Reproducibility of swollen sinuses in broilers by experimental infection with avian metapneumovirus subtypes A and B of turkey origin and their comparative pathogenesis

Aung, Ye Htut; Liman, Martin; Neumann, Ulrich; Rautenschlein, Silke

doi:10.1080/03079450701802222

Cited by 32 publications

(17 citation statements)

References 51 publications

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“…As Fig. 9B and a previous report indicate (47), the lung, trachea, oropharynx, and spleen of chickens are permissive for aMPV/B infection. These results suggested that these specific tissues facilitated aMPV/B infection via TMPRSS12 cleavage of the F protein.…”

Section: Ampv/b Grows In Vitro Without the Addition Of Trypsinsupporting

confidence: 73%

TMPRSS12 Is an Activating Protease for Subtype B Avian Metapneumovirus

Yun

Zhang

Liu

et al. 2016

J Virol

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The entry of avian metapneumovirus (aMPV) into host cells initially requires the fusion of viral and cell membranes, which is exclusively mediated by fusion (F) protein. Proteolysis of aMPV F protein by endogenous proteases of host cells allows F protein to induce membrane fusion; however, these proteases have not been identified. Here, we provide the first evidence that the transmembrane serine protease TMPRSS12 facilitates the cleavage of subtype B aMPV (aMPV/B) F protein. We found that overexpression of TMPRSS12 enhanced aMPV/B F protein cleavage, F protein fusogenicity, and viral replication. Subsequently, knockdown of TMPRSS12 with specific small interfering RNAs (siRNAs) reduced aMPV/B F protein cleavage, F protein fusogenicity, and viral replication. We also found a cleavage motif in the aMPV/B F protein (amino acids 100 and 101) that was recognized by TMPRSS12. The histidine, aspartic acid, and serine residue (HDS) triad of TMPRSS12 was shown to be essential for the proteolysis of aMPV/B F protein via mutation analysis. Notably, we observed TMPRSS12 mRNA expression in target organs of aMPV/B in chickens. Overall, our results indicate that TMPRSS12 is crucial for aMPV/B F protein proteolysis and aMPV/B infectivity and that TMPRSS12 may serve as a target for novel therapeutics and prophylactics for aMPV. A vian metapneumovirus (aMPV), a member of the genus Metapneumovirus in the subfamily Pneumovirinae of the family Paramyxoviridae, causes acute rhinotracheitis (TRT) in turkeys and swollen head syndrome (SHS) in chickens (1-3). Thus, aMPV is a major disease threat to the turkey and chicken industries (4, 5). However, no effective vaccine or drug is currently available for large commercial poultry producers to prevent or treat aMPV (6). Based on a phylogenetic analysis, aMPV is divided into four subtypes: aMPV/A, aMPV/B, aMPV/C, and aMPV/D (7, 8). IMPORTANCE Proteolysis of the aMPV F protein is a prerequisite for F protein-mediated membrane fusion of virus and cell and for aMPV in-The entry of paramyxoviruses into host cells initially requires the fusion of viral and cell membranes, which is mediated by one or more viral glycoproteins on the exterior of the viral envelope (9-12). For metapneumoviruses like aMPV, fusion (F) protein alone, without the help of an attachment protein, can induce membrane fusion (13-16). Consistent with this observation, recombinant aMPV lacking the small hydrophobic (SH) and attachment (G) glycoproteins replicates efficiently in vivo and vitro (17,18). Collectively, these results suggest that aMPV F protein alone can mediate membrane fusion and viral infection.The prerequisite for paramyxovirus F protein mediation of membrane fusion is cleavage of the F protein, followed by a conformational change (19)(20)(21)(22). The paramyxovirus F protein is synthesized as a full-length precursor (F0) that is subsequently cleaved by cellular proteases to generate F1 and F2. Cleavage of F0 exposes a fusion peptide at the N terminus of F1 that is responsible for mediating membrane fusi...

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Section: Ampv/b Grows In Vitro Without the Addition Of Trypsinsupporting

confidence: 73%

TMPRSS12 Is an Activating Protease for Subtype B Avian Metapneumovirus

Yun

Zhang

Liu

et al. 2016

J Virol

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“…These infections are mainly characterized by nasal discharge, tracheal and facial congestion, and swollen infraorbital sinuses. 1 In laying birds, infection results in egg drops and poor egg quality. 2 aMPV belongs to the genus Metapneumovirus within the subfamily Pneumovirinae of family Paramyxoviridae and has a nonsegmented, single-stranded, negative-sense RNA genome.…”

Section: Introductionmentioning

confidence: 99%

Avian metapneumovirus subgroup C induces autophagy through the ATF6 UPR pathway

et al. 2017

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An increasing number of studies have demonstrated that macroautophagy/autophagy plays an important role in the infectious processes of diverse pathogens. However, it remains unknown whether autophagy is induced in avian metapneumovirus (aMPV)-infected host cells, and, if so, how this occurs. Here, we report that aMPV subgroup C (aMPV/C) induces autophagy in cultured cells. We demonstrated this relationship by detecting classical autophagic features, including the formation of autophagsomes, the presence of GFP-LC3 puncta and the conversation of LC3-I into LC3-II. Also, we used pharmacological regulators and siRNAs targeting ATG7 or LC3 to examine the role of autophagy in aMPV/C replication. The results showed that autophagy is required for efficient replication of aMPV/C. Moreover, infection with aMPV/C promotes autophagosome maturation and induces a complete autophagic process. Finally, the ATF6 pathway, of which one component is the unfolded protein response (UPR), becomes activated in aMPV/C-infected cells. Knockdown of ATF6 inhibited aMPV/C-induced autophagy and viral replication. Collectively, these results not only show that autophagy promotes aMPV/C replication in the cultured cells, but also reveal that the molecular mechanisms underlying aMPV/C-induced autophagy depends on regulation of the ER stress-related UPR pathway.

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“…Avian metapneumovirus (aMPV) belongs to the genus Metapneumovirus in the subfamily Pneumovirinae of the family Paramyxoviridae 1 . aMPV causes acute rhinotracheitis in turkeys of all ages and swollen head syndrome in chickens, resulting in a major economic burden for poultry farmers 2 . Since aMPV was first detected in South Africa in 1978, aMPV has been reported in many countries 3 .…”

mentioning

confidence: 99%

Trypsin- and low pH-mediated fusogenicity of avian metapneumovirus fusion proteins is determined by residues at positions 100, 101 and 294

Yun

Guan

Liu

et al. 2015

Sci Rep

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Avian metapneumovirus (aMPV) and human metapneumovirus (hMPV) are members of the genus Metapneumovirus in the subfamily Pneumovirinae. Metapneumovirus fusion (F) protein mediates the fusion of host cells with the virus membrane for infection. Trypsin- and/or low pH-induced membrane fusion is a strain-dependent phenomenon for hMPV. Here, we demonstrated that three subtypes of aMPV (aMPV/A, aMPV/B, and aMPV/C) F proteins promoted cell-cell fusion in the absence of trypsin. Indeed, in the presence of trypsin, only aMPV/C F protein fusogenicity was enhanced. Mutagenesis of the amino acids at position 100 and/or 101, located at a putative cleavage region in aMPV F proteins, revealed that the trypsin-mediated fusogenicity of aMPV F proteins is regulated by the residues at positions 100 and 101. Moreover, we demonstrated that aMPV/A and aMPV/B F proteins mediated cell-cell fusion independent of low pH, whereas the aMPV/C F protein did not. Mutagenesis of the residue at position 294 in the aMPV/A, aMPV/B, and aMPV/C F proteins showed that 294G played a critical role in F protein-mediated fusion under low pH conditions. These findings on aMPV F protein-induced cell-cell fusion provide new insights into the molecular mechanisms underlying membrane fusion and pathogenesis of aMPV.

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Reproducibility of swollen sinuses in broilers by experimental infection with avian metapneumovirus subtypes A and B of turkey origin and their comparative pathogenesis

Cited by 32 publications

References 51 publications

TMPRSS12 Is an Activating Protease for Subtype B Avian Metapneumovirus

TMPRSS12 Is an Activating Protease for Subtype B Avian Metapneumovirus

Avian metapneumovirus subgroup C induces autophagy through the ATF6 UPR pathway

Trypsin- and low pH-mediated fusogenicity of avian metapneumovirus fusion proteins is determined by residues at positions 100, 101 and 294

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