• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Opin Immunol. Author manuscript; available in PMC Aug 11, 2012.
Published in final edited form as:
PMCID: PMC3163725
NIHMSID: NIHMS318626

The pathogenesis of influenza virus infections: the contributions of virus and host factors

Abstract

Influenza viruses cause acute respiratory inflammation in humans and symptoms such as high fever, body aches, and fatigue. Usually these symptoms improve after several days; however, the 2009 pandemic H1N1 influenza virus [influenza A(H1N1)2009] is more pathogenic than seasonal influenza viruses and the pathogenicity of highly pathogenic H5N1 viruses is still higher. The 1918 influenza pandemic virus caused severe pneumonia, resulting in an estimated 50 million deaths worldwide. Several virulence factors have been identified in these virus strains, but host factors are also responsible for the pathogenesis of infections caused by virulent viruses. Here, we review the contributions of both virus and host factors to the pathogenesis of these viral infections.

Introduction

Influenza viruses possess RNA as their genome and belong to the family Orthomyxoviridae[1]. Influenza A viruses (IAV), together with influenza B viruses, cause respiratory illness in humans. Wild aquatic birds are the natural reservoir of IAV[2]. Influenza pandemics occur when humans are introduced to IAVs with hemagglutinin (HA) to which they are immunologically naïve[3]. We have experienced four pandemics since the beginning of 20th century: Spanish influenza (H1N1) in 1918/1919, Asian influenza (H2N2) in 1957, Hong Kong influenza (H3N2) in 1968, and H1N1 influenza in 2009. Of these pandemic viruses, the 1918 virus was the most devastating, causing massive acute pulmonary hemorrhage and edema[4]. Since antibiotics were not available then, secondary bacterial pneumonia was a major cause of death among those infected with the virus[5]. Until recently, it has been difficult to precisely evaluate the pathogenicity of the 1918 virus relative to other influenza virus strains. However, in 1999, the reverse genetics of influenza virus was established, enabling us and others to generate the 1918 virus from cloned cDNAs[6]. Infection of cynomolgus macaques with 1918 virus generated by reverse genetics resulted in severe lung damage and high virus titers, as well as disruption of the macaques’ antiviral immune responses[7]. These studies directly demonstrated that the 1918 virus possessed sufficiently high pathogenicity to cause fatal pulmonary disease.

The genome of IAV consists of eight RNA segments, encoding HA, neuraminidase (NA), nucleoprotein (NP), M1, M2, nonstructural protein (NS) 1, NS2, polymerase acidic protein (PA), polymerase basic (PB) 1, PB1-F2, and PB2. Recently, research has focused on using reverse genetics to elucidate the role of each viral protein in the pathogenicity of influenza viruses. The range of severity of diseases caused by genetically similar IAV in humans is extremely wide, indicating that host conditions play an important role in determining the pathogenesis of IAV. Experiments with mammals such as mice, guinea pigs, ferrets, and non-human primates, are employed to analyze the involvement of host factors in IAV infections, while gene-targeted mouse models are useful for testing the function of individual host genes in vivo. The secretion of type 1 interferon is induced by viral infection and produces antiviral factors; IFNβ knock-out mice are susceptible to influenza virus[8]. Therefore, type I IFN is a key molecule in the innate immune responses to infection with influenza virus and the magnitude of the type I IFN response influences the pathogenicity of the virus. Thus, the pathogenesis of influenza virus infection in humans depends on a combination of virus and host factors.

Virulence factors

The influenza viral proteins play a role in the lung pathology of humans. Among these proteins, HA is responsible for targeting cells for infection (Table) [911]. The HA of seasonal IAV binds to α2-6 sialylated glycans, which are expressed on the surface of the epithelial cells of the upper respiratory tract in humans[12]. Since inflammation caused by seasonal IAV infection is mainly limited to the upper respiratory tract, the disease is mild. Nonetheless, the viruses spread easily among human populations mediated by nasal discharges that contain high titers of live virus. Highly pathogenic avian H5N1 influenza viruses (HPAIV), however, preferentially recognize α2-3 sialylated glycans and primarily infect type 2 pneumocytes in the human lung[12]. Therefore, HPAIV infection often results in severe pneumonia in humans[13]. Because the primary target cells of HPAIV are deep in the lower respiratory tract, it is difficult for HPAIV to cause widespread infection among humans. Mutations in the HAs of H5N1 viruses confer upon these mutants the ability to bind to α2-6 as well as α2-3 sialylated glycans[14]. In the case of influenza A(H1N1)2009, a D222G substitution in HA, which was observed in severe and fatal cases, changes the receptor binding specificity of the virus from α2-6 to α2-3 sialylated glycans [11,15]. A study using cultures of human tracheobronchial epithelial cells showed that influenza A(H1N1)2009 with the D222G substitution in its HA could infect ciliated bronchial cells [11]. This cell tropism alteration mediated by an HA mutation may increase the severity of pneumonia. Therefore, we must carefully monitor the HAs of avian H5N1 viruses for amino acid mutations that may alter their pandemic potential as well as the HA of influenza A(H1N1)2009 for mutations that produce strains with higher pathogenicity.

Table
Mutations in viral proteins that influence viral pathogenicity

HA also influences pathogenicity via its susceptibility to host proteases. For influenza viruses to be infectious, their HAs must be cleaved into two subunits, HA1 and HA2[16]. The HA of seasonal IAV possesses a single arginine at the cleavage site and is cleaved by trypsin-like proteases that are produced by respiratory and gastrointestinal cells. In contrast, the HA of HPAIV possesses multiple basic amino acids at the cleavage site and is susceptible to ubiquitous furin and PC6, which reside in the trans-Golgi network[17]. This is one reason why HPAIV cause severe systemic infection leading to multiple organ failure and death.

The viral RNA polymerase complex consists of PA, PB1, and PB2. This complex is responsible for the transcription and replication of the viral genome. Several mutations in PA and PB2 support better replication of avian viruses in mammalian cells (Table)[1822]. Therefore, it is important to monitor mutations in the genes of the RNA polymerase complex to detect viruses that replicate well in humans. A/Vietnam/1203/04 (VN1203) H5N1 virus, which was isolated from a fatal human case, is highly lethal to ferrets and mice[23,24]. When the viral RNA polymerase genes of VN1203 were replaced with those of a low pathogenic H5N1 virus, the pathogenicity of VN1203 was dramatically reduced in these animals[24]. Watanabe et al. also demonstrated that the RNA polymerase complex and NP played a role in the pathogenicity of the 1918 pandemic virus[25]. Thus, the viral RNA polymerase complex also contributes to IAV pathogenicity in mammals.

The PB1 segment encodes a 90-amino acid protein, PB1-F2, that preferentially localizes to the mitochondria of infected cells[26]. PB1-F2 induces apoptosis and is a known virulence factor[27]. The amino acid change N665S in PB1-F2 was found to be responsible for the high virulence of both the 1918 pandemic and H5N1 viruses[28]. This mutation increases the secretion of proinflammatory cytokines, such as TNF-α, and virus titers in the lungs. Other viral proteins, such as NA and NS1, are also implicated in the virulence of IAV. NA is important for efficient viral replication[29], while NS1 antagonizes interferon production in virus-infected cells.

Host factors

The immune system protects the host from infection with influenza virus. Therefore, the pathogenesis of influenza virus depends on the function of the immune system. When IAV infect respiratory epithelial cells or alveolar macrophages, the single-stranded RNA of the influenza virus is recognized by toll-like receptor (TLR) 7 and retinoic acid-inducible gene-I (RIG-I)[30,31]. The signaling pathways of TLR7 and RIG-I induce the production of type I IFNs and activate antiviral host responses[32]. However, IAV can escape from the innate immune response by using NS1 to interfere with the RIG-I signaling pathway (Table) [3337]. A recent study revealed that NS1 inhibits the function of tripartite motif (TRIM) 25 in the ubiquitination of RIG-I, which is an essential step in the type I IFN response[38]. Because the NS1 of the 1918 virus efficiently suppressed the expression of IFN-regulated genes, NS1 is believed to contribute to pathogenesis by controlling antiviral innate immune responses[39]. NS1 also binds to protein kinase R (PKR), a well-known antiviral protein. The binding of NS1 and PKR inhibits the antiviral function of PKR by down-regulating the translation of the viral mRNA, which is mediated by phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α)[40]. The NS1 amino acids at positions 123–127 are essential for PKR binding and a mutation of these residues affects pathogenicity in mice [35,36]. In addition to the type I IFN response, RIG-I and TLR7 induce the production of inflammatory proteins mediated by NF-κB activation[41]. Therefore, influenza virus infection induces the upregulation of several inflammatory cytokines and chemokines, such as IL-1β, IL-6, IL-8, TNFα, CCL2 (MCP-1), CCL3 (MIP-1α), CCL5 (RANTES), and CXCL10 (IP-10)[42]. Among them, CCL2 recruits macrophages to the virus-infected lung[43]. CCR2-(a receptor of CCL2) positive macrophages express tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), which induces alveolar epithelial cell apoptosis[44]. CCR2 deficiency in IAV-infected mice inhibits macrophage migration to the lung and increases survival rates[45]. Thus, macrophages that migrate to influenza-infected lung play a pathogenic role in pulmonary inflammation. In lung infected with highly pathogenic IAV, such as the 1918 virus or avian H5N1 viruses, sizeable numbers of neutrophils are also recruited to the inflamed lung[42]. This suggests that neutrophils also contribute to IAV pathogenesis; however, the role of neutrophils in IAV infection remains unclear because neutrophils limit virus replication and lung inflammation[46].

To maintain homeostasis during IAV infection, a regulatory immune system exists in the lung. CD200, a cell surface glycoprotein, is expressed on respiratory epithelial cells, and the CD200 receptor (CD200R) is expressed by myeloid cells, including macrophages, dendritic cells, and granulocytes[47,48]. In the uninfected state, CD200R expression on alveolar macrophages is maintained by IL-10 and TGFβ[49]. However, in lungs infected with IAV, CD200R expression is upregulated on these macrophages[49]. Experiments using CD200−/− mice revealed that CD200-mediated CD200R activation on lung macrophages inhibits the recruitment of immune cells, the production of proinflammatory cytokines, such as TNFα and IL-6, and inflammation in the IAV-infected lung[49]. Since TNFα and IL-6 increase CD200R expression on alveolar macrophages, there is negative feedback of inflammatory responses controlled by CD200R. CD200R+ alveolar macrophages thus have an important role in resolving inflammation in IAV-infected lung[49]. IL-10 is known to be a major regulatory cytokine that inhibits inflammatory responses[50]. IL-10-producing effector CD8 T cells are a major source of IL-10 in acute lung infection with IAV, and IL-10 produced by this CD8 T cell subset controls the excessive lung inflammation caused by IAV infection[51]. Furthermore, a recent study shows that IL-2, produced by CD4 T cells, and IL-27 have a synergistic role in the generation of IL-10-producing CD8 T cells[52]. IL-27, a member of the IL-12 family, is produced by macrophages, dendritic cells, and neutrophils[5355]. Thus, multiple cell-cell interactions regulate the immune response to IAV infection and maintain the homeostasis of the respiratory immune system (Figure 1).

Figure
A model depicting the multi-cellular interactions that regulate the inflammatory response during influenza virus infection. Influenza virus infection induces innate immune responses mediated by the TLR7 and RIG-I signaling pathways. Pulmonary macrophages ...

As discussed above, the innate immune response is indispensable for the protection of the host against IAV infection. Therefore, a lack of type 1 IFN results in an increase in virus dissemination and susceptibility to IAV infection, including H5N1 viruses [56,57]. However, the unregulated response of proinflammatory cytokines and chemokines induced by TLR signaling can harm rather than protect respiratory organs. For example, virus clearance in the lung was better in CD200−/− mice than in wild-type mice because CD200−/− mice activated their innate response via their alveolar macrophages[49]. However, this uncontrolled innate immune response led to severe lung inflammation in the CD200−/− mice[49]. Therefore, innate immunity is like a two-edged sword with two distinct roles in the pathogenesis of IAV infection. In contrast, adaptive immunity, which involves viral antigen-specific antibodies and cytotoxic T lymphocyte activity, efficiently eliminates virus-infected cells and enables hosts to recover from viral infectious diseases. Immunodeficiency of B cells or T cells (RAG−/− mice) results in high susceptibility to IAV infection[58]. Therefore, adaptive immunity provides essential protection from IAV infection and effective prevention of repeat infection. Yet, a surprising number of severe diseases in middle-aged adults, who generally had normal immune function, were reported during the 2009 (H1N1) pandemic[59]. Interestingly, low affinity antibodies in sera and immune complexes with low affinity antibodies were detected in individuals with severe pneumonia[60]. Furthermore, examination of lung sections from fatal cases of influenza A(H1N1)2009 infection revealed C4d deposition around the bronchi, indicating that an abnormal adaptive immune response may have contributed to the influenza pathogenesis.

Summary

The pathogenicity of influenza virus is dependent on the function of viral proteins and on host immune responses, including innate and acquired immunity, indicating the importance of both viral factors and the host immune system for influenza pathogenesis. A recent report showed that commensal microflora is important for the appropriate activation of pulmonary dendritic cells to induce influenza virus-specific immune responses[61]. Therefore, the environmental conditions that surround the host and virus, including commensal microflora, must also be considered as factors contributing to viral pathogenesis. Despite extensive research on IAV pathogenesis, we still do not have effective therapies for IAV infection, except for antiviral drugs. Moreover, the emergence of drug-resistant viruses jeopardizes the effectiveness of these agents (Table)[6264]. Controlling excessive host responses could serve as the basis of new strategies for the treatment of severe cases of IAV infection. A comprehensive understanding of how virus pathogenesis is mediated by various factors should assist in the development of new therapies to combat highly pathogenic IAV infections.

Highlights

The pathogenicity of influenza A virus (IVA) depends on interactions between virus and host proteins. Among the viral proteins, HA is responsible for determining the target animal species, organs, and cell-types for IVA. The NS1 protein of IVA inhibits IFN-I production in virus-infected cells by interfering with the RIG-I signaling pathway. Pulmonary macrophages induce epithelial cell apoptosis, which is mediated by the TRAIL-DR6 interaction in the IVA-infected lung.

Acknowledgements

We thank Susan Watson for editing the manuscript. The authors were supported by the Exploratory Research for Advanced Technology (ERATO) program of the Japan Science and Technology Agency (JST), by a grant-in-aid for Specially Promoted Research from the Ministries of Education, Culture, Sport, Science, and Technology, by a grant-in-aid from Health, Labor, and Welfare of Japan, by a Contract Research Fund for the Program of Founding Research Centers for Emerging and Reemerging infectious Diseases, and by National Institute of Allergy and Infectious Disease Public Health Service research grants.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as

• of special interest

•• of outstanding interest

1. Wright PFNG, Kawaoka Y. Orthomyxoviruses. Fields Virology. 2007:1691–1740.
2. Shinya K, Makino A, Kawaoka Y. Emerging and reemerging influenza virus infections. Vet Pathol. 2010;47:53–57. [PubMed]
3. Horimoto T, Kawaoka Y. Influenza: lessons from past pandemics, warnings from current incidents. Nat Rev Microbiol. 2005;3:591–600. [PubMed]
4. Taubenberger JK, Reid AH, Janczewski TA, Fanning TG. Integrating historical, clinical and molecular genetic data in order to explain the origin and virulence of the 1918 Spanish influenza virus. Philos Trans R Soc Lond B Biol Sci. 2001;356:1829–1839. [PMC free article] [PubMed]
5. Morens DM, Taubenberger JK, Fauci AS. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: Implications for pandemic influenza preparedness. Journal of Infectious Diseases. 2008;198:962–970. [PMC free article] [PubMed]
6. Neumann G, Watanabe T, Ito H, Watanabe S, Goto H, Gao P, Hughes M, Perez DR, Donis R, Hoffmann E, et al. Generation of influenza A viruses entirely from cloned cDNAs. Proc Natl Acad Sci U S A. 1999;96:9345–9350. [PMC free article] [PubMed]
7. Kobasa D, Jones SM, Shinya K, Kash JC, Copps J, Ebihara H, Hatta Y, Kim JH, Halfmann P, Hatta M, et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature. 2007;445:319–323. [PubMed]
8. Koerner I, Kochs G, Kalinke U, Weiss S, Staeheli P. Protective role of beta interferon in host defense against influenza A virus. J Virol. 2007;81:2025–2030. [PMC free article] [PubMed]
9. de Wit E, Munster VJ, van Riel D, Beyer WE, Rimmelzwaan GF, Kuiken T, Osterhaus AD, Fouchier RA. Molecular determinants of adaptation of highly pathogenic avian influenza H7N7 viruses to efficient replication in the human host. J Virol. 2010;84:1597–1606. [PMC free article] [PubMed]
10. Tumpey TM, Maines TR, Van Hoeven N, Glaser L, Solorzano A, Pappas C, Cox NJ, Swayne DE, Palese P, Katz JM, et al. A two-amino acid change in the hemagglutinin of the 1918 influenza virus abolishes transmission. Science. 2007;315:655–659. [PubMed]
11. Liu Y, Childs RA, Matrosovich T, Wharton S, Palma AS, Chai W, Daniels R, Gregory V, Uhlendorff J, Kiso M, et al. Altered receptor specificity and cell tropism of D222G hemagglutinin mutants isolated from fatal cases of pandemic A(H1N1) 2009 influenza virus. J Virol. 2010;84:12069–12074. [PMC free article] [PubMed]
12. Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y. Avian flu: influenza virus receptors in the human airway. Nature. 2006;440:435–436. [PubMed]
13. Korteweg C, Gu J. Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. Am J Pathol. 2008;172:1155–1170. [PMC free article] [PubMed]
14. Yamada S, Suzuki Y, Suzuki T, Le MQ, Nidom CA, Sakai-Tagawa Y, Muramoto Y, Ito M, Kiso M, Horimoto T, et al. Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors. Nature. 2006;444:378–382. [PubMed]
15. Mak GC, Au KW, Tai LS, Chuang KC, Cheng KC, Shiu TC, Lim W. Association of D222G substitution in haemagglutinin of 2009 pandemic influenza A (H1N1) with severe disease. Euro Surveill. 2010;15 [PubMed]
16. Klenk HD, Garten W. Host cell proteases controlling virus pathogenicity. Trends in Microbiology. 1994;2:39–43. [PubMed]
17. Horimoto T, Nakayama K, Smeekens SP, Kawaoka Y. Proprotein-processing endoproteases PC6 and furin both activate hemagglutinin of virulent avian influenza viruses. J Virol. 1994;68:6074–6078. [PMC free article] [PubMed]
18. Bussey KA, Bousse TL, Desmet EA, Kim B, Takimoto T. PB2 residue 271 plays a key role in enhanced polymerase activity of influenza A viruses in mammalian host cells. J Virol. 2010;84:4395–4406. [PMC free article] [PubMed]
19. Hatta M, Hatta Y, Kim JH, Watanabe S, Shinya K, Nguyen T, Lien PS, Le QM, Kawaoka Y. Growth of H5N1 influenza A viruses in the upper respiratory tracts of mice. PLoS Pathog. 2007;3:1374–1379. [PMC free article] [PubMed]
20. Munster VJ, de Wit E, van Riel D, Beyer WE, Rimmelzwaan GF, Osterhaus AD, Kuiken T, Fouchier RA. The molecular basis of the pathogenicity of the Dutch highly pathogenic human influenza A H7N7 viruses. J Infect Dis. 2007;196:258–265. [PubMed]
21. Li Z, Chen H, Jiao P, Deng G, Tian G, Li Y, Hoffmann E, Webster RG, Matsuoka Y, Yu K. Molecular basis of replication of duck H5N1 influenza viruses in a mammalian mouse model. J Virol. 2005;79:12058–12064. [PMC free article] [PubMed]
22. Song MS, Pascua PN, Lee JH, Baek YH, Lee OJ, Kim CJ, Kim H, Webby RJ, Webster RG, Choi YK. The polymerase acidic protein gene of influenza a virus contributes to pathogenicity in a mouse model. J Virol. 2009;83:12325–12335. [PMC free article] [PubMed]
23. Govorkova EA, Rehg JE, Krauss S, Yen HL, Guan Y, Peiris M, Nguyen TD, Hanh TH, Puthavathana P, Long HT, et al. Lethality to ferrets of H5N1 influenza viruses isolated from humans and poultry in 2004. J Virol. 2005;79:2191–2198. [PMC free article] [PubMed]
24. Salomon R, Franks J, Govorkova EA, Ilyushina NA, Yen HL, Hulse-Post DJ, Humberd J, Trichet M, Rehg JE, Webby RJ, et al. The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04. J Exp Med. 2006;203:689–697. [PMC free article] [PubMed]
25. Watanabe T, Watanabe S, Shinya K, Kim JH, Hatta M, Kawaoka Y. Viral RNA polymerase complex promotes optimal growth of 1918 virus in the lower respiratory tract of ferrets. Proc Natl Acad Sci U S A. 2009;106:588–592. [PubMed]
• This study demonstrates that the viral RNA polymerase complex (PA, PB1, PB2, and NP) is responsible for the pathogenesis of the 1918 pandemic virus in ferrets.
26. Chen W, Calvo PA, Malide D, Gibbs J, Schubert U, Bacik I, Basta S, O'Neill R, Schickli J, Palese P, et al. A novel influenza A virus mitochondrial protein that induces cell death. Nat Med. 2001;7:1306–1312. [PubMed]
27. Zamarin D, Garcia-Sastre A, Xiao X, Wang R, Palese P. Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog. 2005;1 e4. [PMC free article] [PubMed]
28. Conenello GM, Zamarin D, Perrone LA, Tumpey T, Palese P. A single mutation in the PB1-F2 of H5N1 (HK/97) and 1918 influenza A viruses contributes to increased virulence. PLoS Pathog. 2007;3:1414–1421. [PMC free article] [PubMed]
29. Pappas C, Aguilar PV, Basler CF, Solorzano A, Zeng H, Perrone LA, Palese P, Garcia-Sastre A, Katz JM, Tumpey TM. Single gene reassortants identify a critical role for PB1, HA, and NA in the high virulence of the 1918 pandemic influenza virus. Proc Natl Acad Sci U S A. 2008;105:3064–3069. [PMC free article] [PubMed]
30. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science. 2004;303:1529–1531. [PubMed]
31. Pichlmair A, Schulz O, Tan CP, Naslund TI, Liljestrom P, Weber F, Reis e Sousa C. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates. Science. 2006;314:997–1001. [PubMed]
32. Kumagai Y, Takeuchi O, Akira S. Pathogen recognition by innate receptors. J Infect Chemother. 2008;14:86–92. [PubMed]
33. Jiao P, Tian G, Li Y, Deng G, Jiang Y, Liu C, Liu W, Bu Z, Kawaoka Y, Chen H. A single-amino-acid substitution in the NS1 protein changes the pathogenicity of H5N1 avian influenza viruses in mice. J Virol. 2008;82:1146–1154. [PMC free article] [PubMed]
34. Zhou H, Zhu J, Tu J, Zou W, Hu Y, Yu Z, Yin W, Li Y, Zhang A, Wu Y, et al. Effect on virulence and pathogenicity of H5N1 influenza A virus through truncations of NS1 eIF4GI binding domain. J Infect Dis. 2010;202:1338–1346. [PubMed]
35. Pu J, Wang J, Zhang Y, Fu G, Bi Y, Sun Y, Liu J. Synergism of co-mutation of two amino acid residues in NS1 protein increases the pathogenicity of influenza virus in mice. Virus Res. 2010;151:200–204. [PubMed]
36. Min JY, Li S, Sen GC, Krug RM. A site on the influenza A virus NS1 protein mediates both inhibition of PKR activation and temporal regulation of viral RNA synthesis. Virology. 2007;363:236–243. [PubMed]
37. Seo SH, Hoffmann E, Webster RG. Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nat Med. 2002;8:950–954. [PubMed]
38. Gack MU, Albrecht RA, Urano T, Inn KS, Huang IC, Carnero E, Farzan M, Inoue S, Jung JU, Garcia-Sastre A. Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I. Cell Host Microbe. 2009;5:439–449. [PubMed]
•• This paper reveals the molecular mechanism by which the NS1 protein blocks the RIG-I signaling pathway. This was the first paper to show that a direct interaction between NS1 and TRIM25 participates in the inhibition of the antiviral IFN response.
39. Geiss GK, Salvatore M, Tumpey TM, Carter VS, Wang X, Basler CF, Taubenberger JK, Bumgarner RE, Palese P, Katze MG, et al. Cellular transcriptional profiling in influenza A virus-infected lung epithelial cells: the role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza. Proc Natl Acad Sci U S A. 2002;99:10736–10741. [PMC free article] [PubMed]
40. Li S, Min JY, Krug RM, Sen GC. Binding of the influenza A virus NS1 protein to PKR mediates the inhibition of its activation by either PACT or double-stranded RNA. Virology. 2006;349:13–21. [PubMed]
41. Kawai T, Akira S. Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci. 2008;1143:1–20. [PubMed]
42. Perrone LA, Plowden JK, Garcia-Sastre A, Katz JM, Tumpey TM. H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog. 2008;4 e1000115. [PMC free article] [PubMed]
43. Lin KL, Suzuki Y, Nakano H, Ramsburg E, Gunn MD. CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality. J Immunol. 2008;180:2562–2572. [PubMed]
44. Herold S, Steinmueller M, von Wulffen W, Cakarova L, Pinto R, Pleschka S, Mack M, Kuziel WA, Corazza N, Brunner T, et al. Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand. J Exp Med. 2008;205:3065–3077. [PMC free article] [PubMed]
45. Dawson TC, Beck MA, Kuziel WA, Henderson F, Maeda N. Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus. Am J Pathol. 2000;156:1951–1959. [PMC free article] [PubMed]
46. Tate MD, Ioannidis LJ, Croker B, Brown LE, Brooks AG, Reading PC. The role of neutrophils during mild and severe influenza virus infections of mice. PLoS One. 2011;6 e17618. [PMC free article] [PubMed]
• By using a mAb that can deplete neutrophils specifically in mice, the authors of this study showed that neutrophils have a protective role in the lung of influenza virus-infected mice.
47. Wright GJ, Cherwinski H, Foster-Cuevas M, Brooke G, Puklavec MJ, Bigler M, Song Y, Jenmalm M, Gorman D, McClanahan T, et al. Characterization of the CD200 receptor family in mice and humans and their interactions with CD200. J Immunol. 2003;171:3034–3046. [PubMed]
48. Wright GJ, Puklavec MJ, Willis AC, Hoek RM, Sedgwick JD, Brown MH, Barclay AN. Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function. Immunity. 2000;13:233–242. [PubMed]
49. Snelgrove RJ, Goulding J, Didierlaurent AM, Lyonga D, Vekaria S, Edwards L, Gwyer E, Sedgwick JD, Barclay AN, Hussell T. A critical function for CD200 in lung immune homeostasis and the severity of influenza infection. Nat Immunol. 2008;9:1074–1083. [PubMed]
50. Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol. 2008;180:5771–5777. [PubMed]
51. Sun J, Madan R, Karp CL, Braciale TJ. Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nat Med. 2009;15:277–284. [PubMed]
•• See annotation to Ref. [52••]
52. Sun J, Dodd H, Moser EK, Sharma R, Braciale TJ. CD4+ T cell help and innate-derived IL-27 induce Blimp-1-dependent IL-10 production by antiviral CTLs. Nat Immunol. 2011;12:327–334. [PubMed]
•• This sudy, with Ref. [51••], demonstrates that CD8 effector T cells mainly produce IL-10 to inhibit inflammation in lungs infected with influenza virus and shows the cellular and molecular mechanisms of the development of IL-10-producing CD8 effector cells.
53. Wirtz S, Becker C, Fantini MC, Nieuwenhuis EE, Tubbe I, Galle PR, Schild HJ, Birkenbach M, Blumberg RS, Neurath MF. EBV-induced gene 3 transcription is induced by TLR signaling in primary dendritic cells via NF-kappa B activation. J Immunol. 2005;174:2814–2824. [PubMed]
54. Liu J, Guan X, Ma X. Regulation of IL-27 p28 gene expression in macrophages through MyD88- and interferon-gamma-mediated pathways. J Exp Med. 2007;204:141–152. [PMC free article] [PubMed]
55. Wirtz S, Tubbe I, Galle PR, Schild HJ, Birkenbach M, Blumberg RS, Neurath MF. Protection from lethal septic peritonitis by neutralizing the biological function of interleukin 27. J Exp Med. 2006;203:1875–1881. [PMC free article] [PubMed]
56. Szretter KJ, Gangappa S, Belser JA, Zeng H, Chen H, Matsuoka Y, Sambhara S, Swayne DE, Tumpey TM, Katz JM. Early control of H5N1 influenza virus replication by the type I interferon response in mice. J Virol. 2009;83:5825–5834. [PMC free article] [PubMed]
57. Garcia-Sastre A, Durbin RK, Zheng H, Palese P, Gertner R, Levy DE, Durbin JE. The role of interferon in influenza virus tissue tropism. J Virol. 1998;72:8550–8558. [PMC free article] [PubMed]
58. Bot A, Reichlin A, Isobe H, Bot S, Schulman J, Yokoyama WM, Bona CA. Cellular mechanisms involved in protection and recovery from influenza virus infection in immunodeficient mice. J Virol. 1996;70:5668–5672. [PMC free article] [PubMed]
59. Chowell G, Bertozzi SM, Colchero MA, Lopez-Gatell H, Alpuche-Aranda C, Hernandez M, Miller MA. Severe respiratory disease concurrent with the circulation of H1N1 influenza. N Engl J Med. 2009;361:674–679. [PubMed]
60. Monsalvo AC, Batalle JP, Lopez MF, Krause JC, Klemenc J, Hernandez JZ, Maskin B, Bugna J, Rubinstein C, Aguilar L, et al. Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes. Nat Med. 2011;17:195–199. [PubMed]
•• This is the first paper to suggest that C4d depositon mediated by immune complexes in the lung is involved in the pathogenicity of influenza virus in human cases of influenza A(H1N1)2009.
61. Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, Iwasaki A. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci U S A. 2011;108:5354–5359. [PubMed]
•• This study shows that intestinal microflora constitutively activate pulmonary dendritic cells. This preactivation of dendritic cells is important for the induction of antiviral immune responses when influenza viruses invade the lung.
62. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, Hayden FG, Sugaya N, Kawaoka Y. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet. 2004;364:759–765. [PubMed]
63. Herlocher ML, Carr J, Ives J, Elias S, Truscon R, Roberts N, Monto AS. Influenza virus carrying an R292K mutation in the neuraminidase gene is not transmitted in ferrets. Antiviral Res. 2002;54:99–111. [PubMed]
64. Le QM, Kiso M, Someya K, Sakai YT, Nguyen TH, Nguyen KH, Pham ND, Ngyen HH, Yamada S, Muramoto Y, et al. Avian flu: isolation of drug-resistant H5N1 virus. Nature. 2005;437:1108. [PubMed]

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...