scholarly journals Influenza A virus undergoes compartmentalized replication in vivo dominated by stochastic bottlenecks

2021 ◽  
Author(s):  
Katherine A. Amato ◽  
Luis A. Haddock ◽  
Katarina M. Braun ◽  
Victoria Meliopoulos ◽  
Brandi Livingston ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Influenza A ◽  
Viral Diversity ◽  
Upper Respiratory Tract ◽  
Influenza A Viruses ◽  
Genetic Bottlenecks ◽  
Upper Respiratory ◽  
Dominant Genotype ◽  
Lung Lobes

AbstractTransmission of influenza A viruses (IAV) between hosts is subject to numerous physical and biological barriers that impose genetic bottlenecks, constraining viral diversity and adaptation. The presence of bottlenecks within individual hosts and their potential impacts on evolutionary pathways taken during infection and subsequent transmission are poorly understood. To address this knowledge gap, we created highly diverse IAV libraries bearing molecular barcodes on two independent gene segments, enabling high-resolution tracking and quantification of unique virus lineages within hosts. Here we show that IAV infection in lungs is characterized by multiple within-host bottlenecks that result in “islands” of infection in lung lobes, each with genetically distinct populations. We performed site-specific inoculation of barcoded IAV in the upper respiratory tract of ferrets and tracked viral diversity as infection spread to the trachea and lungs. We observed compartmentalized replication of discrete barcoded populations within the lobes of the lung. Bottlenecks stochastically sampled individual viruses from the upper respiratory tract or the trachea that became the dominant genotype in a particular lobe. These populations are shaped strongly by founder effects, with no evidence for positive selection. The segregated sites of replication highlight the jackpot-style events that contribute to within-host influenza virus evolution and may account for low rates of intrahost adaptation.

scholarly journals Mutations in haemagglutinin that affect receptor binding and pH stability increase replication of a PR8 influenza virus with H5 HA in the upper respiratory tract of ferrets and may contribute to transmissibility

2013 ◽  
Vol 94 (6) ◽  
pp. 1220-1229 ◽  
Author(s):  
Holly Shelton ◽  
Kim L. Roberts ◽  
Eleonora Molesti ◽  
Nigel Temperton ◽  
Wendy S. Barclay
Keyword(s):  
Respiratory Tract ◽  
Influenza A ◽  
Vaccine Virus ◽  
Ph Stability ◽  
Upper Respiratory Tract ◽  
Influenza A Viruses ◽  
Viral Shedding ◽  
H5n1 Influenza ◽  
Upper Respiratory ◽  
Pandemic Strains

The H5N1 influenza A viruses have circulated widely in the avian population for 10 years with only sporadic infection of humans observed and no sustained human to human transmission. Vaccination against potential pandemic strains is one strategy in planning for future influenza pandemics; however, the success of live attenuated vaccines for H5N1 has been limited, due to poor replication in the human upper respiratory tract (URT). Mutations that increase the ability of H5N1 viruses to replicate in the URT will aid immunogenicity of these vaccines and provide information about humanizing adaptations in H5N1 strains that may signal transmissibility. As well as mediating receptor interactions, the haemagglutinin (HA) protein of influenza facilitates fusion of the viral membrane and genome entry into the host cell; this process is pH dependent. We have shown in this study that the pH at which a panel of avian influenza HA proteins, including H5, mediate fusion is higher than that for human influenza HA proteins, and that mutations in the H5 HA can reduce the pH of fusion. Coupled with receptor switching mutations, increasing the pH stability of the H5 HA resulted in increased viral shedding of H5N1 from the nasal cavity of ferrets and contact transmission to a co-housed animal. Ferret serum antibodies induced by infection with any of the mutated H5 HA viruses neutralized HA pseudotyped lentiviruses bearing homologous or heterologous H5 HAs, suggesting that this strategy to increase nasal replication of a vaccine virus would not compromise vaccine efficacy.

scholarly journals Coinfection of Streptococcus pneumoniae reduces airborne transmission of influenza virus

2020 ◽  
Author(s):  
Karina Mueller Brown ◽  
Valerie Le Sage ◽  
Andrea J. French ◽  
Jennifer E. Jones ◽  
Gabriella H. Padovani ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Streptococcus Pneumoniae ◽  
Respiratory Tract ◽  
Influenza A ◽  
Respiratory Viruses ◽  
Upper Respiratory Tract ◽  
Influenza A Viruses ◽  
Airborne Transmission ◽  
Upper Respiratory ◽  
Synergistic Relationship

AbstractSecondary bacterial infection, especially with Streptococcus pneumoniae (Spn), is a common complication in fatal and ICU cases of influenza virus infection. During the H1N1 pandemic of 2009 (H1N1pdm09), there was higher mortality in healthy young adults due to secondary bacterial pneumonia, with Spn being the most frequent bacterial species. Previous studies in mice and ferrets have suggested a synergistic relationship between Spn and influenza viruses. In this study, we used the ferret model to study whether airborne transmission of H1N1pdm09 was influenced by coinfection with two Spn serotypes: type 2 (D39) and type 19F (BHN97). We found that coinfected animals experienced more severe clinical symptoms as well as increased bacterial colonization of the upper respiratory tract. In contrast, we observed that coinfection resulted in reduced airborne transmission of influenza virus. Only 1/3 animals coinfected with D39 transmitted H1N1pdm09 virus to a naïve recipient compared to 3/3 transmission efficiency in animals infected with influenza virus alone. A similar trend was seen in coinfection with BHN97, suggesting that coinfection with Spn reduces influenza virus airborne transmission. The decrease in transmission does not appear to be caused by decreased stability of H1N1pdm09 in expelled droplets in the presence of Spn. Rather, coinfection resulted in decreased viral shedding in the ferret upper respiratory tract. Thus, we conclude that coinfection enhances colonization and airborne transmission of Spn but decreases replication and transmission of H1N1pdm09. Our data points to an asymmetrical relationship between these two pathogens rather than a synergistic one.SignificanceAirborne transmission of respiratory viruses is influenced by many host and environmental parameters. The complex interplay between bacterial and viral coinfections on transmission of respiratory viruses has been understudied. We demonstrate that coinfection with Streptococcus pneumoniae reduces airborne transmission of influenza A viruses by decreasing viral titers in the upper respiratory tract. Instead of implicating a synergistic relationship between bacteria and virus, our work demonstrates an asymmetric relationship where bacteria benefit from the virus but where the fitness of influenza A viruses is negatively impacted by coinfection. The implications of exploring how microbial communities can influence the fitness of pathogenic organisms is a novel avenue for transmission control of pandemic respiratory viruses.

Protection of human upper respiratory tract cell lines against sulphur mustard toxicity by hexamethylenetetramine (HMT)

1998 ◽  
Vol 17 (7) ◽  
pp. 373-379 ◽  
Author(s):  
D J Andrew ◽  
C D Lindsay
Keyword(s):  
Respiratory Tract ◽  
Cell Lines ◽  
Chemical Warfare Agent ◽  
Chemical Warfare ◽  
Upper Respiratory Tract ◽  
Sulphur Mustard ◽  
Human Lung Cells ◽  
Effective Prophylaxis ◽  
Upper Respiratory

1. Sulphur mustard (`mustard gas', HD) is a highly toxic chemical warfare agent which affects the skin and respiratory tract. The primary targets of inhaled HD are the epithelia of the upper respiratory tract. Hexamethylenetetramine (HMT) has been shown to protect human lung cells against HD toxicity and has also been shown to be effective in vivo against the chemical warfare agent phosgene. The ability of HMT to protect against the toxicity of HD was investigated in the human upper respiratory tract cell lines BEAS-2B and RPMI 2650. 2. HD was highly toxic to both cell lines, with LC50 values of 15 - 30 mM. HMT, at a concentration of 10 mM, was shown to protect the cell lines against the toxic effects of 20 mM and 40 mM HD. Results demonstrated that it was necessary for HMT to be in situ at the time of exposure to HD for effective cytoprotection. No protection was seen when cells were treated with HMT following exposure to HD, or where HMT was removed prior to HD exposure. 3. Results suggest that HMT may be effective prophylaxis for exposure to HD by inhalation.

scholarly journals A study of intranasally administered interferon A (rIFN-α2A) for the seasonal prophylaxis of natural viral infections of the upper respiratory tract in healthy volunteers

1988 ◽  
Vol 101 (3) ◽  
pp. 611-621 ◽  
Author(s):  
G. A Tannock ◽  
S. M Gillett ◽  
R. S Gillett ◽  
R. D Barry ◽  
M. J Hensley ◽  
...  
Keyword(s):  
Tract Infection ◽  
Respiratory Tract ◽  
Healthy Volunteers ◽  
Respiratory Tract Infection ◽  
Influenza A ◽  
Controlled Study ◽  
Response Analysis ◽  
Upper Respiratory Tract ◽  
Double Blind ◽  
Upper Respiratory

SUMMARYThe efficacy of interferon A (rIFN-α2A), an Escherichia coli-derived interferon, in the prophylaxis of acute upper respiratory tract infection, was evaluated in a community-based double-blind placebo-controlled study in the Australian winter of 1985. The trial population of 412 healthy volunteers (190 males and 222 females, aged 18–65 years) self-administered 1·5, 3·0 and 6·0 megaunits (MU) of interferon A per day or a placebo, intranasally for 28 days.The period of study coincided with an outbreak of H3N2 influenza A (detected in 35 of the 107 acute specimens) as well as substantial numbers of respiratory syncytial virus and adenovirus infections. Rhinoviruses were isolated from only three specimens. In many cases, subjects had laboratory and clinical evidence of having had more than one respiratory tract infection during the period of the study. Viruses were detected in 54 or 107 acute specimens (49%).No statistically significant differences were noted between the various treatment groups in the incidence of laboratory-proven viral infection (virus isolation and/or antibody response). Analysis of reported symptoms indicated that blood-tinged mucus and nasal stuffiness occurred more frequently with higher doses of interferon. There appeared to be no clinical benefit from the use of interferon A in the amelioration of symptoms.

scholarly journals Type I Interferon Signaling Is a Common Factor Driving Streptococcus pneumoniae and Influenza A Virus Shedding and Transmission

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tonia Zangari ◽  
Mila B. Ortigoza ◽  
Kristen L. Lokken-Toyli ◽  
Jeffrey N. Weiser
Keyword(s):  
Streptococcus Pneumoniae ◽  
Respiratory Tract ◽  
Influenza A Virus ◽  
Influenza A ◽  
Common Factor ◽  
Type I ◽  
Upper Respiratory Tract ◽  
Content Type ◽  
Infant Mouse ◽  
Upper Respiratory

ABSTRACT The dynamics underlying respiratory contagion (the transmission of infectious agents from the airways) are poorly understood. We investigated host factors involved in the transmission of the leading respiratory pathogen Streptococcus pneumoniae. Using an infant mouse model, we examined whether S. pneumoniae triggers inflammatory pathways shared by influenza A virus (IAV) to promote nasal secretions and shedding from the upper respiratory tract to facilitate transit to new hosts. Here, we show that amplification of the type I interferon (IFN-I) response is a critical host factor in this process, as shedding and transmission by both IAV and S. pneumoniae were decreased in pups lacking the common IFN-I receptor (Ifnar1−/− mice). Additionally, providing exogenous recombinant IFN-I to S. pneumoniae-infected pups was sufficient to increase bacterial shedding. The expression of IFN-stimulated genes (ISGs) was upregulated in S. pneumoniae-infected wild-type (WT) but not Ifnar1−/− mice, including genes involved in mucin type O-glycan biosynthesis; this correlated with an increase in secretions in S. pneumoniae- and IAV-infected WT compared to Ifnar1−/− pups. S. pneumoniae stimulation of ISGs was largely dependent on its pore-forming toxin, pneumolysin, and coinfection with IAV and S. pneumoniae resulted in synergistic increases in ISG expression. We conclude that the induction of IFN-I signaling appears to be a common factor driving viral and bacterial respiratory contagion. IMPORTANCE Respiratory tract infections are a leading cause of childhood mortality and, globally, Streptococcus pneumoniae is the leading cause of mortality due to pneumonia. Transmission of S. pneumoniae primarily occurs through direct contact with respiratory secretions, although the host and bacterial factors underlying transmission are poorly understood. We examined transmission dynamics of S. pneumoniae in an infant mouse model and here show that S. pneumoniae colonization of the upper respiratory tract stimulates host inflammatory pathways commonly associated with viral infections. Amplification of this response was shown to be a critical host factor driving shedding and transmission of both S. pneumoniae and influenza A virus, with infection stimulating expression of a wide variety of genes, including those involved in the biosynthesis of mucin, a major component of respiratory secretions. Our findings suggest a mechanism facilitating S. pneumoniae contagion that is shared by viral infection.

scholarly journals Pathogenesis and Transmission of Genetically Diverse Swine-Origin H3N2 Variant Influenza A Viruses from Multiple Lineages Isolated in the United States, 2011–2016

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Xiangjie Sun ◽  
Joanna A. Pulit-Penaloza ◽  
Jessica A. Belser ◽  
Claudia Pappas ◽  
Melissa B. Pearce ◽  
...  
Keyword(s):  
United States ◽  
Respiratory Tract ◽  
Influenza A ◽  
Seasonal Influenza ◽  
The United States ◽  
Influenza Viruses ◽  
Upper Respiratory Tract ◽  
Pandemic Preparedness

ABSTRACTWhile several swine-origin influenza A H3N2 variant (H3N2v) viruses isolated from humans prior to 2011 have been previously characterized for their virulence and transmissibility in ferrets, the recent genetic and antigenic divergence of H3N2v viruses warrants an updated assessment of their pandemic potential. Here, four contemporary H3N2v viruses isolated during 2011 to 2016 were evaluated for their replicative ability in bothin vitroandin vivoin mammalian models as well as their transmissibility among ferrets. We found that all four H3N2v viruses possessed similar or enhanced replication capacities in a human bronchial epithelium cell line (Calu-3) compared to a human seasonal influenza virus, suggestive of strong fitness in human respiratory tract cells. The majority of H3N2v viruses examined in our study were mildly virulent in mice and capable of replicating in mouse lungs with different degrees of efficiency. In ferrets, all four H3N2v viruses caused moderate morbidity and exhibited comparable titers in the upper respiratory tract, but only 2 of the 4 viruses replicated in the lower respiratory tract in this model. Furthermore, despite efficient transmission among cohoused ferrets, recently isolated H3N2v viruses displayed considerable variance in their ability to transmit by respiratory droplets. The lack of a full understanding of the molecular correlates of virulence and transmission underscores the need for close genotypic and phenotypic monitoring of H3N2v viruses and the importance of continued surveillance to improve pandemic preparedness.IMPORTANCESwine-origin influenza viruses of the H3N2 subtype, with the hemagglutinin (HA) and neuraminidase (NA) derived from historic human seasonal influenza viruses, continue to cross species barriers and cause human infections, posing an indelible threat to public health. To help us better understand the potential risk associated with swine-origin H3N2v viruses that emerged in the United States during the 2011-2016 influenza seasons, we use bothin vitroandin vivomodels to characterize the abilities of these viruses to replicate, cause disease, and transmit in mammalian hosts. The efficient respiratory droplet transmission exhibited by some of the H3N2v viruses in the ferret model combined with the existing evidence of low immunity against such viruses in young children and older adults highlight their pandemic potential. Extensive surveillance and risk assessment of H3N2v viruses should continue to be an essential component of our pandemic preparedness strategy.

scholarly journals Microbiome disturbance and resilience dynamics of the upper respiratory tract in response to influenza A virus infection in humans and ferrets

2018 ◽  
Author(s):  
Drishti Kaul ◽  
Raveen Rathnasinghe ◽  
Marcela Ferres ◽  
Gene S. Tan ◽  
Aldo Barrera ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Respiratory Tract ◽  
Influenza A Virus ◽  
Influenza A ◽  
Cellular Damage ◽  
Upper Respiratory Tract ◽  
Upper Respiratory ◽  
Influenza A Virus Infection ◽  
Over Time

AbstractInfection with influenza can be aggravated by bacterial co-infections, which often results in disease exacerbation because of host responses and cellular damage. The native upper respiratory tract (URT) microbiome likely plays a role, yet the effects of influenza infection on the URT microbiome are largely unknown. We performed a longitudinal study to assess the temporal dynamics of the URT microbiomes of uninfected and influenza virus-infected humans and ferrets. Uninfected human patients and ferret URT microbiomes had stable “heathy ecostate” communities both within and between individuals. In contrast, infected patients and ferrets exhibited large changes in bacterial community composition over time and between individuals. The “unhealthy” ecostates of infected individuals progressed towards the “healthy ecostate” over time, coinciding with viral clearance and recovery. Blooms of Pseudomonas were a statistically associated constant in the disturbed microbiomes of infected individuals. The dynamic and resilient nature of the microbiome during influenza virus infection in multiple hosts provides a compelling rationale for the maintenance of the microbiome homeostasis as a potential therapeutic target to prevent IAV associated bacterial co-infections.One Sentence SummaryDynamics of the upper respiratory tract microbiome during influenza A virus infection

scholarly journals Secretory IgA in Mucosa of Pharynx and Larynx Plays an Important Role against Influenza A Virus Infection in Kidney Yang Deficiency Syndrome Model

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Shaozhe Zhao ◽  
Lei Yuan ◽  
Yi Li ◽  
Longchan Liu ◽  
Zixin Luo ◽  
...  
Keyword(s):  
High Risk ◽  
Virus Infection ◽  
Respiratory Tract ◽  
Influenza A Virus ◽  
Influenza A ◽  
Morbidity And Mortality ◽  
Secretory Iga ◽  
Upper Respiratory Tract ◽  
Gene Expressions ◽  
Upper Respiratory

Objective. Influenza virus poses a major threat to human health and has serious morbidity and mortality which commonly occurs in high-risk populations. Pharynx and larynx of the upper respiratory tract mucosa is the first defense line against influenza virus infection. However, the ability of the pharynx and larynx organ to eliminate the influenza pathogen is still not clear under different host conditions. Methods. In this study, a mouse model of kidney yang deficiency syndrome (KYDS) was used to mimic high-risk peoples. Two different methods of influenza A (H1N1) virus infection by nasal dropping or tracheal intubation were applied to these mice, which were divided into four groups: normal intubation (NI) group, normal nasal dropping (ND) group, model intubation (MI) group, and model nasal dropping (MD) group. The normal control (NC) group was used as a negative control. Body weight, rectal temperature, and survival rate were observed every day. Histopathologic changes, visceral index, gene expressions of H1N1, cytokine expressions, secretory IgA (SIgA) antibodies of tracheal lavage fluids in the upper respiratory tract, and bronchoalveolar lavage fluids were analyzed by ELISA. Results. The MD group had an earlier serious morbidity and mortality than the others. MI and NI groups became severe only in the 6th to 7th day after infection. The index of the lung increased significantly in NI, MI, and MD groups. Conversely, indices of the thymus and spleen increased significantly in NC and ND groups. H&E staining showed severe tissue lesions in MD, MI, and NI groups. H1N1 gene expressions were higher in the MD group compared with the MI group on the 3rd day; however, the MD group decreased significantly on the 7th day. IL-6 levels increased remarkably, and SIgA expressions decreased significantly in the MD group compared with the NC group. Conclusions. SIgA secretions are influenced directly by different conditions of the host in the pharynx and larynx in the upper respiratory tract mucosa. In the KYDS virus disease mode, SIgA expressions could be inhibited severely, which leads to serious morbidity and mortality after influenza A virus infection. The SIgA expressions of the pharynx and larynx would be an important target in high-risk populations against the influenza A virus for vaccine or antiviral drugs research.

Antiviral Properties of Food Plants Could Help to Reduce Contagion and Severity in SARS-CoV-2 Infections

2021 ◽  
Vol 07 ◽  
Author(s):  
Betina Cardoso
Keyword(s):  
Respiratory Tract ◽  
Literature Search ◽  
Food Plants ◽  
Upper Respiratory Tract ◽  
Site Specific ◽  
In Vivo Experiments ◽  
Upper Respiratory ◽  
Novel Coronavirus

Introduction: The importance of an immediate tool to help patients and prevent viral diffusion of new pneumonia caused by 2019 novel coronavirus (2019-nCoV or SARS-CoV-2) that causes the disease COVID-19 becomes evident. Recent articles have reported on body site-specific SARS-CoV-2 infection, showing very active replication in the throat and upper respiratory tract when symptoms were still mild, and thus being efficient in viral transmission in sputum. Material and Methods: An alternative that may be feasible is to resort to scientific studies that demonstrate the antiviral potential of medicinal plants species through in-vitro and in-vivo experiments to alleviate symptoms and prevent the spread of contagion. A literature search in Scopus and PubMed on herbs and foods with antiviral properties was performed. Results: Herbs and foods with demonstrated antiviral potential have been identified, which could limit SARS-CoV-2 spreading by interfering on ACE2 protein on infection sites. The analysis of transdisciplinary knowledge allows us to connect previous research on the action of common plants and foods on viruses to limit the replication of SARS-CoV-2 in the throat and upper respiratory tract. Conclusions: Herbs and foods with demonstrated antiviral potential have been identified, which could limit SARS-CoV-2 spreading by interfering on ACE2 protein on infection sites. The analysis of transdisciplinary knowledge allows us to connect previous research on the action of common plants and foods on viruses to limit the replication of SARS-CoV-2 in the throat and upper respiratory tract.

scholarly journals Identification of Influenza A Virus PB2 Residues Involved in Enhanced Polymerase Activity and Virus Growth in Mammalian Cells at Low Temperatures

2015 ◽  
Vol 89 (15) ◽  
pp. 8042-8049 ◽  
Author(s):  
Tsuyoshi Hayashi ◽  
Saintedym Wills ◽  
Kendra A. Bussey ◽  
Toru Takimoto
Keyword(s):  
Influenza Virus ◽  
Low Temperature ◽  
Respiratory Tract ◽  
Mammalian Cells ◽  
Influenza A ◽  
Polymerase Activity ◽  
Upper Respiratory Tract ◽  
Virus Growth ◽  
Avian Origin ◽  
Upper Respiratory

ABSTRACTMutations in the polymerase genes are known to play a major role in avian influenza virus adaptation to mammalian hosts. Despite having avian origin PA and PB2, the 2009 pandemic H1N1 virus (pH1N1) can replicate well in mammalian respiratory tracts, suggesting that these proteins have acquired mutations for efficient growth in humans. We have previously shown that PA from the pH1N1 virus A/California/04/09 (Cal) strongly enhances activity of an otherwise avian polymerase complex derived from A/chicken/Nanchang/3-120/01 (Nan) in mammalian cells. However, this enhancement was observed at 37°C but not at the lower temperature of 34°C. An additional introduction of Cal PB2 enhanced activity at 34°C, suggesting the presence of unidentified residues in Cal PB2 that are required for efficient growth at low temperature. Here, we sought to determine the key PB2 residues which confer enhanced polymerase activity and virus growth in human cells at low temperature. Using a reporter gene assay, we identified novel mutations, PB2 V661A and V683T/A684S, which are involved in enhanced Cal polymerase activity at low temperature. The PB2 T271A mutation, which we previously reported, also contributed to enhanced activity. The growth of recombinant Cal containing PB2 with Nan residues 271T/661V/683V/684A was strongly reduced in human cells compared to wild-type virus at low temperature. Among the four residues, 271A and 684S are conserved in human and pH1N1 viruses but not in avian viruses, suggesting an important role in mammalian adaptation of pH1N1 virus.IMPORTANCEThe PB2 protein plays a key role in the host adaptation, cold sensitivity, and pathogenesis of influenza A virus. Despite containing an avian origin PB2 lacking the mammalian adaptive mutations 627K or 701N, pH1N1 influenza virus strains can replicate efficiently in the low temperature upper respiratory tract of mammals, suggesting the presence of unknown mutations in the pH1N1 PB2 protein responsible for its low temperature adaptation. Here, in addition to PB2 271A, which has been shown to increase polymerase activity, we identified novel PB2 residues 661A and 683T/684S in pH1N1 which confer enhanced polymerase activity and virus growth in mammalian cells especially at low temperature. Our findings suggest that the presence of these PB2 residues contributes to efficient replication of the pH1N1 virus in the upper respiratory tract, which resulted in efficient human-to-human transmission of this virus.

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