Differential pulmonary transcriptomic profiles in murine lungs infected with low and highly virulent influenza H3N2 viruses reveal dysregulation of TREM1 signaling, cytokines, and chemokines

Ivan, Fransiskus Xaverius; Rajapakse, Jagath C.; Welsch, Roy E.; Rozen, Steve; Narasaraju, Teluguakula; Xiong, Gordon M.; Engelward, Bevin P.; Chow, Vincent T. K.

doi:10.1007/s10142-011-0247-y

Cited by 28 publications

(20 citation statements)

References 47 publications

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“…The numbers of deregulated host genes at 8 hpi for HK-wt (H3N2) in M1 cells were comparable to that published for mouse lungs infected with wt or mouse adapted A/Aichi/2/1968 (H3N2) at 12 hpi with 36 or 22 dysreguated genes respectively [73]. This pattern of host gene regulation was host dependent and was reversed for the F103L and M106I single mutations in the human cells but again the low effect, in this case of the F103L mutation, was dominant in the F103L + M106I combination.…”

Section: Discussionsupporting

confidence: 75%

Influenza A/Hong Kong/156/1997(H5N1) virus NS1 gene mutations F103L and M106I both increase IFN antagonism, virulence and cytoplasmic localization but differ in binding to RIG-I and CPSF30

Dankar

Miranda

Forbes

et al. 2013

Virol J

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BackgroundThe genetic basis for avian to mammalian host switching in influenza A virus is largely unknown. The human A/HK/156/1997 (H5N1) virus that transmitted from poultry possesses NS1 gene mutations F103L + M106I that are virulence determinants in the mouse model of pneumonia; however their individual roles have not been determined. The emergent A/Shanghai/patient1/2013(H7N9)-like viruses also possess these mutations which may contribute to their virulence and ability to switch species.MethodsNS1 mutant viruses were constructed by reverse genetics and site directed mutagenesis on human and mouse-adapted backbones. Mouse infections assessed virulence, virus yield, tissue infection, and IFN induction. NS1 protein properties were assessed for subcellular distribution, IFN antagonism (mouse and human), CPSF30 and RIG-I domain binding, host transcription (microarray); and the natural prevalence of 103L and 106I mutants was assessed.ResultsEach of the F103L and M106I mutations contributes additively to virulence to reduce the lethal dose by >800 and >3,200 fold respectively by mediating alveolar tissue infection with >100 fold increased infectious yields. The 106I NS1 mutant lost CPSF binding but the 103L mutant maintained binding that correlated with an increased general decrease in host gene expression in human but not mouse cells. Each mutation positively modulated the inhibition of IFN induction in mouse cells and activation of the IFN-β promoter in human cells but not in combination in human cells indicating negative epistasis. Each of the F103L and M106I mutations restored a defect in cytoplasmic localization of H5N1 NS1 in mouse cells. Human H1N1 and H3N2 NS1 proteins bound to the CARD, helicase and RD RIG-I domains, whereas the H5N1 NS1 with the same consensus 103F and 106M mutations did not bind these domains, which was totally or partially restored by the M106I or F103L mutations respectively.ConclusionsThe F103L and M106I mutations in the H5N1 NS1 protein each increased IFN antagonism and mediated interstitial pneumonia in mice that was associated with increased cytoplasmic localization and altered host factor binding. These mutations may contribute to the ability of previous HPAI H5N1 and recent LPAI H7N9 and H6N1 (NS1-103L+106M) viruses to switch hosts and cause disease in humans.

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Section: Discussionsupporting

confidence: 75%

Influenza A/Hong Kong/156/1997(H5N1) virus NS1 gene mutations F103L and M106I both increase IFN antagonism, virulence and cytoplasmic localization but differ in binding to RIG-I and CPSF30

Dankar

Miranda

Forbes

et al. 2013

Virol J

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“…Increased inflammatory cytokine expression in whole mouse lung tissue infected with different mouse-adapted pathogenic/virulent IAV subtypes have been described previously using a transcriptomic approach [55, 59–65]. The 2009 pandemic H1N1 virus induced increased expression of CXCL10 , OASL , OAS2 , IFIH1 , USP18 and XAF1 [65].…”

Section: Discussionmentioning

confidence: 86%

“…The 2009 pandemic H1N1 virus induced increased expression of CXCL10 , OASL , OAS2 , IFIH1 , USP18 and XAF1 [65]. Similarly, up-regulated expression of inflammatory cytokines ( CXCL10 , CXCL11 , CXCL9 , CXCL13 , CCL9 , CCL5 , IL-6 , IL1 , IL1A , IL1B , TNF , and TNF-α ) and ISGs ( GBP2 , GBP4 , GTP1 , ISG15 , DdX58 , IFIH1 ) were shown in virulent H3N2/HK31 virus infections [59–61]. In addition, the lung transcriptome of HPAI H5N1 virus infection in susceptible mouse revealed increased expression of inflammatory cytokines ( CCL2 , CXCL2 , and TNF-α , CSF3 ) and interferon responses ( IFN-α , IFN-β , IL28B , IFNA4 , IFNA5 ), which were associated with increased viral load and disease severity [62, 63].…”

Section: Discussionmentioning

confidence: 99%

Systems-based approach to examine the cytokine responses in primary mouse lung macrophages infected with low pathogenic avian Influenza virus circulating in South East Asia

et al. 2017

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BackgroundInfluenza A virus (IAV) is a major public health concern, being responsible for the death of approximately half a million people each year. Zoonotic transmissions of the virus from swine and avian origin have occurred in the past, and can potentially lead to the emgergence of new IAV stains in future pandemics. Pulmonary macrophages have been implicated in disease severity in the lower airway, and understanding the host response of macrophages infected with avian influenza viruses should provide new therapeutic strategies.ResultsWe used a systems-based approach to investigate the transcriptome response of primary murine lung macrophages (PMФ) infected with the mouse-adapted H1N1/WSN virus and low pathogenic avian influenza (LPAI) viruses H5N2 and H5N3. The results showed that the LPAI viruses H5N2 and H5N3 can infect PMФ with similar efficiency to the H1N1/WSN virus. While all viruses induced antiviral responses, the H5N3 virus infection resulted in higher expression levels of cytokines and chemokines associated with inflammatory responses.ConclusionsThe LPAI H5N2 and H5N3 viruses are able to infect murine lung macrophages. However, the H5N3 virus was associated with increased expression of pro-inflammatory mediators. Although the H5N3 virus it is capable of inducing high levels of cytokines that are associated with inflammation, this property is distinct from its inability to efficiently replicate in a mammalian host.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3803-6) contains supplementary material, which is available to authorized users.

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“…By contrast, the pool of genes induced during ΔF2 Nig06 infection is mainly involved in the mounting of an immune response: Trem1, Kng1, Nfatc2ip and Xcr1 are particularly implicated in mediation of inflammation, cytokine induction and leukocyte chemoattraction [37].…”

Section: Resultsmentioning

confidence: 99%

Kinetic Characterization of PB1-F2-Mediated Immunopathology during Highly Pathogenic Avian H5N1 Influenza Virus Infection

et al. 2013

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The PB1-F2 protein encoded by influenza A viruses can contribute to virulence, a feature that is dependent of its sequence polymorphism. Whereas PB1-F2 from some H1N1 viruses were shown to exacerbate the inflammatory response within the airways, the contribution of PB1-F2 to highly pathogenic avian influenza virus (HPAIV) virulence in mammals remains poorly described. Using a H5N1 HPAIV strain isolated from duck and its PB1-F2 knocked-out mutant, we characterized the dynamics of PB1-F2-associated host response in a murine model of lethal pneumonia. The mean time of death was 10 days for the two viruses, allowing us to perform global transcriptomic analyses and detailed histological investigations of the infected lungs at multiple time points. At day 2 post-infection (pi), while no histopathological lesion was observed, PB1-F2 expression resulted in a significant inhibition of cellular pathways involved in macrophage activation and in a transcriptomic signature suggesting that it promotes damage to the epithelial barrier. At day 4 pi, the gene profile associated with PB1-F2 expression revealed dysfunctions in NK cells activity. At day 8 pi, PB1-F2 expression was strongly associated with increased transcription of genes encoding chemokines and cytokines implicated in the recruitment of granulocytes, as well as expression of a number of genes encoding enzymes expressed by neutrophils. These transcriptomic data were fully supported by the histopathological analysis of the mice lungs which evidenced more severe inflammatory lesions and enhanced recruitment of neutrophils in the context of PB1-F2 expression, and thus provided a functional corroboration to the insight obtained in this work. In summary, our study shows that PB1-F2 of H5N1 HPAIV markedly influences the expression of the host transcriptome in a different way than its H1N1 counterparts: H5N1 PB1-F2 first delays the initial immune response but increases the pulmonary inflammatory response during the late stages of infection.

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Differential pulmonary transcriptomic profiles in murine lungs infected with low and highly virulent influenza H3N2 viruses reveal dysregulation of TREM1 signaling, cytokines, and chemokines

Cited by 28 publications

References 47 publications

Influenza A/Hong Kong/156/1997(H5N1) virus NS1 gene mutations F103L and M106I both increase IFN antagonism, virulence and cytoplasmic localization but differ in binding to RIG-I and CPSF30

Influenza A/Hong Kong/156/1997(H5N1) virus NS1 gene mutations F103L and M106I both increase IFN antagonism, virulence and cytoplasmic localization but differ in binding to RIG-I and CPSF30

Systems-based approach to examine the cytokine responses in primary mouse lung macrophages infected with low pathogenic avian Influenza virus circulating in South East Asia

Kinetic Characterization of PB1-F2-Mediated Immunopathology during Highly Pathogenic Avian H5N1 Influenza Virus Infection

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