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Viral transcriptomic analysis of single cell-sorted of DF1 or MDCK cell lines infected with influenza A virus

ABSTRACT: Infection with a single influenza A virus (IAV) is only rarely sufficient to initiate productive infection. Here, we exploit both single cell approaches and whole-animal systems to show that the extent of IAV reliance on multiple infection varies with virus strain and host species. Influenza A/guinea fowl/HK/WF10/99 (H9N2) [GFHK99] virus exhibits strong dependence on collective interactions in mammalian systems. This reliance focuses viral progeny production within coinfected cells and therefore results in frequent genetic exchange through reassortment. In contrast, GFHK99 virus has greatly reduced dependence on multiple infection in avian systems, indicating a role for host factors in viral collective interactions. Genetic mapping implicated the viral polymerase as a major driver of multiple infection dependence. Mechanistically, quantification of incomplete viral genomes showed that their complementation only partly accounts for the observed reliance on coinfection. Indeed, even when all polymerase components are detected in single cell mRNA sequencing, robust polymerase activity of GFHK99 virus in mammalian cells is reliant on multiple infection. In sum, IAV collective interactions not only augment reassortment, but can also overcome species-specific barriers to infection. These findings underscore the importance of virus-virus interactions in IAV infection, evolution and emergence. We used a single-cell sequencing platform (10x Genomics) to elucidate the differential infection rate of an avian influenza A virus on an avian cell line (DF1) and a mammalian (MDCK) cell line. Our work on IAV reassortment has raised new questions about the fundamental strategies that drive influenza virus evolution. Our data indicate that a large majority of influenza virus genomesare incomplete within cells, comprising less than the eight complete segments normally found in a replication competent infectious viral particle. This led us to ask: what underlying mechanisms give rise to incomplete genomes? What constitute an infectious unit? What are the implications for viral diversification, evolution and spread. By addressing these questions, we will advance he field by deepening our understanding how viral infections are initiated and propagated.

ORGANISM(S): Canis lupus familiaris Gallus gallus

PROVIDER: GSE135553 | GEO | 2020/06/16

REPOSITORIES: GEO

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Project description:Miao2010 - Innate and adaptive immune responses to primary Influenza A Virus infection This model is described in the article: Quantifying the early immune response and adaptive immune response kinetics in mice infected with influenza A virus. Miao H, Hollenbaugh JA, Zand MS, Holden-Wiltse J, Mosmann TR, Perelson AS, Wu H, Topham DJ. J. Virol. 2010 Jul; 84(13): 6687-6698 Abstract: Seasonal and pandemic influenza A virus (IAV) continues to be a public health threat. However, we lack a detailed and quantitative understanding of the immune response kinetics to IAV infection and which biological parameters most strongly influence infection outcomes. To address these issues, we use modeling approaches combined with experimental data to quantitatively investigate the innate and adaptive immune responses to primary IAV infection. Mathematical models were developed to describe the dynamic interactions between target (epithelial) cells, influenza virus, cytotoxic T lymphocytes (CTLs), and virus-specific IgG and IgM. IAV and immune kinetic parameters were estimated by fitting models to a large data set obtained from primary H3N2 IAV infection of 340 mice. Prior to a detectable virus-specific immune response (before day 5), the estimated half-life of infected epithelial cells is approximately 1.2 days, and the half-life of free infectious IAV is approximately 4 h. During the adaptive immune response (after day 5), the average half-life of infected epithelial cells is approximately 0.5 days, and the average half-life of free infectious virus is approximately 1.8 min. During the adaptive phase, model fitting confirms that CD8(+) CTLs are crucial for limiting infected cells, while virus-specific IgM regulates free IAV levels. This may imply that CD4 T cells and class-switched IgG antibodies are more relevant for generating IAV-specific memory and preventing future infection via a more rapid secondary immune response. Also, simulation studies were performed to understand the relative contributions of biological parameters to IAV clearance. This study provides a basis to better understand and predict influenza virus immunity. This model is hosted on BioModels Database and identified by: BIOMD0000000546. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Viral transcriptomic analysis of single cell-sorted of DF1 or MDCK cell lines infected with influenza A virus

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