Browsing by Subject "Influenza A Virus, H3N2 Subtype"
Now showing 1 - 8 of 8
- Results Per Page
- Sort Options
Item Open Access A crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection.(Nature communications, 2018-10-24) Fourati, Slim; Talla, Aarthi; Mahmoudian, Mehrad; Burkhart, Joshua G; Klén, Riku; Henao, Ricardo; Yu, Thomas; Aydın, Zafer; Yeung, Ka Yee; Ahsen, Mehmet Eren; Almugbel, Reem; Jahandideh, Samad; Liang, Xiao; Nordling, Torbjörn EM; Shiga, Motoki; Stanescu, Ana; Vogel, Robert; Respiratory Viral DREAM Challenge Consortium; Pandey, Gaurav; Chiu, Christopher; McClain, Micah T; Woods, Christopher W; Ginsburg, Geoffrey S; Elo, Laura L; Tsalik, Ephraim L; Mangravite, Lara M; Sieberts, Solveig KThe response to respiratory viruses varies substantially between individuals, and there are currently no known molecular predictors from the early stages of infection. Here we conduct a community-based analysis to determine whether pre- or early post-exposure molecular factors could predict physiologic responses to viral exposure. Using peripheral blood gene expression profiles collected from healthy subjects prior to exposure to one of four respiratory viruses (H1N1, H3N2, Rhinovirus, and RSV), as well as up to 24 h following exposure, we find that it is possible to construct models predictive of symptomatic response using profiles even prior to viral exposure. Analysis of predictive gene features reveal little overlap among models; however, in aggregate, these genes are enriched for common pathways. Heme metabolism, the most significantly enriched pathway, is associated with a higher risk of developing symptoms following viral exposure. This study demonstrates that pre-exposure molecular predictors can be identified and improves our understanding of the mechanisms of response to respiratory viruses.Item Open Access A host transcriptional signature for presymptomatic detection of infection in humans exposed to influenza H1N1 or H3N2.(PLoS One, 2013) Woods, Christopher W; McClain, Micah T; Chen, Minhua; Zaas, Aimee K; Nicholson, Bradly P; Varkey, Jay; Veldman, Timothy; Kingsmore, Stephen F; Kingsmore, Stephen F; Huang, Yongsheng; Lambkin-Williams, Robert; Gilbert, Anthony G; Hero, Alfred O; Ramsburg, Elizabeth; Glickman, Seth; Lucas, Joseph E; Carin, Lawrence; Ginsburg, Geoffrey SThere is great potential for host-based gene expression analysis to impact the early diagnosis of infectious diseases. In particular, the influenza pandemic of 2009 highlighted the challenges and limitations of traditional pathogen-based testing for suspected upper respiratory viral infection. We inoculated human volunteers with either influenza A (A/Brisbane/59/2007 (H1N1) or A/Wisconsin/67/2005 (H3N2)), and assayed the peripheral blood transcriptome every 8 hours for 7 days. Of 41 inoculated volunteers, 18 (44%) developed symptomatic infection. Using unbiased sparse latent factor regression analysis, we generated a gene signature (or factor) for symptomatic influenza capable of detecting 94% of infected cases. This gene signature is detectable as early as 29 hours post-exposure and achieves maximal accuracy on average 43 hours (p = 0.003, H1N1) and 38 hours (p-value = 0.005, H3N2) before peak clinical symptoms. In order to test the relevance of these findings in naturally acquired disease, a composite influenza A signature built from these challenge studies was applied to Emergency Department patients where it discriminates between swine-origin influenza A/H1N1 (2009) infected and non-infected individuals with 92% accuracy. The host genomic response to Influenza infection is robust and may provide the means for detection before typical clinical symptoms are apparent.Item Open Access Gene Expression Profiles Link Respiratory Viral Infection, Platelet Response to Aspirin, and Acute Myocardial Infarction.(PLoS One, 2015) Rose, Jason J; Voora, Deepak; Cyr, Derek D; Lucas, Joseph E; Zaas, Aimee K; Woods, Christopher W; Newby, L Kristin; Kraus, William E; Ginsburg, Geoffrey SBACKGROUND: Influenza infection is associated with myocardial infarction (MI), suggesting that respiratory viral infection may induce biologic pathways that contribute to MI. We tested the hypotheses that 1) a validated blood gene expression signature of respiratory viral infection (viral GES) was associated with MI and 2) respiratory viral exposure changes levels of a validated platelet gene expression signature (platelet GES) of platelet function in response to aspirin that is associated with MI. METHODS: A previously defined viral GES was projected into blood RNA data from 594 patients undergoing elective cardiac catheterization and used to classify patients as having evidence of viral infection or not and tested for association with acute MI using logistic regression. A previously defined platelet GES was projected into blood RNA data from 81 healthy subjects before and after exposure to four respiratory viruses: Respiratory Syncytial Virus (RSV) (n=20), Human Rhinovirus (HRV) (n=20), Influenza A virus subtype H1N1 (H1N1) (n=24), Influenza A Virus subtype H3N2 (H3N2) (n=17). We tested for the change in platelet GES with viral exposure using linear mixed-effects regression and by symptom status. RESULTS: In the catheterization cohort, 32 patients had evidence of viral infection based upon the viral GES, of which 25% (8/32) had MI versus 12.2% (69/567) among those without evidence of viral infection (OR 2.3; CI [1.03-5.5], p=0.04). In the infection cohorts, only H1N1 exposure increased platelet GES over time (time course p-value = 1e-04). CONCLUSIONS: A viral GES of non-specific, respiratory viral infection was associated with acute MI; 18% of the top 49 genes in the viral GES are involved with hemostasis and/or platelet aggregation. Separately, H1N1 exposure, but not exposure to other respiratory viruses, increased a platelet GES previously shown to be associated with MI. Together, these results highlight specific genes and pathways that link viral infection, platelet activation, and MI especially in the case of H1N1 influenza infection.Item Open Access H3N2 influenza infection elicits more cross-reactive and less clonally expanded anti-hemagglutinin antibodies than influenza vaccination.(PloS one, 2011-01) Moody, M Anthony; Zhang, Ruijun; Walter, Emmanuel B; Woods, Christopher W; Ginsburg, Geoffrey S; McClain, Micah T; Denny, Thomas N; Chen, Xi; Munshaw, Supriya; Marshall, Dawn J; Whitesides, John F; Drinker, Mark S; Amos, Joshua D; Gurley, Thaddeus C; Eudailey, Joshua A; Foulger, Andrew; DeRosa, Katherine R; Parks, Robert; Meyerhoff, R Ryan; Yu, Jae-Sung; Kozink, Daniel M; Barefoot, Brice E; Ramsburg, Elizabeth A; Khurana, Surender; Golding, Hana; Vandergrift, Nathan A; Alam, S Munir; Tomaras, Georgia D; Kepler, Thomas B; Kelsoe, Garnett; Liao, Hua-Xin; Haynes, Barton FDuring the recent H1N1 influenza pandemic, excess morbidity and mortality was seen in young but not older adults suggesting that prior infection with influenza strains may have protected older subjects. In contrast, a history of recent seasonal trivalent vaccine in younger adults was not associated with protection.To study hemagglutinin (HA) antibody responses in influenza immunization and infection, we have studied the day 7 plasma cell repertoires of subjects immunized with seasonal trivalent inactivated influenza vaccine (TIV) and compared them to the plasma cell repertoires of subjects experimentally infected (EI) with influenza H3N2 A/Wisconsin/67/2005. The majority of circulating plasma cells after TIV produced influenza-specific antibodies, while most plasma cells after EI produced antibodies that did not react with influenza HA. While anti-HA antibodies from TIV subjects were primarily reactive with single or few HA strains, anti-HA antibodies from EI subjects were isolated that reacted with multiple HA strains. Plasma cell-derived anti-HA antibodies from TIV subjects showed more evidence of clonal expansion compared with antibodies from EI subjects. From an H3N2-infected subject, we isolated a 4-member clonal lineage of broadly cross-reactive antibodies that bound to multiple HA subtypes and neutralized both H1N1 and H3N2 viruses. This broad reactivity was not detected in post-infection plasma suggesting this broadly reactive clonal lineage was not immunodominant in this subject.The presence of broadly reactive subdominant antibody responses in some EI subjects suggests that improved vaccine designs that make broadly reactive antibody responses immunodominant could protect against novel influenza strains.Item Open Access Nasopharyngeal Protein Biomarkers of Acute Respiratory Virus Infection.(EBioMedicine, 2017-03) Burke, Thomas W; Henao, Ricardo; Soderblom, Erik; Tsalik, Ephraim L; Thompson, J Will; McClain, Micah T; Nichols, Marshall; Nicholson, Bradly P; Veldman, Timothy; Lucas, Joseph E; Moseley, M Arthur; Turner, Ronald B; Lambkin-Williams, Robert; Hero, Alfred O; Woods, Christopher W; Ginsburg, Geoffrey SInfection of respiratory mucosa with viral pathogens triggers complex immunologic events in the affected host. We sought to characterize this response through proteomic analysis of nasopharyngeal lavage in human subjects experimentally challenged with influenza A/H3N2 or human rhinovirus, and to develop targeted assays measuring peptides involved in this host response allowing classification of acute respiratory virus infection. Unbiased proteomic discovery analysis identified 3285 peptides corresponding to 438 unique proteins, and revealed that infection with H3N2 induces significant alterations in protein expression. These include proteins involved in acute inflammatory response, innate immune response, and the complement cascade. These data provide insights into the nature of the biological response to viral infection of the upper respiratory tract, and the proteins that are dysregulated by viral infection form the basis of signature that accurately classifies the infected state. Verification of this signature using targeted mass spectrometry in independent cohorts of subjects challenged with influenza or rhinovirus demonstrates that it performs with high accuracy (0.8623 AUROC, 75% TPR, 97.46% TNR). With further development as a clinical diagnostic, this signature may have utility in rapid screening for emerging infections, avoidance of inappropriate antibacterial therapy, and more rapid implementation of appropriate therapeutic and public health strategies.Item Open Access Phylodynamic inference and model assessment with approximate bayesian computation: influenza as a case study.(PLoS Comput Biol, 2012) Ratmann, O; Donker, G; Meijer, A; Fraser, C; Koelle, KA key priority in infectious disease research is to understand the ecological and evolutionary drivers of viral diseases from data on disease incidence as well as viral genetic and antigenic variation. We propose using a simulation-based, Bayesian method known as Approximate Bayesian Computation (ABC) to fit and assess phylodynamic models that simulate pathogen evolution and ecology against summaries of these data. We illustrate the versatility of the method by analyzing two spatial models describing the phylodynamics of interpandemic human influenza virus subtype A(H3N2). The first model captures antigenic drift phenomenologically with continuously waning immunity, and the second epochal evolution model describes the replacement of major, relatively long-lived antigenic clusters. Combining features of long-term surveillance data from The Netherlands with features of influenza A (H3N2) hemagglutinin gene sequences sampled in northern Europe, key phylodynamic parameters can be estimated with ABC. Goodness-of-fit analyses reveal that the irregularity in interannual incidence and H3N2's ladder-like hemagglutinin phylogeny are quantitatively only reproduced under the epochal evolution model within a spatial context. However, the concomitant incidence dynamics result in a very large reproductive number and are not consistent with empirical estimates of H3N2's population level attack rate. These results demonstrate that the interactions between the evolutionary and ecological processes impose multiple quantitative constraints on the phylodynamic trajectories of influenza A(H3N2), so that sequence and surveillance data can be used synergistically. ABC, one of several data synthesis approaches, can easily interface a broad class of phylodynamic models with various types of data but requires careful calibration of the summaries and tolerance parameters.Item Open Access Temporal dynamics of host molecular responses differentiate symptomatic and asymptomatic influenza a infection.(PLoS Genet, 2011-08) Huang, Yongsheng; Zaas, Aimee K; Rao, Arvind; Dobigeon, Nicolas; Woolf, Peter J; Veldman, Timothy; Øien, N Christine; McClain, Micah T; Varkey, Jay B; Nicholson, Bradley; Carin, Lawrence; Kingsmore, Stephen; Kingsmore, Stephen; Woods, Christopher W; Ginsburg, Geoffrey S; Hero, Alfred OExposure to influenza viruses is necessary, but not sufficient, for healthy human hosts to develop symptomatic illness. The host response is an important determinant of disease progression. In order to delineate host molecular responses that differentiate symptomatic and asymptomatic Influenza A infection, we inoculated 17 healthy adults with live influenza (H3N2/Wisconsin) and examined changes in host peripheral blood gene expression at 16 timepoints over 132 hours. Here we present distinct transcriptional dynamics of host responses unique to asymptomatic and symptomatic infections. We show that symptomatic hosts invoke, simultaneously, multiple pattern recognition receptors-mediated antiviral and inflammatory responses that may relate to virus-induced oxidative stress. In contrast, asymptomatic subjects tightly regulate these responses and exhibit elevated expression of genes that function in antioxidant responses and cell-mediated responses. We reveal an ab initio molecular signature that strongly correlates to symptomatic clinical disease and biomarkers whose expression patterns best discriminate early from late phases of infection. Our results establish a temporal pattern of host molecular responses that differentiates symptomatic from asymptomatic infections and reveals an asymptomatic host-unique non-passive response signature, suggesting novel putative molecular targets for both prognostic assessment and ameliorative therapeutic intervention in seasonal and pandemic influenza.Item Open Access The impact of host immune status on the within-host and population dynamics of antigenic immune escape.(J R Soc Interface, 2012-10-07) Luo, Shishi; Reed, Michael; Mattingly, Jonathan C; Koelle, KatiaAntigenically evolving pathogens such as influenza viruses are difficult to control owing to their ability to evade host immunity by producing immune escape variants. Experimental studies have repeatedly demonstrated that viral immune escape variants emerge more often from immunized hosts than from naive hosts. This empirical relationship between host immune status and within-host immune escape is not fully understood theoretically, nor has its impact on antigenic evolution at the population level been evaluated. Here, we show that this relationship can be understood as a trade-off between the probability that a new antigenic variant is produced and the level of viraemia it reaches within a host. Scaling up this intra-host level trade-off to a simple population level model, we obtain a distribution for variant persistence times that is consistent with influenza A/H3N2 antigenic variant data. At the within-host level, our results show that target cell limitation, or a functional equivalent, provides a parsimonious explanation for how host immune status drives the generation of immune escape mutants. At the population level, our analysis also offers an alternative explanation for the observed tempo of antigenic evolution, namely that the production rate of immune escape variants is driven by the accumulation of herd immunity. Overall, our results suggest that disease control strategies should be further assessed by considering the impact that increased immunity--through vaccination--has on the production of new antigenic variants.