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Superinfection and cell regeneration can lead to chronic viral coinfections.

ABSTRACT: Molecular diagnostic techniques have revealed that approximately 43% of the patients hospitalized with influenza-like illness are infected by more than one viral pathogen, sometimes leading to long-lasting infections. It is not clear how the heterologous viruses interact within the respiratory tract of the infected host to lengthen the duration of what are usually short, self-limiting infections. We develop a mathematical model which allows for single cells to be infected simultaneously with two different respiratory viruses (superinfection) to investigate the possibility of chronic coinfections. We find that a model with superinfection and cell regeneration has a stable chronic coinfection fixed point, while superinfection without cell regeneration produces only acute infections. This analysis suggests that both superinfection and cell regeneration are required to sustain chronic coinfection via this mechanism since coinfection is maintained by superinfected cells that allow slow-growing infections a chance to infect cells and continue replicating. This model provides a possible mechanism for chronic coinfection independent of any viral interactions via the immune response.

SUBMITTER: Pinky L

PROVIDER: S-EPMC7094138 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Superinfection and cell regeneration can lead to chronic viral coinfections.

Pinky Lubna L González-Parra Gilberto G Dobrovolny Hana M HM

Journal of theoretical biology 20190111

Molecular diagnostic techniques have revealed that approximately 43% of the patients hospitalized with influenza-like illness are infected by more than one viral pathogen, sometimes leading to long-lasting infections. It is not clear how the heterologous viruses interact within the respiratory tract of the infected host to lengthen the duration of what are usually short, self-limiting infections. We develop a mathematical model which allows for single cells to be infected simultaneously with two ...[more]

PMID: 30639572

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Project description:Viral respiratory infections, especially acute bronchiolitis, play a key role in the development of asthma in childhood. However, most studies have focused on respiratory syncytial virus or rhinovirus infections and none of them have compared the long-term evolution of single versus double or multiple viral infections.Our aim was to compare the frequency of asthma development at 6-8 years in children with previous admission for bronchiolitis associated with single versus double or multiple viral infection.A cross-sectional study was performed in 244 children currently aged 6-8 years, previously admitted due to bronchiolitis between September 2008 and December 2011. A structured clinical interview and the ISAAC questionnaire for asthma symptoms for 6-7-year-old children, were answered by parents by telephone. Specimens of nasopharyngeal aspirate for virological study (polymerase chain reaction) and clinical data were prospectively taken during admission for bronchiolitis.Median current age at follow-up was 7.3 years (IQR: 6.7-8.1). The rate of recurrent wheezing was 82.7% in the coinfection group and 69.7% in the single-infection group, p = 0.06. The number of wheezing-related admissions was twice as high in coinfections than in single infections, p = 0.004. Regarding the ISAAC questionnaire, 30.8% of coinfections versus 15% of single infections, p = 0.01, presented "wheezing in the last 12 months", data that strongly correlate with current prevalence of asthma. "Dry cough at night" was also reported more frequently in coinfections than in single infections, p = 0.02. The strongest independent risk factors for asthma at 6-8 years of age were: age > 9 months at admission for bronchiolitis (OR: 3.484; CI95%: 1.459-8.317, p:0.005), allergic rhinitis (OR: 5.910; 95%CI: 2.622-13.318, p<0.001), and viral coinfection-bronchiolitis (OR: 3.374; CI95%: 1.542-7.386, p:0.01).Asthma at 6-8 years is more frequent and severe in those children previously hospitalized with viral coinfection-bronchiolitis compared with those with single infection. Allergic rhinitis and older age at admission seem also to be strong independent risk factors for asthma development in children previously hospitalised because of bronchiolitis.

Project description:Defining the specific factors that govern the evolution and transmission of influenza A virus (IAV) populations is of critical importance for designing more-effective prediction and control strategies. Superinfection, the sequential infection of a single cell by two or more virions, plays an important role in determining the replicative and evolutionary potential of IAV populations. The prevalence of superinfection during natural infection and the specific mechanisms that regulate it remain poorly understood. Here, we used a novel single virion infection approach to directly assess the effects of individual IAV genes on superinfection efficiency. Rather than implicating a specific viral gene, this approach revealed that superinfection susceptibility is determined by the total number of viral gene segments expressed within a cell. IAV particles that express a complete set of viral genes potently inhibit superinfection, while semi-infectious particles (SIPs) that express incomplete subsets of viral genes do not. As a result, virus populations that contain more SIPs undergo more-frequent superinfection. We further demonstrate that viral replicase activity is responsible for inhibiting subsequent infection. These findings identify both a major determinant of IAV superinfection potential and a prominent role for SIPs in promoting viral coinfection.IMPORTANCE Superinfection, the sequential infection of a single cell by two or more virions, plays an important role in determining the replicative and evolutionary potential of influenza A virus (IAV) populations. The specific mechanisms that regulate superinfection during natural infection remain poorly understood. Here, we show that superinfection susceptibility is determined by the total number of viral genes expressed within a cell and is independent of their specific identity. Virions that express a complete set of viral genes potently inhibit superinfection, while the semi-infectious particles (SIPs) that make up the bulk of IAV populations and express incomplete subsets of viral genes do not. As a result, viral populations with more SIPs undergo more-frequent superinfection. These findings identify both the primary determinant of IAV superinfection potential and a prominent role for SIPs in promoting coinfection.

Project description:BackgroundViral hepatitis deaths from acute infection, cirrhosis, and liver cancer have risen from the tenth to the seventh leading cause of death worldwide between 1990 and 2013. Even in the oral direct acting antiviral (DAA) agent era there are still large numbers of patients with unmet needs. Medications approved for treatment of chronic hepatitis B virus (HBV) infection do not eradicate HBV often requiring treatment for life associated with risks of adverse reactions, drug resistance, nonadherence, and increased cost. Although DAAs increased virologic cure rates well over 90% in all hepatitis C virus (HCV) genotypes, HCV infection still cannot be cured in a small but significant minority of patients. While most of the medical issues of HCV treatment have been solved, the current costs of DAAs are prohibitive.ResultsThe post-infection viral superinfection treatment (SIT) platform technology has been clinically proven to be safe and effective to resolve acute and persistent viral infections in 42 HBV and HCV patients (20 HBV, 22 HCV), and in 4 decompensated patients (2 HBV, 2 HCV). SIT employs a non-pathogenic avian double stranded RNA (dsRNA) virus, a potent activator of antiviral gene responses. Unexpectedly, SIT is active against unrelated DNA (HBV) and RNA (HCV) viruses. SIT does not require lifelong therapy, which is a major advantage considering present HBV treatments. The new viral drug candidate (R903/78) is homogeneously produced by reverse genetics in Vero cells. R903/78 has exceptional pH and temperature stability and also excellent long-term stability; therefore, it can be orally administered, stored and shipped without freezing. Since R903/78 is easy to stockpile, the post-infection SIT could also alleviate the logistic hurdles of surge capacity in vaccine production during viral pandemics.ConclusionTo help large number of HBV and HCV patients with unmet needs, broad-spectrum antiviral drugs effective against whole classes of viruses are urgently needed. The innovative SIT technological platform will be a great additional armament to conquer viral hepatitis, which is still a major cause of death and disability worldwide.

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Superinfection and cell regeneration can lead to chronic viral coinfections.

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Superinfection and cell regeneration can lead to chronic viral coinfections.

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