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1: Microbes Infect. 2005 Apr;7(4):674-81. Epub 2005 Mar 22.
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Pathogenic significance of alpha-N-acetylgalactosaminidase activity found in the hemagglutinin of influenza virus.
Division of Molecular Biology and Virology, Socrates Institute for Therapeutic Immunology, 1040 66th Avenue, Philadelphia, PA 19126-3305, USA. [email protected]
Serum vitamin D3-binding protein (Gc protein) is the precursor for the principal macrophage activating factor (MAF). The precursor activity of serum Gc protein was reduced in all influenza virus-infected patients. These patient sera contained alpha-N-acetylgalactosaminidase (Nagalase) that deglycosylates Gc protein. Deglycosylated Gc protein cannot be converted to MAF, thus it loses the MAF precursor activity, leading to immunosuppression. An influenza virus stock contained a large amount of Nagalase activity. A sucrose gradient centrifugation analysis of the virus stock showed that the profile of Nagalase activity corresponds to that of hemagglutinating activity. When these gradient fractions were treated with 0.01% trypsin for 30 min, the Nagalase activity of each fraction increased significantly, suggesting that the Nagalase activity resides on an outer envelope protein of the influenza virion and is enhanced by the proteolytic process. After disruption of influenza virions with sodium deoxycholate, fractionation of the envelope proteins with mannose-specific lectin affinity column along with electrophoretic analysis of the Nagalase peak fraction revealed that Nagalase is the intrinsic component of the hemagglutinin (HA). Cloned HA protein exhibited Nagalase activity only if treated with trypsin. Since both fusion capacity and Nagalase activity of HA protein are expressed by proteolytic cleavage, Nagalase activity appears to be an enzymatic basis for the fusion process. Thus, Nagalase plays dual roles in regulating both infectivity and immunosuppression.
PMID: 15848273
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1: Med Hypotheses. 2006;67(3):578-87. Epub 2006 Apr 18.
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A nutritional supplement formula for influenza A (H5N1) infection in humans.
By early February 2006, the World Health Organization had reported 165 human cases of H5N1 influenza since December 2003, with 88 fatalities. However, the avian H5N1 influenza virus apparently is not yet efficiently transmitted between humans. Though a near-term possibility of a global H5N1 influenza pandemic remains, currently there is no vaccine or anti-viral drug that is proven to be safe and effective in preventing or treating H5N1 influenza in humans. There is thus a compelling public interest in developing alternative prophylaxis and treatment strategies for H5N1 influenza, which would need to address the complex pathogenesis of H5N1 influenza that is responsible for its apparently unusually high virulence. The authors present here a significant body of medical and scientific evidence to support the prophylactic use of a carefully designed nutritional supplement formulation that may antagonize the major pathogenic processes of H5N1 influenza in humans. Through several independently-mediated mechanisms, the formulations may: (a) degrade H5N1 virulence by directly affecting the virus itself, (b) inhibit H5N1 viral replication by maintaining cellular redox equilibrium in host cells, (c) inhibit H5N1 replication by a blockade of the nuclear-cytoplasmic translocation of the viral ribonucleoproteins and reduced expression of late viral proteins related to the inhibition of protein kinase C activity and its dependent pathways, (d) down-regulate activation and proliferation of proinflammatory cytokines in respiratory epithelial cells and macrophages that are implicated in the pathogenesis of H5N1 influenza, and (e) protect the lungs and other vital organs from virus- and cytokine-induced oxidative stress by supplying and maintaining sufficient levels of exogenous and endogenous antioxidants. Key mediators in these processes include selenium, vitamin E, NAC/glutathione, resveratrol, and quercetin. Taken prophylactically, and throughout the duration and recovery of an H5N1 infection, the nutritional supplement formula may aid humans infected with H5N1 influenza to survive with a reduced likelihood of major complications, and may provide a relatively low-cost strategy for individuals as well as government, public-health, medical, health-insurance, and corporate organizations to prepare more prudently for an H5N1 pandemic. Some evidence also indicates that the supplement formulation may be effective as an adjunctive to H5N1 vaccine and anti-viral treatments, and should be tested as such.
PMID: 16624496 [PubMed - indexed for MEDLINE]
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1: PLoS Pathog. 2008 Aug 1;4(8):e1000115.
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H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice.
Immunology and Pathogenesis Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Collaborating Centers for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
Fatal human respiratory disease associated with the 1918 pandemic influenza virus and potentially pandemic H5N1 viruses is characterized by severe lung pathology, including pulmonary edema and extensive inflammatory infiltrate. Here, we quantified the cellular immune response to infection in the mouse lung by flow cytometry and demonstrate that mice infected with highly pathogenic (HP) H1N1 and H5N1 influenza viruses exhibit significantly high numbers of macrophages and neutrophils in the lungs compared to mice infected with low pathogenic (LP) viruses. Mice infected with the 1918 pandemic virus and a recent H5N1 human isolate show considerable similarities in overall lung cellularity, lung immune cell sub-population composition, and cellular immune temporal dynamics. Interestingly, while these similarities were observed, the HP H5N1 virus consistently elicited significantly higher levels of pro-inflammatory cytokines in whole lungs and primary human macrophages, revealing a potentially critical difference in the pathogenesis of H5N1 infections. Primary mouse and human macrophages and dendritic cells were also susceptible to 1918 and H5N1 influenza virus infection in vitro. These results together indicate that infection with HP influenza viruses such as H5N1 and the 1918 pandemic virus leads to a rapid cell recruitment of macrophages and neutrophils into the lungs, suggesting that these cells play a role in acute lung inflammation associated with HP influenza virus infection.
PMID: 18670648 [PubMed - indexed for MEDLINE]
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