glycoprotein, TM M121R 40 A33R 30
LSDV123 114061–114573 (171) MYX AF170726 569 56 171 EEV protein, SP, TM L M122R 56 A34R 42
LSDV124 114604–115176 (191) RFV AF170722 418 46 181 M123R 44 A35R 33
LSDV125 115216–116079 (288) RFV AF170722 657 41 288 E M124R 41
LSDV126 116141–116683 (181) Yaba-like DV AJ293568 164 33 155 EEV glycoprotein, TM M125R 31 A36R 25
LSDV127 116697–117515 (273) RFV AF170722 620 43 273 M126R 43 A37R 26
LSDV128 118424–117525 (300) MYX AF170726 489 38 271 CD47-like protein, TM M128L 38 A38L 26
LSDV129 118522–118890 (123) MYX AF170726 126 35 116 M130R 35
LSDV130 118962–119204 (81) Yaba-like DV AJ293568 156 45 80
LSDV131 119263–119745 (161) MYX AF170726 528 60 158 Superoxide dismutase-like protein L M131R 60 A45R 35
LSDV132 119783–120310 (176) SP
LSDV133 120343–122019 (559) MYX AF170726 1728 61 553 DNA ligase M133R 61 A50R 53
LSDV134 122176–128250 (2025) MYX AF170726 5102 53 1987 VAR B22R homologue, TM M134R 53
LSDV135 128323–129402 (360) Yaba-like DV AJ293568 475 37 316 IFN-α/β binding protein, SP M135R 28 B19R 32
LSDV136 129453–129911 (153) MYX AF170726 292 40 145 A52R-like family protein E M136R 40 K7R 24
LSDV137 129980–130984 (335) Yaba-like DV AJ293568 721 43 338 E,L M137R 39 A51R 30
LSDV138 131017–131574 (186) Yaba-like DV AJ293568 285 51 106 Ig domain, OX-2-like protein, SP, TM M141R 48
LSDV139 131616–132530 (305) MYX AF170726 1054 66 300 Ser/Thr protein kinase, DNA replication M142R 66 B1R 50
LSDV140 132565–133284 (240) RFV L26342 556 43 230 N1R/p28-like host range RING finger protein M143R 43
LSDV141 133336–134010 (225) Yaba-like DV AJ293568 362 38 204 EEV host range protein, SP, TM M144R 35 B5R 27
LSDV142 134015–134416 (134) MYX AF170726 222 43 109 Secreted virulence factor M146R 43 N1L 24
LSDV143 134456–135361 (302) RFV JQ1743 776 52 262 Tyrosine protein kinase-like protein M147R 51
LSDV144 135533–137173 (547) VV P24768 456 28 516 Kelch-like protein M140R 26 A55R 28
LSDV145 137222–139123 (634) RFV AF170722 1113 36 662 Ankyrin repeat protein M148R 34 B4R 25
LSDV146 139255–140493 (413) VV U94848 1030 52 388 Phospholipase D-like protein M022L 29 K4L 52
LSDV147 140557–142050 (498) RFV AF170722 973 40 498 Ankyrin repeat protein M149R 39 B4R 25
LSDV148 142101–143441 (447) Yaba-like DV AJ293568 670 35 454 Ankyrin repeat protein E M148R 29 B4R 26
LSDV149 143465–144475 (337) Yaba-like DV AJ293568 771 44 334 Serpin, SP, TM E,L M151R 38 C12L 38
LSDV150 144517–144999 (161) Yaba-like DV AJ293568 125 27 155 A52R-like family protein E M139R 27 A52R 24
LSDV151 145045–146694 (550) Yaba-like DV AJ293568 519 30 515 Kelch-like protein E M140R 26 A55R 28
LSDV152 146764–148230 (489) RFV AF170722 467 27 481 Ankyrin repeat protein E M005 24 B4R 25
LSDV153 148278–148550 (91) SPV P32230 217 46 91 SP M004.1 43
LSDV154 148623–149342 (240) P18386 MYX AF002684 378 37 231 ER-localized apoptosis regulator, SP, TM E M004 37 B9R 37
LSDV155 149595–149987 (131) P18388 MYX AJ012282 242 43 131 M003.2 43
LSDV156 150061–150537 (159) P18387 RFV P25949 308 46 143 A52R-like family protein, SP M003.1 42 B15R 34
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a

Accession numbers are from the GenBank or SwissProtein database. 

b

Yaba MTV, Yaba monkey tumor virus. 

c

aa, amino acids. 

d

Function was deduced either from the degree of similarity to known genes or from the presence of Prosite signatures. TM, a Z score of > 1.96 was used for the prediction of transmembrane (TM) domains with the MEMSAT computer program (32); SP, N-terminal signal peptide (Z score of >3.5 within 40 amino acids of the N terminus using the SIGCLEAVE computer program (ftp://ftp.ebi.ac.uk/pub/software/unix/EMBOSS/) [51]). ER, endoplasmic reticulum. 

e

Putative promoters (E, early; I, intermediate; L, late) were identified as previously described (2). 

f

Best-matching ORF from the MYX genome (accession no. AF170726). 

g

Best-matching ORF from the VV COP genome (accession no. M35027), with the exception of the VV WR 8.9-kDa protein (accession no. P07608)(LSDV093) frameshifted in VV COP. 

Nucleic acid biogenesis, virion structure, and virion assembly.

LSDV contains the majority of conserved poxviral genes involved in basic replicative mechanisms, including at least 26 genes encoding RNA polymerase subunits, mRNA transcription initiation, elongation, and termination factors, and enzymes which direct posttranscriptional processing of viral mRNA (41) (Table 1). Also present in LSDV are seven homologues of ChPV genes necessary for, or potentially involved in, DNA replication, including LSDV039, LSDV077, LSDV082, LSDV083, LSDV112, LSDV133, and LSDV139 (41). LSDV proteins potentially involved in nucleotide metabolism include homologues of thymidine kinase, dUTP pyrophosphatase, and the small subunit of ribonucleotide reductase (Table 1). LSDV contains the same complement of nucleotide metabolism genes found in the leporipoxviruses and, like the leporipoxviruses, it lacks a large subunit of ribonucleotide reductase (52). This shared complement likely reflects phylogenetic relatedness but may also be significant in cell and/or tissue tropism.

LSDV encodes at least 30 homologues of poxviral proteins known to be structural or involved in virion morphogenesis and assembly (Table 1). These include proteins present in the virion core; proteins present in the intracellular mature virus (IMV) and associated membranes; potential enzymes involved in protein modification, DNA packaging, and redox activity; and at least four VV proteins found in or associated with the release of extracellular enveloped virions (EEV) (Table 1). Additionally, LSDV095, LSDV126, and LSDV141, although significantly different from VV A4L core protein, A36R EEV protein, and B5R EEV protein, respectively, were annotated here as putative structural protein homologues based on similar genomic position and other conserved features. LSDV, like molluscum contagiosum virus (MCV) and fowlpox virus (FPV), lacks an obvious homologue of the VV IMV membrane protein D8L, a cell surface binding protein which is also present in the leporipoxviruses.

Host-related functions.

LSDV contains a number of potential host range genes with likely functions in modulation or evasion of host immune responses, in modulation or inhibition of host cell apoptosis, and in aspects of cell and/or tissue tropism. Many potential LSDV host range genes are similar in sequence and in terminal genomic location to genes present in other poxviruses. However, LSDV encodes a unique complement genes which dictate its specific host range properties.

Six LSDV proteins are potentially secreted and are likely involved in the disruption or modulation of host immune responses, as indicated by the presence of potential signal peptide sequences and/or similarity to other secreted immunomodulators. These include homologues of cellular and viral interleukin-10 (IL-10), gamma interferon (IFN-γ) receptor (R), IL-1R, IFN-α/β binding protein, and IL-18 binding protein (Table 1). Similar to other IL-10 homologues present in orf virus and some herpesviruses, LSDV005 strongly resembles cellular IL-10 in the carboxyl terminus and likely has similar immunoregulatory and immunosuppressive activities (22, 40). Notably, phylogenetic analysis indicates that LSDV005 is divergent from both cellular IL-10 (43% amino acid identity) and orf virus IL-10 (48% amino acid identity), which is very similar to ovine IL-10 (81% amino acid identity). This suggests an independent and more recent acquisition of host IL-10 into orf virus than into LSDV. LSDV is the first poxvirus known to encode two proteins, in addition to poxvirus IFN-α/β binding proteins, with similarity to IL-1 R (LSDV013 and LSDV006). LSDV013 contains the three immunoglobulin (Ig) domains common to IL-1R and likely functions as an IL-1 binding protein. LSDV006 lacks a third Ig domain in the carboxyl terminus and may perform a similar or perhaps alternative immunomodulatory function.

LSDV contains four potentially membrane localized, immunomodulatory proteins. Homologues of a G protein-coupled CC chemokine receptor (GPCR), CD47, and poxvirus OX-2-like proteins potentially bind extracellular factors and/or influence intracellular signal transduction mechanisms to affect immune mechanisms or host range (7, 35, 37, 45) (Table 1). LSDV010 and homologues in swinepox virus (SPV), Yaba-like disease virus (Yaba-like DV), and leporipoxviruses are similar to several immunomodulatory proteins found in gammaherpesviruses. All contain the cysteine-rich amino-terminal motif (CWICX10–11CXCX4–7HX2CX3WX8–16CX2C) previously noted as similar to the C4HC3 LAP/PHD finger motif and two positionally conserved transmembrane domains located in central to carboxyl-terminal regions (data not shown) (43). The gammaherpesvirus proteins affect virus-induced inhibition of class I major histocompatibility antigen (MHC-I)-mediated antigen presentation through decreased cell surface expression of MHC-I and can downregulate the expression of natural killer (NK) cell activation ligands to effectively inhibit NK cell-mediated cytotoxicity (31, 50). LSDV010, like the gammaherpesvirus proteins, may function in viral immune evasion.

Several LSDV proteins are likely to have intracellular roles in immune modulation or immune evasion. These include homologues of VV PKR inhibitors (LSDV014 and LSDV034) which confer resistance to the antiviral effects of IFN (Table 1). Poxviral serine proteinase inhibitors (serpins) are known to perform anti-inflammatory roles, and the single serpin encoded in LSDV (LSDV149) is similar to Yaba-like DV 149R, myxoma virus (MYX) M151R, and the single serpin in SPV (37; C. L. Afonso et al., unpublished data). Notably, LSDV001, LSDV009, LSDV136, LSDV150, and LSDV156 genes are similar to a group of poxviral genes which includes VV A52R and others previously described as a gene family (Family 5 [48]) (data not shown). Although the function of most genes in this group is not known, VV A52R functions as an antagonist for host cell IL-1 and Toll-like receptor-mediated intracellular signaling, including IL-1R, Toll-like receptor 4, and IL-18R-mediated induction of NF-κB activation (6). The potential for IL-1/Toll-like receptor inhibition by a family of poxvirus proteins is significant considering the role of IL-1/Toll-like receptor signaling in the induction of innate immune responses and inflammation (21).

LSDV encodes six homologues of other poxviral proteins known to affect virus virulence, virus growth in specific cell types, and/or cellular apoptotic responses (Table 1). These include homologues of epidermal growth factor (EGF), VV C7L host range, N1L virulence, and A14.5L virulence proteins, MYX M004 and M011L anti-apoptosis proteins, and the rabbit fibroma virus (RFV) N1R/ectromelia virus p28 host range factor. LSDV also encodes five proteins containing ankyrin repeat motifs, two of which (LSDV145 and LSDV147) appear to be orthologues of proteins encoded in leporipoxviruses and SPV based on genomic position, amino acid similarity, and phylogenetic analysis (7, 52; Afonso et al., unpublished) (Table 1). Poxviral ankyrin repeat genes have been associated with host range functions in MYX, cowpox virus, and VV and may inhibit virally induced apoptosis (28, 42, 49). It has been suggested that specific complements of ankyrin genes dictate poxvirus host range, and the same is likely for LSDV (3, 47).

Three LSDV genes are homologues of poxvirus genes resembling cellular enzymes (Table 1). These include LSDV146, which resembles the VV K4L phospholipase D-like protein thus far found only in VV and LSDV. Notably, LSDV proteins similar to Cu-Zn superoxide dismutase (LSDV131) and tyrosine protein kinase (LSDV143) resemble other poxvirus homologues (in leporipoxviruses and orthopoxviruses and in leporipoxviruses and FPV, respectively) in that they lack residues that would predict enzymatic activity.

In terminal genomic regions, LSDV encodes several homologues of poxvirus proteins with unknown function, including VV C10L and 8.9 kD proteins, which interact with VV host range and morphogenesis proteins, respectively, a yatapoxvirus protein (LSDV130), and a homologue of the variola virus B22R putative membrane protein (Table 1) (39). LSDV encodes three proteins (LSDV019, LSDV144, and LSDV151) that contain four to five imperfect carboxyl-terminal repeats similar to those found in the Drosophila kelch protein and other poxvirus kelch-like proteins (Table 1). Notably, LSDV potentially encodes two proteins (LSDV022 and LSDV132) that lack homology to other known proteins.

Comparison LSDV to other ChPV.

LSDV is very similar to other ChPVs in overall genome structure and composition, including the presence of a central conserved core of genes, adjacent variable region containing many genes with host related functions, and ITRs (2, 3, 7, 29, 38, 46, 52). Most of the LSDV genome is highly colinear with those of other ChPV (Table 1) (24). Sixty-five percent of the LSDV genome (LSDV024 to LSDV123) consists of a central core of genes conserved across divergent ChPV genera (2, 29, 46). LSDV gene colinearity is most conserved, however, with Yaba-like DV and leporipoxviruses (83% of the LSDV genome, from LSDV016 to LSDV143) (Table 1). Overall amino acid identity is higher between LSDV and MYX proteins (56% average) and between LSDV and Yaba-like DV proteins (57% average) than between LSDV and VV proteins (49% average). Thus, the genomes of LSDV, Yaba-like DV, and leporipoxviruses appear to be relatively well conserved in gene content, gene arrangement, and amino acid identity (Table 1).

The terminal genomic regions of LSDV encode many of the proteins with probable functions involving host range, virulence, and immune modulation. At the amino acid level, many of these LSDV proteins are less similar to their homologues than are proteins encoded in the conserved central core region, and several are most similar to cellular proteins (Table 1). Although terminal regions are similar to leporipoxviruses, yatapoxviruses, and SPV in gene content, several LSDV genes have homologues in other ChPV genera (Table 1). For instance, LSDV homologues of IL-1 binding protein, IL-10, GPCR, and VV C10L are absent in the closely related leporipoxviruses, and LSDV homologues of IL-10, IFN-γR, MYX M004, DNA ligase, superoxide dismutase-like protein, tyrosine protein kinase-like protein, and phospholipase D are absent in Yaba-like DV. LSDV lacks many genes for virulence and/or host range proteins found in other poxviruses. These include the 35-kDa secreted chemokine binding protein (leporipoxviruses and orthopoxviruses), tumor necrosis factor receptor homologues (leporipoxviruses and orthopoxviruses), MDA-7 cytokine-like protein (Yaba-like DV), MHC-I-like proteins (Yaba-like DV, SPV, and MCV), semaphorin-like protein (orthopoxviruses, FPV), glutathione peroxidase (MCV and FPV), hydroxysteroid dehydrogenase (Yaba-like DV, orthopoxviruses, MCV, and FPV), CPD photolyase (leporipoxviruses and FPV), lysophospholipase (Yaba-like DV and orthopoxviruses), and sialyltransferase (leporipoxviruses). LSDV contains only one serpin-like protein and one GPCR-like protein, while other poxviruses contain multiple distinct serpin proteins (Yaba-like DV, leporipoxviruses, orthopoxviruses, and FPV) and GPCR proteins (Yaba-like DV and FPV). LSDV also lacks homologues of poxviral A type inclusion proteins (orthopoxviruses, MCV, and FPV) (24).

Finally, LSDV genes were nearly identical (97 to 100% amino acid identity) to 16 genes previously sequenced from either LSDV or ShPV (Table 1). The terminal regions of LSDV strain 2490 were highly similar to regions sequenced from two ShPV isolates (25). Interestingly, greater conservation was seen between LSDV strain 2490 and a nonpathogenic Kenya ShPV (KS) isolate than was observed between KS and a pathogenic India ShPV isolate whose homologue of LSDV002 is disrupted (25). Comparative analysis of the LSDV genome sequence with those of ShPV and GPV will help define the genetic basis of CaPV host range.

Conclusions.

LSDV gene content and organization indicates a close structural and functional relationship to other ChPV, particularly to yatapoxviruses and leporipoxviruses. The highest conservation occurs with genes involved in basic replicative mechanisms, including mRNA biogenesis, DNA replication, and virion structure and assembly. Terminal genomic sequences contain a unique complement of at least 34 genes which are in gene families or likely function in virulence, host range, and/or immune evasion. An improved understanding of how these genes affect LSDV/host interactions will permit the engineering of novel vaccine viruses and expression vectors with enhanced efficacy and greater versatility. Additionally, the LSDV genomic sequence provides a basis from which comparisons with other CaPVs may be made, thus contributing to our understanding of the genetic basis of CaPV virulence and host range.

ACKNOWLEDGMENTS

We thank J. Lubroth for providing the 2490 strain of LSDV and A. Zsak and A. Ciupryk for excellent technical assistance.

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