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Host envelope glycoprotein processing proteases are indispensable for entry into human cells by seasonal and highly pathogenic avian influenza viruses

Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Kuramoto-cho 3-18-15, Tokushima 770-8503, Japan.
Journal of molecular and genetic medicine: an international journal of biomedical research 02/2008; 3(1):167-75.
Source: PubMed

ABSTRACT Influenza A virus (IAV) is one of the most common infectious pathogens in humans and causes considerable morbidity and mortality. The recent spread of highly-pathogenic avian IAV H5N1 viruses has reinforced the importance of pandemic preparedness. In the pathogenesis of IAV infection, cellular proteases play critical roles in the process of viral entry into cells that subsequently leads to tissue damage in the infected organs. Since there are no processing protease for the viral membrane fusion glycoprotein hemagglutinin precursor (HA(0)) in IAV, entry of the virus into cells is determined primarily by the host cellular HA(0) processing proteases that proteolytically activate membrane fusion activity. HA(0) of seasonal human IAV has the consensus cleavage site motif Q(E)-T/X-R and is selectively processed by at least seven different trypsin-type processing proteases identified to-date in animal model experiments using mouse-adapted IAV or gene expression system in MDCK cells. As is the case for the highly pathogenic avian influenza (HPAI) A virus, endoproteolytic processing of the HA(0) occurs through ubiquitous cellular processing proteases, which selectively recognize the multi-basic consensus cleavage site motifs, such as R-X-K/R-R, and K-X-K/R-R. The cleavage enzymes for the R-X-K/R-R motif, but not K-X-K/R-R motif, have been reported to be furin and pro-protein convertase (PC)5/6 in the trans-Golgi network. Here we report new members of type II transmembrane serine proteases of the cell membrane, mosaic serine protease large form (MSPL) and its splice variant TMPRSS13, which recognize and cleave both R-X-K/R-R and K-X-K/R-R motifs without calcium. Furthermore, IAV infection significantly up-regulates a latent ectopic pancreatic trypsin, one of the potent HA processing proteases, and pro-matrix metalloprotease-9, in various organs. These proteases may synergistically damage the blood-brain barrier in the brain and basement membrane of blood vessels in various organs, resulting in severe edema and multiple organ failure. In this review, we discuss these proteases as new drug target molecules for IAV treatment acting by inhibition of IAV multiplication and prevention of multiple organ failure, other than anti-viral agents, viral neuraminidase inhibitors.

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    • "The function of HA is to recognize host sialic acid residue as an entry receptor [4,5], and to fuse viral envelope with vesicle's membrane [5,6] after the linker peptide between subdomain HA1 and HA2 of HA is cleaved by host trypsin-like proteases. Virulent H5 and H7 hemagglutinins [7] have a polybasic cleavage site that is exposed and cleavable by furin or other proprotein convertases [8,9] which enables the virus to infect multiple organs and leads to multisystem failure [7]. A second factor correlating to the high pathogenicity of H5N1 influenza virus is the PB2 subunit in polymerase complex [10,11]. "
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    • "Most of the TTSPs identified so far recognize a single R at position P1, but the newly isolated MSPL/TMPRSS13 has unique substrate specificities of the preferential recognition of a paired basic residue at the cleavage site [41] [43] [44]. Thus, MSPL/TMPRSS13, which are ubiquitously expressed in the plasma membranes, particularly highly expressed in the lungs, brain and vascular epithelial cells of human and chicken [42] [43], can activate various fusogenic viral envelope glycoproteins of HPAI viral strains. To clarify the roles of MSPL and TMPRSS13 in the proteolytic activation of HA of HPAI viruses, we searched for cells that express MSPL/TMPRSS13 at below detection levels and found human endothelial cell line ECV304 as the corresponding cell line. "
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