Taronna R Maines

Centers for Disease Control and Prevention, Атланта, Michigan, United States

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Publications (37)288.77 Total impact

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    ABSTRACT: Intranasal instillation of virus in a liquid suspension (IN) is the most frequently employed method to inoculate small mammalian models with influenza virus, but does not reflect a natural route of exposure. In contrast, inoculation via aerosol inhalation (AR) more closely resembles human exposure to influenza virus. Studies in mice have yielded conflicting results regarding virulence induced by virus inoculated by these routes, and have not controlled for potential strain-specific differences, or examined contemporary influenza viruses and avian viruses with pandemic potential. We used a whole-body AR inoculation method to compare infectivity and disease progression of a highly pathogenic H5N1, a low pathogenic H7N9, and a 2009 H1N1 virus with traditional IN inoculation in the mouse model. Generally comparable levels of morbidity and mortality were observed with all viruses examined using either inoculation route, indicating that both IN and AR delivery are appropriate for murine studies investigating influenza virus pathogenicity. Published by Elsevier Inc.
    Virology 07/2015; 481. DOI:10.1016/j.virol.2015.02.041 · 3.28 Impact Factor
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    ABSTRACT: In March 2013, diagnosis of the first reported case of human infection with a novel avian-origin influenza A(H7N9) virus occurred in eastern China. Most human cases have resulted in severe respiratory illness and, in some instances, death. Currently there are no licensed vaccines against H7N9 virus, which continues to cause sporadic human infections. Recombinant virus-like particles (VLPs) have been previously shown to be safe and effective vaccines for influenza. In this study, we evaluated the immunogenicity and protective efficacy of a H7N9 VLP vaccine in the ferret challenge model. Purified recombinant H7N9 VLPs morphologically resembled influenza virions and elicited high-titer serum hemagglutination inhibition (HI) and neutralizing antibodies specific for A/Anhui/1/2013 (H7N9) virus. H7N9 VLP-immunized ferrets subsequently challenged with homologous virus displayed reductions in fever, weight loss, and virus shedding compared to these parameters in unimmunized control ferrets. H7N9 VLP was also effective in protecting against lung and tracheal infection. The addition of either ISCOMATRIX or Matrix-M1 adjuvant improved immunogenicity and protection of the VLP vaccine against H7N9 virus. These results provide support for the development of a safe and effective human VLP vaccine with potent adjuvants against avian influenza H7N9 virus with pandemic potential. Copyright © 2015. Published by Elsevier Ltd.
    Vaccine 03/2015; 33(18). DOI:10.1016/j.vaccine.2015.03.009 · 3.49 Impact Factor
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    ABSTRACT: The seasonality of influenza virus infections in temperate climates and the role of environmental conditions like temperature and humidity in the transmission of influenza virus through the air are not well understood. Using ferrets housed at four different environmental conditions, we evaluated the respiratory droplet transmission of two influenza viruses (a seasonal H3N2 virus and an H3N2 variant virus, the etiologic virus of a swine to human summertime infection) and concurrently characterized the aerosol shedding profiles of infected animals. Comparisons were made among the different temperature and humidity conditions and between the two viruses to determine if the H3N2 variant virus exhibited enhanced capabilities that may have contributed to the infections occurring in the summer. We report here that although increased levels of H3N2 variant virus were found in ferret nasal wash and exhaled aerosol samples compared to the seasonal H3N2 virus, enhanced respiratory droplet transmission was not observed under any of the environmental settings. However, overall environmental conditions were shown to modulate the frequency of influenza virus transmission through the air. Transmission occurred most frequently at 23°C/30%RH, while the levels of infectious virus in aerosols exhaled by infected ferrets agree with these results. Improving our understanding of how environmental conditions affect influenza virus infectivity and transmission may reveal ways to better protect the public against influenza virus infections.
    PLoS ONE 01/2015; 10(5):e0125874. DOI:10.1371/journal.pone.0125874 · 3.53 Impact Factor
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    ABSTRACT: The study of respiratory pathogens has traditionally been performed by examining virus exposure to and infection of respiratory tract tissues. However, these studies typically overlook the role of ocular surfaces, which represent both a potential site of virus replication and a portal of entry for the establishment of a respiratory infection. To model transocular virus entry in a mammalian species, we established a novel inoculation method that delivers an aerosol inoculum exclusively to the ferret ocular surface. Using influenza as a representative respiratory pathogen, we found that both human and avian viruses mounted a productive respiratory infection in ferrets following ocular-only aerosol inoculation, and demonstrated that H5N1 exposure can result in a fatal infection at viral doses below 10 PFU or for as little as 2 minutes of virus exposure. Ferrets inoculated by the ocular aerosol route with avian (H7N7, H7N9) or human (H1N1, H3N2v) viruses were capable of transmitting virus to naïve animals in direct contact or respiratory droplet models, respectively. Our results reveal that ocular-only exposure to virus-containing aerosols constitutes a valid exposure route for a potentially fatal respiratory infection, even among viruses which do not demonstrate an ocular tropism, underscoring the public health implications of ocular exposure in clinical or occupational health settings.
    Journal of Virology 06/2014; 88(17). DOI:10.1128/JVI.01067-14 · 4.65 Impact Factor
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    ABSTRACT: Evaluation of: Nishiura H, Yen H-L, Cowling BJ. Sample size considerations for one-to-one animal transmission studies of the influenza A viruses. PLoS ONE 8(1), e55358 (2013). There is an urgent need to model in a laboratory setting the capacity of wild-type influenza viruses to transmit between mammals, to determine the molecular determinants and identify biological properties that confer influenza virus transmissibility, and to explore both pharmaceutical and nonpharmaceutical methods to inhibit virus transmission. Owing to its close physiologic match to humans, researchers typically utilize the ferret to measure influenza virus transmissibility. Nishiura et al. highlight the dilemma facing researchers utilizing the ferret transmission model: how to provide high-quality data to guide public health efforts, while ensuring the ethical use of animals in limited-size, individual, one-to-one transmission experiments. However, the responsible interpretation of data generated using this model can overcome this potential limitation. A closer examination of previously published studies utilizing this model as it is currently employed reveals that the 'sample size' of these studies is not always as small as it may appear.
    Future Microbiology 08/2013; 8:961-5. DOI:10.2217/fmb.13.64 · 3.82 Impact Factor
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    ABSTRACT: On 29 March 2013, the Chinese Center for Disease Control and Prevention confirmed the first reported case of human infection with an avian influenza A(H7N9) virus. The recent human infections with H7N9 virus, totalling over 130 cases with 39 fatalities to date, have been characterized by severe pulmonary disease and acute respiratory distress syndrome (ARDS). This is concerning because H7 viruses have typically been associated with ocular disease in humans, rather than severe respiratory disease. This recent outbreak underscores the need to better understand the pathogenesis and transmission of these viruses in mammals. Here we assess the ability of A/Anhui/1/2013 and A/Shanghai/1/2013 (H7N9) viruses, isolated from fatal human cases, to cause disease in mice and ferrets and to transmit to naive animals. Both H7N9 viruses replicated to higher titre in human airway epithelial cells and in the respiratory tract of ferrets compared to a seasonal H3N2 virus. Moreover, the H7N9 viruses showed greater infectivity and lethality in mice compared to genetically related H7N9 and H9N2 viruses. The H7N9 viruses were readily transmitted to naive ferrets through direct contact but, unlike the seasonal H3N2 virus, did not transmit readily by respiratory droplets. The lack of efficient respiratory droplet transmission was corroborated by low receptor-binding specificity for human-like α2,6-linked sialosides. Our results indicate that H7N9 viruses have the capacity for efficient replication in mammals and human airway cells and highlight the need for continued public health surveillance of this emerging virus.
    Nature 07/2013; DOI:10.1038/nature12391 · 42.35 Impact Factor
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    ABSTRACT: Influenza viruses pose a major public health burden to communities around the world by causing respiratory infections that can be highly contagious and spread rapidly through the population. Despite extensive research on influenza viruses, the modes of transmission occurring most often among humans are not entirely clear. Contributing to this knowledge gap is the lack of an understanding of the levels of infectious virus present in respirable aerosols exhaled from infected hosts. Here, we use the ferret model to evaluate aerosol shedding patterns and measure the amount of infectious virus present in exhaled respirable aerosols. By comparing these parameters among a panel of human and avian influenza viruses exhibiting diverse respiratory droplet transmission efficiencies, we are able to report that ferrets infected by highly transmissible influenza viruses exhale a greater number of aerosol particles and more infectious virus within respirable aerosols compared to ferrets infected by influenza viruses that do not readily transmit. Our findings improve our understanding of the ferret transmission model and provide support for the potential for influenza virus aerosol transmission.
    Journal of Virology 05/2013; DOI:10.1128/JVI.00719-13 · 4.65 Impact Factor
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    ABSTRACT: H7 subtype influenza A viruses, responsible for numerous outbreaks in land-based poultry in Europe and the Americas, have caused over 100 cases of confirmed or presumed human infection over the last decade. The emergence of a highly pathogenic avian influenza H7N3 virus in poultry throughout the state of Jalisco, Mexico, resulting in two cases of human infection, prompted us to examine the virulence of this virus [A/Mexico/InDRE7218/2012 (MX/7218)] and related avian H7 subtype viruses in mouse and ferret models. Several high and low pathogenicity H7N3 and H7N9 viruses replicated efficiently in the respiratory tract of mice without prior adaptation following intranasal inoculation, but only MX/7218 virus caused lethal disease in this species. H7N3 and H7N9 viruses were also detected in the mouse eye following ocular inoculation. Virus from both H7N3 and H7N9 subtypes replicated efficiently in the upper and lower respiratory tract of ferrets, however, only MX/7218 virus infection caused clinical signs and symptoms and was capable of transmission to naïve ferrets in a direct contact model. Similar to other highly pathogenic H7 viruses, MX/7218 replicated to high titers in human bronchial epithelial cells, yet downregulated numerous genes related to NF-κB-mediated signaling transduction. These findings indicate that the recently isolated North American lineage H7 subtype virus associated with human conjunctivitis is capable of causing severe disease in mice and spreading to naïve contact ferrets, while concurrently retaining the ability to replicate within ocular tissue allowing the eye to serve as a portal of entry.
    Journal of Virology 03/2013; DOI:10.1128/JVI.00154-13 · 4.65 Impact Factor
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    ABSTRACT: While influenza viruses are typically considered respiratory pathogens, the ocular system represents a secondary entry point for virus to establish a productive respiratory infection and the location for rare instances of virus-induced conjunctivitis. We used the ferret model to conduct a side-by-side comparison of virus infectivity, kinetics of viral replication, and induction of host responses following inoculation by either the intranasal or ocular routes with two viruses, A/Netherlands/230/03 (H7N7) and A/Panama/2007/99 (H3N2). We show that ocular inoculation resulted in delayed virus replication and reduced levels of proinflammatory cytokine and chemokine transcript in respiratory tract but not ocular tissues compared with intranasally inoculated animals. We identified numerous proinflammatory mediators with known roles in ocular disease elicited in ferret eye tissue following influenza virus infection. These findings provide a greater understanding of the modulation of host responses following different inoculation routes and underscore the risk associated with ocular exposure to influenza viruses.
    Virology 02/2013; 438(2). DOI:10.1016/j.virol.2013.01.012 · 3.28 Impact Factor
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    ABSTRACT: Tropism and adaptation of influenza viruses to new hosts is partly dependent on the distribution of the sialic acid (SA) receptors to which the viral hemagglutinin (HA) binds. Ferrets have been established as a valuable in vivo model of influenza virus pathogenesis and transmission because of similarities to humans in the distribution of HA receptors and in clinical signs of infection. In this study, we developed a ferret tracheal differentiated primary epithelial cell culture model that consisted of a layered epithelium structure with ciliated and non-ciliated cells on its apical surface. We found that human-like (α2,6-linked) receptors predominated on ciliated cells, whereas avian-like (α2,3-linked) receptors, which were less abundant, were presented on non-ciliated cells. When we compared the tropism and infectivity of three human (H1 and H3) and two avian (H1 and H5) influenza viruses, we observed that the human influenza viruses primarily infected ciliated cells and replicated efficiently, whereas, a highly pathogenic avian H5N1 virus (A/Vietnam/1203/2004) replicated efficiently within non-ciliated cells despite a low initial infection rate. Furthermore, compared to other influenza viruses tested, VN/1203 virus replicated more efficiently in cells isolated from the lower trachea, and at a higher temperature (37°C) compared with a lower temperature (33°C). VN/1203 virus infection also induced higher levels of immune mediator genes, cell death and virus was recovered from the basolateral side of the cell monolayer. This ferret tracheal differentiated primary epithelial cell culture system provides a valuable in vitro model for studying cellular tropism, infectivity, and pathogenesis of influenza viruses.
    Journal of Virology 12/2012; DOI:10.1128/JVI.02885-12 · 4.65 Impact Factor
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    ABSTRACT: The influenza virus H1N1 pandemic of 1918 was one of the worst medical catastrophes in human history. Recent studies have demonstrated that the hemagglutinin (HA) protein of the 1918 virus and 2009 H1N1 pandemic virus [A(H1N1)pdm09], the latter now a component of the seasonal trivalent inactivated influenza vaccine (TIV), share cross-reactive antigenic determinants. In this study, we demonstrate that immunization with the 2010-2011 seasonal TIV induces neutralizing antibodies that cross-react with the reconstructed 1918 pandemic virus in ferrets. TIV-immunized ferrets subsequently challenged with the 1918 virus displayed significant reductions in fever, weight loss, and virus shedding compared to these parameters in nonimmune control ferrets. Seasonal TIV was also effective in protecting against the lung infection and severe lung pathology associated with 1918 virus infection. Our data demonstrate that prior immunization with contemporary TIV provides cross-protection against the 1918 virus in ferrets. These findings suggest that exposure to A(H1N1)pdm09 through immunization may provide protection against the reconstructed 1918 virus which, as a select agent, is considered to pose both biosafety and biosecurity threats.
    Journal of Virology 05/2012; 86(13):7118-25. DOI:10.1128/JVI.00674-12 · 4.65 Impact Factor
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    ABSTRACT: Respiratory viruses represent one of the most substantial infectious disease burdens to the human population today, and in particular, seasonal and pandemic influenza viruses pose a persistent threat to public health worldwide. In recent years, advances in techniques used in experimental research have provided the means to better understand the mechanisms of pathogenesis and transmission of respiratory viruses, and thus more accurately model these infections in the laboratory. Here, we briefly review the model systems used to study influenza virus infections, and focus particularly on recent advances that have increased our knowledge of these formidable respiratory pathogens.
    Trends in Microbiology 04/2012; 20(6):275-81. DOI:10.1016/j.tim.2012.03.006 · 9.81 Impact Factor
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    ABSTRACT: Recent isolation of a novel swine-origin influenza A H3N2 variant virus [A(H3N2)v] from humans in the United States has raised concern over the pandemic potential of these viruses. Here, we analyzed the virulence, transmissibility, and receptor-binding preference of four A(H3N2)v influenza viruses isolated from humans in 2009, 2010, and 2011. High titers of infectious virus were detected in nasal turbinates and nasal wash samples of A(H3N2)v-inoculated ferrets. All four A(H3N2)v viruses possessed the capacity to spread efficiently between cohoused ferrets, and the 2010 and 2011 A(H3N2)v isolates transmitted efficiently to naïve ferrets by respiratory droplets. A dose-dependent glycan array analysis of A(H3N2)v showed a predominant binding to α2-6-sialylated glycans, similar to human-adapted influenza A viruses. We further tested the viral replication efficiency of A(H3N2)v viruses in a relevant cell line, Calu-3, derived from human bronchial epithelium. The A(H3N2)v viruses replicated in Calu-3 cells to significantly higher titers compared with five common seasonal H3N2 influenza viruses. These findings suggest that A(H3N2)v viruses have the capacity for efficient replication and transmission in mammals and underscore the need for continued public health surveillance.
    Proceedings of the National Academy of Sciences 03/2012; 109(10):3944-9. DOI:10.1073/pnas.1119945109 · 9.81 Impact Factor
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    ABSTRACT: While influenza viruses are a common respiratory pathogen, sporadic reports of conjunctivitis following human infection demonstrates the ability of this virus to cause disease outside of the respiratory tract. The ocular surface represents both a potential site of virus replication and a portal of entry for establishment of a respiratory infection. However, the properties which govern ocular tropism of influenza viruses, the mechanisms of virus spread from ocular to respiratory tissue, and the potential differences in respiratory disease initiated from different exposure routes are poorly understood. Here, we established a ferret model of ocular inoculation to explore the development of virus pathogenicity and transmissibility following influenza virus exposure by the ocular route. We found that multiple subtypes of human and avian influenza viruses mounted a productive virus infection in the upper respiratory tract of ferrets following ocular inoculation, and were additionally detected in ocular tissue during the acute phase of infection. H5N1 viruses maintained their ability for systemic spread and lethal infection following inoculation by the ocular route. Replication-independent deposition of virus inoculum from ocular to respiratory tissue was limited to the nares and upper trachea, unlike traditional intranasal inoculation which results in virus deposition in both upper and lower respiratory tract tissues. Despite high titers of replicating transmissible seasonal viruses in the upper respiratory tract of ferrets inoculated by the ocular route, virus transmissibility to naïve contacts by respiratory droplets was reduced following ocular inoculation. These data improve our understanding of the mechanisms of virus spread following ocular exposure and highlight differences in the establishment of respiratory disease and virus transmissibility following use of different inoculation volumes and routes.
    PLoS Pathogens 03/2012; 8(3):e1002569. DOI:10.1371/journal.ppat.1002569 · 8.06 Impact Factor
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    ABSTRACT: Host innate immunity is the first line of defense against invading pathogens, including influenza viruses. Ferrets are well recognized as the best model of influenza virus pathogenesis and transmission, but little is known about the innate immune response of ferrets after infection with this virus. The goal of this study was to investigate the contribution of localized host responses to influenza virus pathogenicity and transmissibility in this model by measuring the level of messenger RNA expression of 12 cytokines and chemokines in the upper and lower respiratory tracts of ferrets infected with H5N1, H1N1, or H3N2 influenza viruses that exhibit diverse virulence and transmissibility in ferrets. We found a strong temporal correlation between inflammatory mediators and the kinetics and frequency of transmission, clinical signs associated with transmission, peak virus shedding, and virulence. Our findings point to a link between localized innate immunity and influenza virus transmission and disease progression.
    The Journal of Infectious Diseases 12/2011; 205(3):474-85. DOI:10.1093/infdis/jir768 · 5.78 Impact Factor
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    ABSTRACT: Continued H5N1 virus infection in humans highlights the need for vaccine strategies that provide cross-clade protection against this rapidly evolving virus. We report a comparative evaluation in ferrets of the immunogenicity and cross-protective efficacy of isogenic mammalian cell-grown, live attenuated influenza vaccine (LAIV) and adjuvanted, whole-virus, inactivated influenza vaccine (IIV), produced from a clade 1 H5N1 6:2 reassortant vaccine candidate (caVN1203-Len17rg) based on the cold-adapted A/Leningrad/134/17/57 (H2N2) master donor virus. Two doses of LAIV or IIV provided complete protection against lethal homologous H5N1 virus challenge and a reduction in virus shedding and disease severity after heterologous clade 2.2.1 H5N1 virus challenge and increased virus-specific serum and nasal wash antibody levels. Although both vaccines demonstrated cross-protective efficacy, LAIV induced higher levels of nasal wash IgA and reduction of heterologous virus shedding, compared with IIV. Thus, enhanced respiratory tract antibody responses elicited by LAIV were associated with improved cross-clade protection.
    The Journal of Infectious Diseases 09/2011; 204(10):1491-9. DOI:10.1093/infdis/jir596 · 5.78 Impact Factor
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    ABSTRACT: Understanding the transmission ability of newly emerging influenza viruses is central to the development of public health preparedness and prevention strategies. Animals are used to model influenza virus infection and transmission, but the routinely used intranasal inoculation of a liquid virus suspension does not reflect natural infection. We report the development of an inoculation method that delivers an influenza virus aerosol inoculum to ferrets and the characterization of size distribution and viable virus present in aerosols shed from infected ferrets during normal breathing and sneezing. By comparing virus deposition, infectivity, virulence, and transmissibility among animals inoculated intranasally or by aerosols with a human (H3N2) or avian (H5N1) influenza virus, we demonstrate that aerosol inoculations more closely resemble a natural, airborne influenza virus infection and that viable virus is measurable in droplets and droplet nuclei exhaled by infected ferrets. These methods will provide improved risk assessment of emerging influenza viruses that pose a threat to public health.
    Proceedings of the National Academy of Sciences 05/2011; 108(20):8432-7. DOI:10.1073/pnas.1100768108 · 9.81 Impact Factor
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    ABSTRACT: Although H5N1 influenza viruses have been responsible for hundreds of human infections, these avian influenza viruses have not fully adapted to the human host. The lack of sustained transmission in humans may be due, in part, to their avian-like receptor preference. Here, we have introduced receptor binding domain mutations within the hemagglutinin (HA) gene of two H5N1 viruses and evaluated changes in receptor binding specificity by glycan microarray analysis. The impact of these mutations on replication efficiency was assessed in vitro and in vivo. Although certain mutations switched the receptor binding preference of the H5 HA, the rescued mutant viruses displayed reduced replication in vitro and delayed peak virus shedding in ferrets. An improvement in transmission efficiency was not observed with any of the mutants compared to the parental viruses, indicating that alternative molecular changes are required for H5N1 viruses to fully adapt to humans and to acquire pandemic capability.
    Virology 03/2011; 413(1):139-47. DOI:10.1016/j.virol.2011.02.015 · 3.28 Impact Factor
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    ABSTRACT: Human infections with highly pathogenic H5N1 avian influenza viruses continue to occur in many parts of the world and pose a considerable public health threat. With the use of animal models, the identification of virulence determinants has been instrumental in improving our understanding of how these viruses cause severe disease in humans. Two genetically similar H5N1 viruses (A/Thailand/16/2004 and A/Thailand/SP83/2004) exhibit high or low virulence phenotypes, respectively, in multiple animal models. Reassortant viruses were generated from this virus pair and evaluated in ferrets. Each of the polymerase genes of A/Thailand/16/2004 virus individually conferred increased virulence to A/Thailand/SP83/2004 virus while the neuraminidase of the low virulence virus reduced virulence and replication efficiency of the virulent virus in ferrets unless the homologous HA was present. Our results demonstrate that H5N1 virus virulence determinants are polygenic and that there is an important correlation between polymerase adaptation, efficient replication in the host, and virulence.
    Virology 03/2011; 413(2):226-30. DOI:10.1016/j.virol.2011.02.005 · 3.28 Impact Factor
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    ABSTRACT: Wild type human influenza viruses do not usually grow well in embryonated hens' eggs, the substrate of choice for the production of inactivated influenza vaccine, and vaccine viruses need to be developed specifically for this purpose. In the event of a pandemic of influenza, vaccine viruses need to be created with utmost speed. At the onset of the current A(H1N1) pandemic in April 2009, a network of laboratories began a race against time to develop suitable candidate vaccine viruses. Two approaches were followed, the classical reassortment approach and the more recent reverse genetics approach. This report describes the development and the characteristics of current pandemic H1N1 candidate vaccine viruses.
    Vaccine 02/2011; 29(9):1836-43. DOI:10.1016/j.vaccine.2010.12.044 · 3.49 Impact Factor

Publication Stats

2k Citations
288.77 Total Impact Points

Institutions

  • 2005–2015
    • Centers for Disease Control and Prevention
      • Influenza Division
      Атланта, Michigan, United States
  • 2007–2012
    • Emory University
      Atlanta, Georgia, United States
    • National Institute of Allergy and Infectious Diseases
      Maryland, United States