scholarly journals Respiratory Bacteria Stabilize and Promote Airborne Transmission of Influenza A Virus

mSystems ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Hannah M. Rowe ◽  
Brandi Livingston ◽  
Elisa Margolis ◽  
Amy Davis ◽  
Victoria A. Meliopoulos ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Bacterial Species ◽  
Bacterial Flora ◽  
Transmission Dynamics ◽  
Environmental Stability ◽  
Upper Respiratory Tract ◽  
Airborne Transmission ◽  
Content Type ◽  
Mortality And Morbidity

Infection with influenza A virus (IAV), especially when complicated with a secondary bacterial infection, is a leading cause of global mortality and morbidity. Gaining a greater understanding of the transmission dynamics of IAV is important during seasonal IAV epidemics and in the event of a pandemic. Direct bacterium-virus interactions are a recently appreciated aspect of infectious disease biology. Direct interactions between IAV and specific bacterial species of the human upper respiratory tract were found to promote the stability and infectivity of IAV during desiccation stress. Viral environmental stability is an important aspect during transmission, suggesting a potential role for bacterial respiratory communities in IAV transmission. Airborne transmission of IAV was abrogated upon depletion of nasal bacterial flora with topical antibiotics. This defect could be functionally complemented by S. pneumoniae coinfection. These data suggest that bacterial coinfection may be an underappreciated aspect of IAV transmission dynamics.

scholarly journals Respiratory bacteria stabilize and promote airborne transmission of influenza A virus

2020 ◽  
Author(s):  
Hannah M. Rowe ◽  
Brandi Livingston ◽  
Elisa Margolis ◽  
Amy Davis ◽  
Victoria A. Meliopoulos ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Influenza A Virus ◽  
Influenza A ◽  
Bacterial Flora ◽  
Environmental Stability ◽  
Human Respiratory Tract ◽  
Airborne Transmission ◽  
Bacterial Populations ◽  
Encapsulated Bacteria ◽  
Respiratory Microbiome

ABSTRACTInfluenza A virus (IAV) is a major pathogen of the human respiratory tract where the virus co-exists and interacts with bacterial populations comprising the respiratory microbiome. Synergies between IAV and respiratory bacterial pathogens promote enhanced inflammation and disease burden that exacerbate morbidity and mortality. We demonstrate that direct interactions between IAV and encapsulated bacteria commonly found in the respiratory tract promote environmental stability and infectivity of IAV. Antibiotic-mediated depletion of the respiratory bacterial flora abrogated IAV transmission in ferret models, indicating that these viral-bacterial interactions are operative for airborne transmission of IAV. Restoring IAV airborne transmission in antibiotic treated ferrets by co-infection with Streptococcus pneumoniae confirmed a role for specific members of the bacterial respiratory community in promoting IAV transmission. These results implicate a role for the bacterial respiratory flora in promoting airborne transmission of IAV.

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 Protection against Streptococcus pneumoniae Invasive Pathogenesis by a Protein-Based Vaccine Is Achieved by Suppression of Nasopharyngeal Bacterial Density during Influenza A Virus Coinfection

2016 ◽  
Vol 85 (2) ◽  
Author(s):  
M. Nadeem Khan ◽  
Qingfu Xu ◽  
Michael E. Pichichero
Keyword(s):  
T Cells ◽  
Streptococcus Pneumoniae ◽  
Influenza A Virus ◽  
Influenza A ◽  
Passive Transfer ◽  
Bacterial Density ◽  
Content Type ◽  
Adult Mice ◽  
Significant Difference ◽  
Colonization Density

ABSTRACTAn increase inStreptococcus pneumoniaenasopharynx (NP) colonization density during a viral coinfection initiates pathogenesis. To mimic naturalS. pneumoniaepathogenesis, we commensally colonized the NPs of adult C57BL/6 mice withS. pneumoniaeserotype (ST) 6A or 8 and then coinfected them with mouse-adapted H1N1 influenza A virus (PR/8/34).S. pneumoniaeestablished effective commensal colonization, and influenza virus coinfection causedS. pneumoniaeNP density to increase, resulting in bacteremia and mortality. We then studied histidine triad protein D (PhtD), anS. pneumoniaeadhesin vaccine candidate, for its ability to prevent invasiveS. pneumoniaedisease in adult and infant mice. In adult mice, the efficacy of PhtD vaccination was compared with that of PCV13. Vaccination with PCV13 led to a greater reduction ofS. pneumoniaeNP density (>2.5 log units) than PhtD vaccination (∼1-log-unit reduction). However, no significant difference was observed with regard to the prevention ofS. pneumoniaebacteremia, and there was no difference in mortality. Depletion of CD4+T cells in PhtD-vaccinated adult mice, but not PCV13-vaccinated mice, caused a loss of vaccine-induced protection. In infant mice, passive transfer of antisera or CD4+T cells from PhtD-vaccinated adult mice led to a nonsignificant reduction in NP colonization density, whereas passive transfer of antisera and CD4+T cells was needed to cause a significant reduction in NP colonization density. For the first time, these data show an outcome with regard to prevention of invasiveS. pneumoniaepathogenesis with a protein vaccine similar to that which occurs with a glycoconjugate vaccine despite a less robust reduction in NP bacterial density.

scholarly journals The human H5N1 influenza A virus polymerase complex is active in vitro over a broad range of temperatures, in contrast to the WSN complex, and this property can be attributed to the PB2 subunit

2008 ◽  
Vol 89 (12) ◽  
pp. 2923-2932 ◽  
Author(s):  
Birgit G. Bradel-Tretheway ◽  
Z. Kelley ◽  
Shikha Chakraborty-Sett ◽  
Toru Takimoto ◽  
Baek Kim ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Influenza A Virus ◽  
Influenza A ◽  
Elevated Temperatures ◽  
Expression System ◽  
Lung Epithelial Cells ◽  
Upper Respiratory Tract ◽  
Polymerase Complex ◽  
H5n1 Influenza

Influenza A virus (IAV) replicates in the upper respiratory tract of humans at 33 °C and in the intestinal tract of birds at close to 41 °C. The viral RNA polymerase complex comprises three subunits (PA, PB1 and PB2) and plays an important role in host adaptation. We therefore developed an in vitro system to examine the temperature sensitivity of IAV RNA polymerase complexes from different origins. Complexes were prepared from human lung epithelial cells (A549) using a novel adenoviral expression system. Affinity-purified complexes were generated that contained either all three subunits (PA/PB1/PB2) from the A/Viet/1203/04 H5N1 virus (H/H/H) or the A/WSN/33 H1N1 strain (W/W/W). We also prepared chimeric complexes in which the PB2 subunit was exchanged (H/H/W, W/W/H) or substituted with an avian PB2 from the A/chicken/Nanchang/3-120/01 H3N2 strain (W/W/N). All complexes were functional in transcription, cap-binding and endonucleolytic activity. Complexes containing the H5N1 or Nanchang PB2 protein retained transcriptional activity over a broad temperature range (30–42 °C). In contrast, complexes containing the WSN PB2 protein lost activity at elevated temperatures (39 °C or higher). The E627K mutation in the avian PB2 was not required for this effect. Finally, the avian PB2 subunit was shown to confer enhanced stability to the WSN 3P complex. These results show that PB2 plays an important role in regulating the temperature optimum for IAV RNA polymerase activity, possibly due to effects on the functional stability of the 3P complex.

scholarly journals Comparison of Adjuvanted-Whole Inactivated Virus and Live-Attenuated Virus Vaccines against Challenge with Contemporary, Antigenically Distinct H3N2 Influenza A Viruses

2018 ◽  
Vol 92 (22) ◽  
Author(s):  
Eugenio J. Abente ◽  
Daniela S. Rajao ◽  
Jefferson Santos ◽  
Bryan S. Kaplan ◽  
Tracy L. Nicholson ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Vaccine Efficacy ◽  
Influenza A ◽  
Rapid Evolution ◽  
The United States ◽  
Upper Respiratory Tract ◽  
Influenza A Viruses ◽  
Partial Protection ◽  
Attenuated Virus ◽  
The Impact

ABSTRACTInfluenza A viruses in swine (IAV-S) circulating in the United States of America are phylogenetically and antigenically distinct. A human H3 hemagglutinin (HA) was introduced into the IAV-S gene pool in the late 1990s, sustained continued circulation, and evolved into five monophyletic genetic clades, H3 clades IV-A to -E, after 2009. Across these phylogenetic clades, distinct antigenic clusters were identified, with three clusters (cyan, red, and green antigenic cluster) among the most frequently detected antigenic phenotypes (Abente EJ, Santos J, Lewis NS, Gauger PC, Stratton J, et al. J Virol 90:8266–8280, 2016,https://doi.org/10.1128/JVI.01002-16). Although it was demonstrated that antigenic diversity of H3N2 IAV-S was associated with changes at a few amino acid positions in the head of the HA, the implications of this diversity for vaccine efficacy were not tested. Using antigenically representative H3N2 viruses, we compared whole inactivated virus (WIV) and live-attenuated influenza virus (LAIV) vaccines for protection against challenge with antigenically distinct H3N2 viruses in pigs. WIV provided partial protection against antigenically distinct viruses but did not prevent virus replication in the upper respiratory tract. In contrast, LAIV provided complete protection from disease and virus was not detected after challenge with antigenically distinct viruses.IMPORTANCEDue to the rapid evolution of the influenza A virus, vaccines require continuous strain updates. Additionally, the platform used to deliver the vaccine can have an impact on the breadth of protection. Currently, there are various vaccine platforms available to prevent influenza A virus infection in swine, and we experimentally tested two: adjuvanted-whole inactivated virus and live-attenuated virus. When challenged with an antigenically distinct virus, adjuvanted-whole inactivated virus provided partial protection, while live-attenuated virus provided effective protection. Additional strategies are required to broaden the protective properties of inactivated virus vaccines, given the dynamic antigenic landscape of cocirculating strains in North America, whereas live-attenuated vaccines may require less frequent strain updates, based on demonstrated cross-protection. Enhancing vaccine efficacy to control influenza infections in swine will help reduce the impact they have on swine production and reduce the risk of swine-to-human transmission.

scholarly journals Vaccination of Macaques with Adjuvanted Formalin-Inactivated Influenza A Virus (H5N1) Vaccines: Protection against H5N1 Challenge without Disease Enhancement

2007 ◽  
Vol 82 (5) ◽  
pp. 2565-2569 ◽  
Author(s):  
Caroline Ruat ◽  
Catherine Caillet ◽  
Alexandre Bidaut ◽  
James Simon ◽  
Albert D. M. E. Osterhaus
Keyword(s):  
Influenza A Virus ◽  
Measles Virus ◽  
Influenza A ◽  
Upper Respiratory Tract ◽  
Disease Exacerbation ◽  
Water Emulsion ◽  
Virus H5n1 ◽  
Oil In Water ◽  
Syncytial Virus ◽  
Oil In Water Emulsion

ABSTRACT We investigated the ability of adjuvanted, inactivated split-virion influenza A virus (H5N1) vaccines to protect against infection and demonstrated that the disease exacerbation phenomenon seen with adjuvanted formaldehyde-inactivated respiratory syncytial virus and measles virus investigational vaccines did not occur with these H5N1 vaccines. Macaques were vaccinated twice with or without an aluminum hydroxide or oil-in-water emulsion adjuvanted vaccine. Three months later, animals were challenged with homologous wild-type H5N1. No signs of vaccine-induced disease exacerbation were seen. With either adjuvant, vaccination induced functional and cross-reactive antibodies and protected the lungs and upper respiratory tract. Without an adjuvant, the vaccine provided partial protection. Best results were obtained with the emulsion adjuvant.

scholarly journals Dynamic Changes in the Streptococcus pneumoniae Transcriptome during Transition from Biofilm Formation to Invasive Disease upon Influenza A Virus Infection

2014 ◽  
Vol 82 (11) ◽  
pp. 4607-4619 ◽  
Author(s):  
Melinda M. Pettigrew ◽  
Laura R. Marks ◽  
Yong Kong ◽  
Janneane F. Gent ◽  
Hazeline Roche-Hakansson ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Influenza A Virus ◽  
Influenza A ◽  
Lactate Production ◽  
Invasive Disease ◽  
Content Type ◽  
Induced Changes ◽  
Upregulated Genes

ABSTRACTStreptococcus pneumoniaeis a leading cause of infectious disease globally. Nasopharyngeal colonization occurs in biofilms and precedes infection. Prior studies have indicated that biofilm-derived pneumococci are avirulent. However, influenza A virus (IAV) infection releases virulent pneumococci from biofilmsin vitroandin vivo. Triggers of dispersal include IAV-induced changes in the nasopharynx, such as increased temperature (fever) and extracellular ATP (tissue damage). We used whole-transcriptome shotgun sequencing (RNA-seq) to compare theS. pneumoniaetranscriptome in biofilms, bacteria dispersed from biofilms after exposure to IAV, febrile-range temperature, or ATP, and planktonic cells grown at 37°C. Compared with biofilm bacteria, actively dispersedS. pneumoniae, which were more virulent in invasive disease, upregulated genes involved in carbohydrate metabolism. Enzymatic assays for ATP and lactate production confirmed that dispersed pneumococci exhibited increased metabolism compared to those in biofilms. Dispersed pneumococci also upregulated genes associated with production of bacteriocins and downregulated colonization-associated genes related to competence, fratricide, and the transparent colony phenotype. IAV had the largest impact on the pneumococcal transcriptome. Similar transcriptional differences were also observed when actively dispersed bacteria were compared with avirulent planktonic bacteria. Our data demonstrate complex changes in the pneumococcal transcriptome in response to IAV-induced changes in the environment. Our data suggest that disease is caused by pneumococci that are primed to move to tissue sites with altered nutrient availability and to protect themselves from the nasopharyngeal microflora and host immune response. These data help explain pneumococcal virulence after IAV infection and have important implications for studies ofS. pneumoniaepathogenesis.

scholarly journals Functional Comparison of Mx1 from Two Different Mouse Species Reveals the Involvement of Loop L4 in the Antiviral Activity against Influenza A Viruses

2015 ◽  
Vol 89 (21) ◽  
pp. 10879-10890 ◽  
Author(s):  
Judith Verhelst ◽  
Jan Spitaels ◽  
Cindy Nürnberger ◽  
Dorien De Vlieger ◽  
Tine Ysenbaert ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Antiviral Activity ◽  
Influenza A Virus ◽  
Mus Musculus ◽  
Influenza A ◽  
Common Mechanism ◽  
Mus Spretus ◽  
Influenza A Viruses ◽  
Content Type ◽  
Mouse Species

ABSTRACTThe interferon-inducedMx1gene is an important part of the mammalian defense against influenza viruses.Mus musculusMx1 inhibits influenza A virus replication and transcription by suppressing the polymerase activity of viral ribonucleoproteins (vRNPs). Here, we compared the anti-influenza virus activity of Mx1 fromMus musculusA2G with that of its ortholog fromMus spretus. We found that the antiviral activity ofM. spretusMx1 was less potent than that ofM. musculusMx1. Comparison of theM. musculusMx1 sequence with theM. spretusMx1 sequence revealed 25 amino acid differences, over half of which were present in the GTPase domain and 2 of which were present in loop L4. However, thein vitroGTPase activity of Mx1 from the two mouse species was similar. Replacement of one of the residues in loop L4 inM. spretusMx1 by the corresponding residue of A2G Mx1 increased its antiviral activity. We also show that deletion of loop L4 prevented the binding of Mx1 to influenza A virus nucleoprotein and, hence, abolished the antiviral activity of mouse Mx1. These results indicate that loop L4 of mouse Mx1 is a determinant of antiviral activity. Our findings suggest that Mx proteins from different mammals use a common mechanism to inhibit influenza A viruses.IMPORTANCEMx proteins are evolutionarily conserved in vertebrates and inhibit a wide range of viruses. Still, the exact details of their antiviral mechanisms remain largely unknown. Functional comparison of theMxgenes from two species that diverged relatively recently in evolution can provide novel insights into these mechanisms. We show that bothMus musculusA2G Mx1 andMus spretusMx1 target the influenza virus nucleoprotein. We also found that loop L4 in mouse Mx1 is crucial for its antiviral activity, as was recently reported for primate MxA. This indicates that human and mouse Mx proteins, which have diverged by 75 million years of evolution, recognize and inhibit influenza A viruses by a common mechanism.

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

Safety and Efficacy of Intravenous Zanamivir in Preventing Experimental Human Influenza A Virus Infection

1999 ◽  
Vol 43 (7) ◽  
pp. 1616-1620 ◽  
Author(s):  
David P. Calfee ◽  
Amy W. Peng ◽  
Lindsey M. Cass ◽  
Monica Lobo ◽  
Frederick G. Hayden
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Controlled Study ◽  
Nasal Discharge ◽  
Upper Respiratory Tract ◽  
Human Influenza ◽  
Safety And Efficacy ◽  
Viral Shedding ◽  
Respiratory Tract Illness ◽  
Double Blinded

ABSTRACT Zanamivir is a potent inhibitor of influenza A and B virus neuraminidases and is active topically in experimental and natural human influenza. We conducted this double-blinded, placebo-controlled study to evaluate the safety and efficacy of intravenously administered zanamivir. Susceptible volunteers were randomized to receive either saline or zanamivir (600 mg) intravenously twice daily for 5 days beginning 4 h prior to intranasal inoculation with ∼105 50% tissue culture infectious doses (TCID50) of influenza A/Texas/36/91 (H1N1) virus. Reductions in the frequency of viral shedding (0% versus 100% in placebo, P < 0.005) and seroconversion (14% versus 100% in placebo, P < 0.005) and decreases in viral titer areas under the curve (0 versus 11.6 [median] log10 TCID50 · day/ml in placebo,P < 0.005) were observed in the zanamivir group, as were reductions in fever (14% versus 88% in placebo,P < 0.05), upper respiratory tract illness (0% versus 100% in placebo, P < 0.005), total symptom scores (1 versus 44 [median] in placebo, P < 0.005), and nasal-discharge weight (3.9 g versus 17.5 g [median] in placebo, P < 0.005). Zanamivir was detectable in nasal lavage samples collected on days 2 and 4 (unadjusted median concentrations, 10.5 and 12.0 ng/ml of nasal wash, respectively). This study demonstrates that intravenously administered zanamivir is distributed to the respiratory mucosa and is protective against infection and illness following experimental human influenza A virus inoculation.

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