Differential pulmonary transcriptomic profiles in murine lungs infected with low and highly virulent influenza H3N2 viruses reveal dysregulation of TREM1 signaling, cytokines, and chemokines
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Investigating the relationships between critical influenza viral mutations contributing to increased virulence and host expression factors will shed light on the process of severe pathogenesis from the systems biology perspective. We previously generated a mouse-adapted, highly virulent influenza (HVI) virus through serial lung-to-lung passaging of a human influenza H3N2 virus strain that causes low virulent influenza (LVI) in murine lungs. This HVI virus is characterized by enhanced replication kinetics, severe lung injury, and systemic spread to major organs. Our gene microarray investigations compared the host transcriptomic responses of murine lungs to LVI virus and its HVI descendant at 12, 48, and 96 h following infection. More intense expression of genes associated with cytokine activity, type 1 interferon response, and apoptosis was evident in HVI at all time-points. We highlighted dysregulation of the TREM1 signaling pathway (an amplifier of cytokine production) that is likely to be upregulated in infiltrating neutrophils in HVI-infected lungs. The cytokine gene expression changes were corroborated by elevated levels of multiple cytokine and chemokine proteins in the bronchoalveolar lavage fluid of infected mice, especially at 12 h post-infection. Concomitantly, the downregulation of genes that mediate proliferative, developmental, and metabolic processes likely contributed to the lethality of HVI as well as lack of lung repair. Overall, our comparative transcriptomic study provided insights into key host factors that influence the dynamics, pathogenesis, and outcome of severe influenza.
KeywordsInfluenza virulence Severe lung damage Pulmonary transcriptomics TREM1 signaling Cytokine/chemokine dysregulation
Financial support was provided by the National Medical Research Council, Singapore, Microbiology Vaccine Initiative, and Singapore-MIT Alliance. We are grateful to M. C. Phoon and Kelly Lau for technical assistance.
Conflicts of interest
The authors declare no conflicts of interest.
- Baskin CR, Bielefeldt-Ohmann H, Tumpey TM, Sabourin PJ, Long JP, García-Sastre A, Tolnay AE, Albrecht R, Pyles JA, Olson PH, Aicher LD, Rosenzweig ER, Murali-Krishna K, Clark EA, Kotur MS, Fornek JL, Proll S, Palermo RE, Sabourin CL, Katze MG (2009) Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus. Proc Natl Acad Sci USA 106:3455–3460PubMedCrossRefGoogle Scholar
- Bermejo-Martin JF, Ortiz de Lejarazu R, Pumarola T, Rello J, Almansa R, Ramírez P, Martin-Loeches I, Varillas D, Gallegos MC, Serón C, Micheloud D, Gomez JM, Tenorio-Abreu A, Ramos MJ, Molina ML, Huidobro S, Sanchez E, Gordón M, Fernández V, Del Castillo A, Marcos MA, Villanueva B, López CJ, Rodríguez-Domínguez M, Galan JC, Cantón R, Lietor A, Rojo S, Eiros JM, Hinojosa C, Gonzalez I, Torner N, Banner D, Leon A, Cuesta P, Rowe T, Kelvin DJ (2009) Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza. Crit Care 13:R201PubMedCrossRefGoogle Scholar
- Cameron CM, Cameron MJ, Bermejo-Martin JF, Ran L, Xu L, Turner PV, Ran R, Danesh A, Fang Y, Chan PK, Mytle N, Sullivan TJ, Collins TL, Johnson MG, Medina JC, Rowe T, Kelvin DJ (2008) Gene expression analysis of host innate immune responses during lethal H5N1 infection in ferrets. J Virol 82:11308–11317PubMedCrossRefGoogle Scholar
- Chow VT, Tambyah PA, Goh KT (2008) To kill a mocking bird flu? Ann Acad Med 37:451–453Google Scholar
- Cillóniz C, Shinya K, Peng X, Korth MJ, Proll SC, Aicher LD, Carter VS, Chang JH, Kobasa D, Feldmann F, Strong JE, Feldmann H, Kawaoka Y, Katze MG (2009) Lethal influenza virus infection in macaques is associated with early dysregulation of inflammatory related genes. PLoS Pathog 5:e1000604PubMedCrossRefGoogle Scholar
- Gibot S (2006) The therapeutic potential of TREM-1 modulation in the treatment of sepsis and beyond. Curr Opin Invest Drugs 7:438–442Google Scholar
- Kash JC, Basler CF, García-Sastre A, Carter V, Billharz R, Swayne DE, Przygodzki RM, Taubenberger JK, Katze MG, Tumpey TM (2004) Global host immune response: pathogenesis and transcriptional profiling of type A influenza viruses expressing the hemagglutinin and neuraminidase genes from the 1918 pandemic virus. J Virol 78:9499–9511PubMedCrossRefGoogle Scholar
- Kobasa D, Jones SM, Shinya K, Kash JC, Copps J, Ebihara H, Hatta Y, Kim JH, Halfmann P, Hatta M, Feldmann F, Alimonti JB, Fernando L, Li Y, Katze MG, Feldmann H, Kawaoka Y (2007) Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 445:319–323PubMedCrossRefGoogle Scholar
- Louzier V, Raoul W, Leroux A, Branellec D, Caillaud JM, Many H, Levame M, Delclaux C, Adnot S, Maitre B (2004) Adenovirus-mediated fibroblast growth factor 1 expression in the lung induces epithelial cell proliferation: consequences to hyperoxic lung injury in rats. Hum Gene Ther 15:793–804PubMedCrossRefGoogle Scholar
- Tumpey TM, García-Sastre A, Taubenberger JK, Palese P, Swayne DE, Pantin-Jackwood MJ, Schultz-Cherry S, Solórzano A, Van Rooijen N, Katz JM, Basler CF (2005) Pathogenicity of influenza viruses with genes from the 1918 pandemic virus: functional roles of alveolar macrophages and neutrophils in limiting virus replication and mortality in mice. J Virol 79:14933–14944PubMedCrossRefGoogle Scholar
- Zaas AK, Chen M, Varkey J, Veldman T, Hero AO, Lucas J, Huang Y, Turner R, Gilbert A, Lambkin-Williams R, Øien NC, Nicholson B, Kingsmore S, Carin L, Woods CW, Ginsburg GS (2009) Gene expression signatures diagnose influenza and other symptomatic respiratory viral infections in humans. Cell Host Microbe 6:207–217PubMedCrossRefGoogle Scholar