Martin L Moore

Emory University, Atlanta, Georgia, United States

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Publications (56)320.5 Total impact

  • BMC Pulmonary Medicine 12/2015; 15(1). DOI:10.1186/s12890-015-0040-0 · 2.49 Impact Factor
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    ABSTRACT: Respiratory syncytial virus (RSV) belongs to the family Paramyxoviridae and is the single most important cause of serious lower respiratory tract infections in young children, yet no highly effective treatment or vaccine is available. To clarify the potential for an anti-G mAb, 131-2G which has both anti-viral and anti-inflammatory effects, to effectively treat RSV disease, we determined the kinetics of its effect compared to the effect of the anti-F mAb, 143-6C on disease in mice. Treatment administered three days after RSV rA2-line19F (r19F) infection showed 131-2G decreased breathing effort, pulmonary mucin levels, weight loss, and pulmonary inflammation earlier and more effectively than treatment with mAb 143-6C. Both mAbs stopped lung virus replication at day 5 post-infection. These data show that, in mice, anti-G protein mAb is superior to treating disease during RSV infection than an anti-F protein mAb similar to Palivizumab. This combination of anti-viral and anti-inflammatory activity makes 131-2G a promising candidate for treating for active human RSV infection. Copyright © 2015 Elsevier Inc. All rights reserved.
    Virology 05/2015; 483:117-125. DOI:10.1016/j.virol.2015.02.035 · 3.28 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2015; 135(2):AB171. DOI:10.1016/j.jaci.2014.12.1496 · 11.25 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2015; 135(2):AB103. DOI:10.1016/j.jaci.2014.12.1269 · 11.25 Impact Factor
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    ABSTRACT: Respiratory syncytial virus (RSV) is the leading cause of viral bronchiolitis in both children and the elderly. There is no vaccine available for the prevention of RSV infection. Here, we generated recombinant influenza virus (PR8/RSV.HA-F) expressing an RSV F243-294 neutralizing epitope in the hemagglutinin (HA) as a chimeric protein. Neutralizing antibodies specific for both RSV and influenza virus were induced by a single intranasal immunization of mice with PR8/RSV.HA-F. Mice that were immunized with PR8/RSV.HA-F were protected against RSV infection comparable with live RSV as evidenced by significant reduction of RSV lung viral loads, as well as the absence of lung eosinophilia and RSV-specific cellular immune responses. In contrast, formalin-inactivated RSV-immunized mice showed severe disease and high cellular immune responses in lungs after RSV infection. These findings support a concept that recombinant influenza virus carrying the RSV F243-294 neutralizing epitope can be developed as a promising RSV vaccine candidate which induces protective neutralizing antibodies but avoids lung immunopathology. Copyright © 2014 Elsevier B.V. All rights reserved.
    Antiviral Research 12/2014; 115. DOI:10.1016/j.antiviral.2014.12.009 · 3.43 Impact Factor
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    ABSTRACT: A first step in primary disease prevention is identifying common, modifiable risk factors that contribute to a significant proportion of disease development. Infant respiratory viral infection and childhood asthma are the two most common acute and chronic diseases of childhood, respectively. Common clinical features and links between these diseases have long been recognized, with early life respiratory syncytial virus (RSV) and rhinovirus (RV) lower respiratory tract infections (LRTI) being strongly associated with increased asthma risk. However, there has long been debate over the role of these respiratory viruses in asthma inception. In this article, we will systematically review the evidence linking early life RSV and RV LRTI with asthma inception and whether they could therefore be targets for primary prevention efforts.
    American Journal of Respiratory and Critical Care Medicine 11/2014; 191(1). DOI:10.1164/rccm.201405-0901PP · 11.99 Impact Factor
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    ABSTRACT: Human respiratory syncytial virus (RSV) lower respiratory tract infection can result in inflammation and mucus plugging of airways. RSV strain A2-line19F induces relatively high viral load and mucus in mice. The line19 fusion (F) protein harbors five unique residues compared to the non-mucus-inducing strains A2 and Long, at positions 79, 191, 357, 371, and 557. We hypothesized that differential fusion activity is a determinant of pathogenesis. In a cell-cell fusion assay, line19 F was more fusogenic than Long F. We changed the residues unique to line 19 F to the corresponding residues in Long F and identified residues 79 and 191 together as responsible for high fusion activity. Surprisingly, mutation of residues 357 or 357 with 371 resulted in gain of fusion activity. Thus, we generated RSV F mutants with a range of defined fusion activity and engineered these into recombinant viruses. We found a clear, positive correlation between fusion activity and early viral load in mice, however, we did not detect a correlation between viral loads and levels of airway mucin expression. The F mutant with the highest fusion activity, A2-line19F-K357T/Y371N, induced high viral loads, severe lung histopathology, and weight loss, but did not induce high levels of airway mucin expression. We defined residues 79/191 as critical for line19 F fusion activity and 357/371 as playing a role in A2-line19F mucus induction. Defining the molecular basis of the role of RSV F in pathogenesis may aid vaccine and therapeutic strategies aimed at this protein.
    Journal of Virology 10/2014; 89(1). DOI:10.1128/JVI.02472-14 · 4.65 Impact Factor
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    ABSTRACT: Respiratory syncytial virus (RSV) is the most important pathogen for lower respiratory tract illness in infants and a high priority for vaccine development. We previously reported that RSV virus-like particles (VLPs) expressing either the fusion (F) or attachment (G) glycoprotein could confer protection against RSV challenge in BALB/c mice. Here, we tested the hypothesis that RSV VLP vaccine efficacy can be enhanced by mixing RSV VLP F and RSV VLP G, and we analyzed host responses to these RSV VLPs. Mice were immunized with VLP F, VLP G, or VLP F + VLP G. Lung viral loads in BALB/c mice following RSV strain A2-line19F challenge were lower in mice vaccinated with RSV VLP F + VLP G compared to VLP F- or VLP G-vaccinated mice. Vaccination with VLP F or VLP F + VLP G induced similar levels of neutralizing antibodies. The enhanced protection against RSV challenge induced by vaccination with RSV VLP F + VLP G correlated with CD8 T cells producing T helper type 1 cytokines. VLP G vaccination alone followed by challenge resulted in immunopathology similar to formalin-inactivated RSV vaccination and RSV challenge. Taken together, mixed VLP F + VLP G provided a high level of protection against RSV without vaccine-induced immunopathology, but VLP G vaccination enhanced disease when used alone.
    Antiviral Research 09/2014; 111. DOI:10.1016/j.antiviral.2014.09.005 · 3.43 Impact Factor
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    ABSTRACT: Background Some investigators find a deficiency in IFN production from airway epithelial cells infected with human rhinovirus in asthma, but whether this abnormality occurs with other respiratory viruses is uncertain. Objective To assess the effect of influenza A virus (IAV) and respiratory syncytial virus (RSV) infection on IFN production and viral level in human bronchial epithelial cells (hBECs) from subjects with and without asthma. Methods Primary-culture hBECs from subjects with mild to severe asthma (n = 11) and controls without asthma (hBECs; n = 7) were infected with live or ultraviolet-inactivated IAV (WS/33 strain), RSV (Long strain), or RSV (A/2001/2-20 strain) with multiplicity of infection 0.01 to 1. Levels of virus along with IFN-β and IFN-λ and IFN-stimulated gene expression (tracked by 2′-5′-oligoadenylate synthetase 1 and myxovirus (influenza virus) resistance 1 mRNA) were determined up to 72 hours postinoculation. Results After IAV infection, viral levels were increased 2-fold in hBECs from asthmatic subjects compared with nonasthmatic control subjects (P < .05) and this increase occurred in concert with increased IFN-λ1 levels and no significant difference in IFNB1, 2′-5′-oligoadenylate synthetase 1, or myxovirus (influenza virus) resistance 1mRNA levels. After RSV infections, viral levels were not significantly increased in hBECs from asthmatic versus nonasthmatic subjects and the only significant difference between groups was a decrease in IFN-λ levels (P < .05) that correlated with a decrease in viral titer. All these differences were found only at isolated time points and were not sustained throughout the 72-hour infection period. Conclusions The results indicate that IAV and RSV control and IFN response to these viruses in airway epithelial cells is remarkably similar between subjects with and without asthma.
    Journal of Allergy and Clinical Immunology 09/2014; 134(6). DOI:10.1016/j.jaci.2014.07.013 · 11.25 Impact Factor
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    ABSTRACT: Background The prevalence of allergic diseases has doubled in developed countries in the past several decades. Cyclooxygenase (COX)-inhibiting drugs augmented allergic diseases in mice by increasing allergic sensitization and memory immune responses. However, whether COX inhibition can promote allergic airway diseases by inhibiting immune tolerance is not known. Objective To determine the role of the COX pathway and prostaglandin I2 (PGI2) signaling through the PGI2 receptor (IP) in aeroallergen-induced immune tolerance. Methods Wild-type (WT) BALB/c mice and IP knockout mice were aerosolized with ovalbumin (OVA) to induce immune tolerance prior to immune sensitization with an intraperitoneal injection of OVA/alum. The COX inhibitor indomethacin or vehicle was administered in drinking water to inhibit enzyme activity during the sensitization phase. Two weeks after sensitization, the mice were challenged with OVA aerosols. Mouse bronchoalveolar lavage fluid was harvested for cell counts and TH2 cytokine measurements. Results WT mice treated with indomethacin had greater numbers of total cells, eosinophils, and lymphocytes, and increased IL-5 and IL-13 protein expression in BAL fluid compared to vehicle-treated mice. Similarly, IP knockout mice had augmented inflammation and TH2 cytokine responses compared to WT mice. In contrast, the PGI2 analog cicaprost attenuated the anti-tolerance effect of COX inhibition. Conclusion COX inhibition abrogated immune tolerance by suppressing PGI2 IP signaling, suggesting that PGI2 signaling promotes immune tolerance and that clinical use of COX-inhibiting drugs may increase the risk of developing allergic diseases.
    Journal of Allergy and Clinical Immunology 09/2014; 134(3). DOI:10.1016/j.jaci.2014.06.004 · 11.25 Impact Factor
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    Jia Meng, Sujin Lee, Anne L Hotard, Martin L Moore
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    ABSTRACT: Respiratory syncytial virus (RSV) is the most important pathogen for lower respiratory tract illness in children for which there is no licensed vaccine. Live-attenuated RSV vaccines are the most clinically advanced in children, but achieving an optimal balance of attenuation and immunogenicity is challenging. One way to potentially retain or enhance immunogenicity of attenuated virus is to mutate virulence genes that suppress host immune responses. The NS1 and NS2 virulence genes of the RSV A2 strain were codon deoptimized according to either human or virus codon usage bias, and the resulting recombinant viruses (dNSh and dNSv, respectively) were rescued by reverse genetics. RSV dNSh exhibited the desired phenotype of reduced NS1 and NS2 expression. RSV dNSh was attenuated in BEAS-2B and primary differentiated airway epithelial cells but not in HEp-2 or Vero cells. In BALB/c mice, RSV dNSh exhibited a lower viral load than did A2, and yet it induced slightly higher levels of RSV-neutralizing antibodies than did A2. RSV A2 and RSV dNSh induced equivalent protection against challenge strains A/1997/12-35 and A2-line19F. RSV dNSh caused less STAT2 degradation and less NF-κB activation than did A2 in vitro. Serial passage of RSV dNSh in BEAS-2B cells did not result in mutations in the deoptimized sequences. Taken together, RSV dNSh was moderately attenuated, more immunogenic, and equally protective compared to wild-type RSV and genetically stable.
    mBio 08/2014; 5(5). DOI:10.1128/mBio.01704-14 · 6.88 Impact Factor
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    ABSTRACT: Respiratory syncytial virus (RSV) is the single most important cause of serious lower respiratory tract infections in young children, yet no highly effective treatment or vaccine is available. In the present study, we investigated the effect of prophylactic treatment with the intact and F(ab’)2 forms of an anti-G protein monoclonal antibody (mAb), 131-2G, on the humoral and cellular adaptive immune response to RSV rA2-line19F (r19F) challenge in BALB/c mice. The F(ab’)2 form of 131-2G does not decrease virus replication but intact 131-2G does. The serum specimens for antibodies and spleen cells for memory T cell responses to RSV antigens were analyzed at 30, 45, 75 and 95 p.i. with/without prior treatment with 131-2G. The ratios of Th2/Th1 antibody isotypes at each time p.i indicated that both forms of mAb 131-2G shifted the subclass response from a Th2 (IgG1 and IgG2b) to a Th1 (IgG2A) bias. The ratio of IgG1/IgG2A antibody titer was 3-fold to 10-fold higher for untreated than mAb treated mice. There was also some increase in IgG (22%±13 increase) and neutralization (32% increase) in antibodies with mAb 131-2G prophylaxis at 75 days p.i. Treatment with 131-2G significantly (p≤0.001) decreased the percent of IL-4 positive CD4 and CD8 in RSV stimulated spleen cells at all times p.i. while percent of IFN-γ T cells significantly (p≤0.001) increased ≥75 days p.i. The shift from a Th2 to a Th1 biased T cell response in treated compared to untreated mice likely was directed by the much higher levels of T-box transcription factor (Tbet) (≥45% vs <10%) in CD4 and CD8 T cells and lower levels of Gata-3 (≤2% vs ≥6%) in CD4 T cells in peptide stimulated, day 75 p.i. spleen cells. These data show that the RSV G protein affects both humoral and cellular adaptive immune responses and induction of 131-2G-like antibodies might improve the safety and long term efficacy of an RSV vaccine.
    Journal of Virology 08/2014; 88(18). DOI:10.1128/JVI.01503-14 · 4.65 Impact Factor
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    ABSTRACT: Respiratory syncytial virus (RSV) is a leading pediatric pathogen that is responsible for a majority of infant hospitalizations due to viral disease. Despite its clinical importance, no vaccine prophylaxis against RSV disease or effective antiviral therapeutic is available. In this study, we established a robust high-throughput drug screening protocol by using a recombinant RSV reporter virus to expand the pool of RSV inhibitor candidates. Mechanistic characterization revealed that a potent newly identified inhibitor class blocks viral entry through specific targeting of the RSV fusion (F) protein. Resistance against this class was induced and revealed overlapping hotspots with diverse, previously identified RSV entry blockers at different stages of preclinical and clinical development. A structural and biochemical assessment of the mechanism of unique, broad RSV cross-resistance against structurally distinct entry inhibitors demonstrated that individual escape hotspots are located in immediate physical proximity in the metastable conformation of RSV F and that the resistance mutations lower the barrier for prefusion F triggering, resulting in an accelerated RSV entry kinetics. One resistant RSV recombinant remained fully pathogenic in a mouse model of RSV infection. By identifying molecular determinants governing the RSV entry machinery, this study spotlights a molecular mechanism of broad RSV resistance against entry inhibition that may affect the impact of diverse viral entry inhibitors presently considered for clinical use and outlines a proactive design for future RSV drug discovery campaigns.
    Proceedings of the National Academy of Sciences 08/2014; 111(33). DOI:10.1073/pnas.1405198111 · 9.81 Impact Factor
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    Christopher C Stobart, Martin L Moore
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    ABSTRACT: RNA viruses are capable of rapid spread and severe or potentially lethal disease in both animals and humans. The development of reverse genetics systems for manipulation and study of RNA virus genomes has provided platforms for designing and optimizing viral mutants for vaccine development. Here, we review the impact of RNA virus reverse genetics systems on past and current efforts to design effective and safe viral therapeutics and vaccines.
    Viruses 07/2014; 6(7):2531-50. DOI:10.3390/v6072531 · 3.28 Impact Factor
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    ABSTRACT: Immune-mediated lung injury is a hallmark of RSV lower respiratory tract illness. STAT4 plays a critical role in CD4+ Th1 lineage differentiation and IFN-γ protein expression by CD4+ T cells. As CD4+ Th1 differentiation is associated with negative regulation of CD4+ Th2 and Th17 differentiation, we hypothesized that RSV infection of STAT4(-/-) mice would result in enhanced lung Th2 and Th17 inflammation and impaired lung Th1 inflammation compared to WT mice. We performed primary and secondary RSV challenge in WT and STAT4(-/-) mice, and used STAT1(-/-) mice as a primary challenge positive control for the development of RSV-specific lung Th2 and Th17 inflammation. Primary RSV challenge of STAT4(-/-) mice resulted in decreased T-bet and IFN-γ expression in CD4+ T cells compared to WT mice. Lung Th2 and Th17 inflammation did not develop in primary RSV-challenged STAT4(-/-) mice. Decreased IFN-γ expression by NK cells, CD4+ T cells, and CD8+ T cells was associated with attenuated weight loss and enhanced viral clearance with primary challenge in STAT4(-/-) mice compared to WT mice. Following secondary challenge, WT and STAT4(-/-) mice also did not develop lung Th2 or Th17 inflammation. In contrast to primary challenge, secondary RSV challenge of STAT4(-/-) mice resulted in enhanced weight loss, increased lung IFN-γ expression, and an increased lung RSV-specific CD8+ T cell response compared to WT mice. These data demonstrate that STAT4 regulates the RSV-specific CD8+ T cell response to secondary infection, but does not independently regulate lung Th2 or Th17 immune responses to RSV challenge.
    Journal of Virology 06/2014; 88(17). DOI:10.1128/JVI.03299-13 · 4.65 Impact Factor
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    ABSTRACT: The Th17 cytokines IL-17A, IL-17F, and IL-22 are critical for the lung immune response to a variety of bacterial pathogens including Klebsiella pneumoniae (KP). Th2 cytokine expression in the airways is a characteristic feature of asthma and allergic airway inflammation. The Th2 cytokines IL-4 and IL-13 diminish ex vivo and in vivo IL-17A expression by Th17 cells. To determine the effect of IL-4 and IL-13 on IL-17-dependent lung immune responses to acute bacterial infection, we developed a combined model in which allergic airway inflammation and lung IL-4 and IL-13 expression were induced by ovalbumin sensitization and challenge prior to acute lung infection with KP. We hypothesized that pre-existing allergic airway inflammation decreases lung IL-17A expression and airway neutrophil recruitment in response to acute KP infection and thereby increases lung KP burden. As hypothesized, we found that allergic airway inflammation decreased KP-induced airway neutrophils and lung IL-17A, IL-17F, and IL-22 expression. Despite the marked reduction in post-infection airway neutrophilia and lung expression of Th17 cytokines, allergic airway inflammation significantly decreased lung KP burden and post-infection mortality. We showed that decreased lung KP burden was independent of IL-4, IL-5, and IL-17A, and partially-dependent on IL-13 and STAT6. Additionally, we demonstrated that decreased lung KP burden associated with allergic airway inflammation was both neutrophil and CCL8-dependent. These findings suggest a novel role for CCL8 in lung antibacterial immunity against KP and suggest new methods of orchestrating lung antibacterial immunity.
    Infection and immunity 06/2014; 82(9). DOI:10.1128/IAI.00035-14 · 4.16 Impact Factor
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    PLoS Pathogens 04/2014; 10(4):e1004016. DOI:10.1371/journal.ppat.1004016 · 8.06 Impact Factor
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    ABSTRACT: Elderly persons are more susceptible to RSV-induced pneumonia than young people, but the molecular mechanism underlying this susceptibility is not well understood. In this study, we used an aged mouse model of RSV-induced pneumonia to examine how aging alters the lung pathology, modulates antiviral gene expressions, and the production of inflammatory cytokines in response to RSV infection. Young (2-3 months) and aged (19-21 months) mice were intranasally infected with mucogenic or non-mucogenic RSV strains, lung histology was examined, and gene expression was analyzed. Upon infection with mucogenic strains of RSV, leukocyte infiltration in the airways was elevated and prolonged in aged mice compared to young mice. Minitab factorial analysis identified several antiviral genes that are influenced by age, infection, and a combination of both factors. The expression of five antiviral genes, including pro-inflammatory cytokines IL-1β and osteopontin (OPN), was altered by both age and infection, while age was associated with the expression of 15 antiviral genes. Both kinetics and magnitude of antiviral gene expression were diminished as a result of older age. In addition to delays in cytokine signaling and pattern recognition receptor induction, we found TLR7/8 signaling to be impaired in alveolar macrophages in aged mice. In vivo, induction of IL-1β and OPN were delayed but prolonged in aged mice upon RSV infection compared to young. In conclusion, this study demonstrates inherent differences in response to RSV infection in young vs. aged mice, accompanied by delayed antiviral gene induction and cytokine signaling.
    PLoS ONE 02/2014; 9(2):e88764. DOI:10.1371/journal.pone.0088764 · 3.53 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2014; 133(2):AB71. DOI:10.1016/j.jaci.2013.12.276 · 11.25 Impact Factor
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    ABSTRACT: Maternal immunization of mice with formalin inactivated respiratory syncytial virus (FI-RSV) resulted in the passive transfer of RSV antibodies but not cellular components to the offspring. The offspring born to FI-RSV immunized mothers showed serum RSV neutralizing activity, effectively controlled lung viral loads without vaccine-enhanced disease, did not induce pulmonary eosinophilia, and cytokine producing cells after live RSV infection. Therefore, this study provides evidence that maternal immunization provides an in vivo model in investigating the roles of antibodies independent of cellular components.
    Antiviral research 01/2014; DOI:10.1016/j.antiviral.2014.01.008 · 3.43 Impact Factor

Publication Stats

574 Citations
320.50 Total Impact Points

Institutions

  • 2009–2015
    • Emory University
      • Department of Pediatrics
      Atlanta, Georgia, United States
  • 2014
    • Children's Healthcare of Atlanta
      Atlanta, Georgia, United States
  • 2006–2014
    • Vanderbilt University
      • • Department of Pediatrics
      • • Department of Medicine
      Нашвилл, Michigan, United States
  • 2013
    • University of Atlanta
      Atlanta, Georgia, United States