Human H5N1 influenza: Current insight into pathogenesisIntroductionPathogenesisClinical syndromeHemagglutinin (HA)The polymerasesThe PB1-F2 proteinThe NS1 proteinTreatmentConclusionReferencesThe International Journal of Biochemistry & Cell Biology 40 (2008) 2671–2674Contents lists available at ScienceDirectThe International Journal of Biochemistry& Cell Biologyjournal homepage: www.elsevier.com/locate/biocelMedicine in focusHuman H5N1 influenza: Current insight into pathogenesisTran Tan Thanha, H. Rogier van Doorna,b, Menno D. de Jonga,b,c,∗aOxford University Clinical Research Unit, Hospital for Tropical Diseases, 190 Ben Ham Tu, District 5, Ho Chi Minh City, Viet NambCentre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford,Centre for Clinical Vaccinology and Tropical Medicine, Oxford, UKcDepartment of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlandsarticle infoArticle history:Received 12 May 2008Received in revised form 30 May 2008Accepted 30 May 2008Available online 6 June 2008Keywords:H5N1InfluenzaEmerging infectionsZoonosisPathogenesisabstractSince their emergence as avian (1996) and zoonotic human pathogens (1997), H5N1influenza viruses have become endemic among poultry in large parts of Asia, but outbreakshave also been seen in Africa and Europe. Transmission from animals to humans remainssporadic, but mortality of human infection is high (63%). To date, reported cases of humanto human transmission have been rare. Patient and laboratory data suggest that highly effi-cient viral replication and the resulting intensified immune response of the human hostare the determining factors in H5N1 pathogenesis and case fatality rate. Therefore, in themanagement of H5N1 disease (early) suppression of viral replication is key.The underlying biochemistry and cell biology of H5N1 pathogenesis and treatment arebriefly discussed in this review.© 2008 Elsevier Ltd. All rights reserved.1. IntroductionInfluenza A viruses belong to the family of Ortho-moyxoviridae. Their genome consists of 8 single-strandednegative sense RNA segments, encoding eleven proteins.Influenza A viruses are classified according to the anti-genicity of their two surface glycoproteins: hemagglutinin(HA) and neuraminidase (NA). To date, 16 HA (H1-16) and9 NA (N1-9) subtypes have been described, all of whichare found in the virus’ natural host: waterfowl. A limitednumber of subtypes have established species-specific lin-eages in humans (H1N1, H2N2, and H3N2). Besides the twosurface glycoproteins, which are essential for virus bindingto (HA) and release from (NA) the host cell, other proteinsknown to be involved in pathogenicity and transmissibil-ity of influenza viruses are the proteins of the replicationcomplex (Polymerase acidic [PA], and basic 1 [PB1] and 2∗Corresponding author at: Oxford University Clinical Research Unit,Hospital for Tropical Diseases, 190 Ben Ham Tu, District 5, Ho Chi MinhCity, Viet Nam. Tel.: +84 8 8384009; fax: +84 8 9238904.E-mail address: [email protected] (M.D. de Jong).[PB2], and the nucleoprotein [NP]) and the non-structuralprotein 1 (NS1) (Peiris et al., 2007)(Fig. 1).Since their emergence as zoonotic human pathogens in1997, highly pathogenic avian influenza H5N1 viruses havespread to large parts of the world. Human infections remainsporadic, but are associated with severe disease and highmortality (63% [241/382], per 30-4-08 (WHO, 2008)). Highviral replication and an increased inflammatory responsewith cytokine dysregulation are thought to play centralroles in the pathogenesis of human disease.2. Pathogenesis2.1. Clinical syndromeMost human cases present as severe pneumonia withrapid progression to acute respiratory distress syndrome(ARDS). Patients show radiological evidence of pneumo-nia, sometimes with bilateral infiltration and collapse orconsolidation. Complications associated with fatal out-come include ARDS and multi-organ failure. Occasionally,encephalitis has been observed. In recovered patients,1357-2725/$ – see front matter © 2008 Elsevier Ltd. All rights reserved.doi:10.1016/j.biocel.2008.05.0192672 T.T. Thanh et al. / The International Journal of Biochemistry & Cell Biology 40 (2008) 2671–2674Fig. 1. Genes and proteins involved in H5N1 pathogenesis, virulence and treatment. PB = Polymerase Basic, PA = Polymerase Acidic, HA = Hemagglutinin,NP = Nucleoprotein, NA = Neuraminidase, M = Matrix, NS = Nonstructural.radiological evidence of lung damage may still be observedafter several months (de Jong and Hien, 2006).High nasopharyngeal viral loads were associated withfatal outcome (de Jong et al., 200 6). Evidence of activelyreplicating H5N1 virus was found in the trachea and lowerrespiratory tract. In addition, viral RNA was demonstratedin autopsy samples of multiple non-respiratory organsincluding intestines, liver, spleen and brain, suggestingwidespread viral dissemination (Abdel-Ghafar et al., 2008).In a pregnant woman, viral RNA and antigen was alsodetected in fetus and placenta (Gu et al., 2007). The isola-tion of H5N1 viruses from plasma suggests that the blood isa route of dissemination from primary infected (respiratorytract) sites to other organs. It remains unknown how H5N1virus reaches the central nervous system: hematogenouslythrough crossing of the blood–brain barrier or continuouslyby spread from peripheral nerve endings, as suggested bystudies in cats and mice (Rimmelzwaan et al., 2006; Tanakaet al., 2003).Patients with severe H5N1 disease often have lym-phopenia, thrombocytopenia, and increased levels ofserum aminotransferases (de Jong and Hien, 2006).Most examined patients have increased levels ofchemokines (interferon [IFN]-inducible protein 10[IP-10], monokine induce d by IFN-␥ [MIG], monocytechemotactic protein-1 [MCP-1], Interleukin [IL]-8) andpro- and anti-inflammatory cytokines (IL6, IFN-␥, IL-10),the levels of most of which were positively correlatedwith both nasopharyngeal virus loads and fatal out-come (de Jong et al., 2006). In vitro experiments inmacrophages and respiratory epithelial cells have shownthat H5N1 viruses may induce cytokine expression toa larger extent than human seasonal influenza viruses(Chan et al., 2005; Cheung et al., 2002). This observedhigh production of cytokines may be explained by strongactivation of the p38 mitogen-activated protein kinase(p38 MAPK) signaling pathway by H5N1 (Lee et al.,2005).2.2.