A novel genetic locus linked to pro-inflammatory cytokines after virulent H5N1 virus infection in mice

... candidate genes in Qivr6.1 To identify the genetic polymorphisms and host genes that are responsible for the difference in production of pro-inflammatory cytokines after HK213 virus infection, we queried available sequence information for genetic polymorphisms between 316 Mb on chromosome 6. Three genes Samd9l , Slc25a13 , and Ica1 contain non-synonymous SNPs, and one gene Col28a1 has a large in-frame deletion spanning three coding exons (exon 16 through 18 in NM_001037865.1) the D2 genotype (Table 1

... influenza virus infection. The reported single nucleotide polymorphisms in Samd9l (rs30759164 (V 169 I) and rs30516773 (I 459 V)), Slc25a13 (rs32512230 (V 583 A) and rs30695207 (A 648 T)), and Ica1 (rs51311141 (A 312 T) and rs6218746 (Q 397 R)) were confirmed by sequencing. Similarly, we also confirmed the in-frame 69 amino-acid deletion in Col28a1 in the D2 genotype. No additional missense or nonsense polymorphisms or deletions and insertions were identified between D2 and B6 in the coding region of any of the other seven host genes that were targeted for sequencing. Table 1 Missense mutation analysis across multiple inbred mouse strains Gene SNP DBA/2J 129/SvImJ A/J SM/J C57BL/6J Balb/cJ Samd9l V 169 I I I I I V I I 459 V V V V V I V Slc25a13 V 583 A A V V V V V A 648 T T A A nd 1 A A Ica1 A 312 T T T T T A A Q 397 R R R R R Q Q Col28a1 Deletion * Del - 2 Del - - - *Based on two flanking non-synonymous SNP (rs30133088 at position 312 and rs30660613 at position 602). 1 nd =no

... mutations in Ica1 . The presence of the 69 amino-acid deletion in Col28a1 was also present in the A/J strain of mice, but not in the susceptible 129/SvImJ or the resistant mouse strains. RNA expression analysis of candidate genes in Qivr6.1 Using previously published RNA expression data [ 13 ] from lungs obtained from D2 and B6 mice infected with H5N1 influenza virus, we identified 41 host genes within Qivr6.1 that were detected by microarray in the context of uninfected or H5N1 IAV infected lung tissue. These included the three polymorphic host genes Samd9l , Ica1 and Slc25a13 , but not Col28a1 . A comparison of baseline RNA expression identified 5 host genes whose expression levels were significantly different (P <0.01), albeit the difference was less than 2-fold. These included Ica1 , Col1a2 , Calcr , Tfpi2 and Bet1 . One probe (1431380_at), detecting a transcript located within an intron of Ica1 , was detected only in B6 animals. Within the locus we also identified host genes whose expression

... 10 5 HK213 virus for 48 hours and the amount of CCL2 produced in the lungs was measured by ELISA. The results are from 5 mice per group and are representative of two experiments. (B) Slc25a13 -/- mice (circles, n =7) and control animals (triangles, n =9) were infected with 10 5 (filled symbols) or 10 6 (open symbols) EID 50 of a highly pathogenic H5N1 influenza A virus (A/Hong Kong/213/03 (HK213)) and weight-loss was monitored for 15 days. Potential role for Samd9l, Ica1 and Col28a1 in

... by changing intra-cellular trafficking of TGN-associated vesicles required for trafficking of the viral glycoproteins HA and NA to the surface of the cells. Interestingly the amino acid residue at position 312 in the C57BL/6J strain was predicted to be damaging (SIFT functional polymorphism prediction program), suggesting that the Ica1 allele in DBA/2J mice may enhance virus replication. Finally, Col28a1 is a von Willebrand factor A domain-containing protein with many imperfections in the

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Gene: COL28A1 - collagen, type XXVIII, alpha 1 - (NCBI)

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