Infection dynamics and virus-induced apoptosis in cell culture-based influenza vaccine production—Flow cytometry and mathematical modeling

Schulze‐Horsel, J.; Schulze, M.; Agalaridis, Georgios; Genzel, Yvonne; Reichl, Udo

doi:10.1016/j.vaccine.2009.02.027

Cited by 89 publications

(118 citation statements)

References 48 publications

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“…Lastly, the observations that DIP found in natural influenza of chickens (9) can suppress the pathogenic effects of virulent virus (4), the promising role of DIP as an effective prophylactic and therapeutic antiviral agent (11,12) and that isolates of LPAI which contain truncated NS1 genes ameliorate patho- (14,34,39,42), and may affect apoptosis and the dynamics of virus production for vaccines (35) encourage us to study further the relationship of PFP, niCKP, DIP, HAP, IFP, and ISP in order to better understand the role these subpopulations play in the pathogenesis and evolution of influenza virus, the formulation of live-attenuated vaccines, and vaccine production.…”

Section: Influenza Virus Kills Cells By Apoptosis (17 40) a Processmentioning

confidence: 99%

Dynamics of Biologically Active Subpopulations of Influenza Virus: Plaque-Forming, Noninfectious Cell-Killing, and Defective Interfering Particles

Marcus

Ngunjiri

Sekellick

2009

J Virol

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The dynamic changes in the temporal appearance and quantity of a new class of influenza virus, noninfectious cell-killing particles (niCKP), were compared to defective interfering particles (DIP). After a single high-multiplicity passage in MDCK cells of an egg-derived stock that lacked detectable niCKP or DIP, both classes of particles appeared in large numbers (>5 ؋ 10 8 /ml), and the plaque-forming particle (PFP) titer dropped ϳ60-fold. After two additional serial high-multiplicity passages the DIP remained relatively constant, the DIP/niCKP ratio reached 10:1, and the PFP had declined by about 10,000-fold. Together, the niCKP and DIP subpopulations constituted ca. 20% of the total hemagglutinating particle population in which these noninfectious biologically active particles (niBAP) were subsumed. DIP neither killed cells nor interfered with the cell-killing (apoptosis-inducing) activity of niCKP or PFP (infectious CKP), even though they blocked the replication of PFP. Relative to the UV-target of ϳ13,600 nucleotides (nt) for inactivation of PFP, the UV target for niCKP was ϳ2,400 nt, consistent with one of the polymerase subunit genes, and that for DIP was ϳ350 nt, consistent with the small DI-RNA responsible for DIP-mediated interference. Thus, niCKP and DIP are viewed as distinct particles with a propensity to form during infection at high multiplicities. These conditions are postulated to cause aberrations in the temporally regulated replication of virus and its packaging, leading to the production of niBAP. DIP have been implicated in the virulence of influenza virus, but the role of niCKP is yet unknown.

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Section: Influenza Virus Kills Cells By Apoptosis (17 40) a Processmentioning

confidence: 99%

Dynamics of Biologically Active Subpopulations of Influenza Virus: Plaque-Forming, Noninfectious Cell-Killing, and Defective Interfering Particles

Marcus

Ngunjiri

Sekellick

2009

J Virol

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“…These cytokines and chemokines are of particular interest because they are produced by a variety of pulmonary cells and can instigate a cascade of physiological changes, including recruitment, proliferation, and activation of immune cells. In particular, a key regulator of virus-induced interferon production, RNA helicase RIG-I, and the interferon-stimulated gene 15 (ISG-15) (13,30). Apoptosis is known to be induced by several influenza virus subtypes through both extracellular and intracellular apoptotic pathways and can contribute to the pathogenesis of influenza.…”

Section: Discussionmentioning

confidence: 99%

The 2009 Pandemic H1N1 and Triple-Reassortant Swine H1N1 Influenza Viruses Replicate Efficiently but Elicit an Attenuated Inflammatory Response in Polarized Human Bronchial Epithelial Cells

Zeng

Pappas

Katz

et al. 2011

J Virol

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“…These parameters may provide novel insights into the dynamics of virus replication that cannot be addressed by conventional experimental techniques. So far, mathematical models have been used to study the replication dynamics of enveloped viruses such as human immunodeficiency virus type 1 (HIV-1) (6-8) and influenza virus (9)(10)(11)(12) in in vitro cell culture. In order to obtain robust and reliable results by mathematical analysis, high-quality time course data are needed.…”

mentioning

confidence: 99%

Quantification of the Dynamics of Enterovirus 71 Infection by Experimental-Mathematical Investigation

Fukuhara

Iwami

Sato

et al. 2013

J Virol

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Enterovirus 71 (EV71) is the causative agent of hand-foot-and-mouth disease and can trigger neurological disorders. EV71 outbreaks are a major public health concern in Asia-Pacific countries. By performing experimental-mathematical investigation, we demonstrate here that viral productivity and transmissibility but not viral cytotoxicity are drastically different among EV71 strains and can be associated with their epidemiological backgrounds. This is the first report demonstrating the dynamics of nonenveloped virus replication in cell culture using mathematical modeling. Human enteroviruses are nonenveloped viruses with a singlestranded positive-sense RNA genome that belong to the family Picornaviridae (1, 2). Enterovirus 71 (EV71) is one of the human enteroviruses and was first described in 1974 (3). It is well known that EV71 is the major causative agent of hand-foot-andmouth disease (HFMD), a common febrile disease occurring mainly in infants and young children (1, 4). Although HFMD is usually self-limiting, EV71 infection can result in neurological disorders such as aseptic meningitis, flaccid paralysis, and fatal encephalitis (1, 4). However, there are no specific therapies for severe EV71 infections.EV71 can be transmitted through the fecal-oral and respiratory routes (1). Since the 1970s, EV71 outbreaks have been periodically reported throughout the world (4, 5). In particular, since the late 1990s, severe EV71 outbreaks have occurred frequently in several countries in the Asia-Pacific region, including Taiwan, mainland China, Malaysia, and Vietnam, and are among the major concerns in the fields of epidemiology and public health in these countries (4, 5).The dynamics of virus replication is complex because this event is composed of the all-at-once creation and destruction of infected cells along with virus propagation. Mathematical analysis is one of the most powerful approaches used to reveal the complicated events in the viral life cycle. By applying mathematical analysis to experimental data, we are able to quantitatively understand the dynamics of virus replication as estimated numerical parameters such as the half-life of infected cells (log2/␦), the burst size of infectious viruses (p/␦; the net amount of virions produced by a cell during its lifetime), and the basic reproductive number (R 0 ϭ p␤T max /␦c; the number of cells newly infected by an infected cell). These parameters may provide novel insights into the dynamics of virus replication that cannot be addressed by conventional experimental techniques. So far, mathematical models have been used to study the replication dynamics of enveloped viruses such as human immunodeficiency virus type 1 (HIV-1) (6-8) and influenza virus (9-12) in in vitro cell culture. In order to obtain robust and reliable results by mathematical analysis, high-quality time course data are needed. Although some mathematical models of nonenveloped viruses focusing on viral replication kinetics in an infected cell have been reported (13-15), there is no report of the use of...

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Infection dynamics and virus-induced apoptosis in cell culture-based influenza vaccine production—Flow cytometry and mathematical modeling

Cited by 89 publications

References 48 publications

Dynamics of Biologically Active Subpopulations of Influenza Virus: Plaque-Forming, Noninfectious Cell-Killing, and Defective Interfering Particles

Dynamics of Biologically Active Subpopulations of Influenza Virus: Plaque-Forming, Noninfectious Cell-Killing, and Defective Interfering Particles

The 2009 Pandemic H1N1 and Triple-Reassortant Swine H1N1 Influenza Viruses Replicate Efficiently but Elicit an Attenuated Inflammatory Response in Polarized Human Bronchial Epithelial Cells

Quantification of the Dynamics of Enterovirus 71 Infection by Experimental-Mathematical Investigation

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