Mechanisms of pneumococcal persistence during carriage.

Summary

Principal Investigator: JEFFREY NEAL WEISER
Abstract: DESCRIPTION (provided by applicant): Streptococcus pneumoniae (the pneumococus) ranks among the five leading causes of infectious death worldwide. This single species accounts for a large proportion of respiratory tract (pneumonia, otitis media) and invasive (sepsis, meningitis) bacterial diseases. The development of efficacious conjugate vaccines for children has been based upon protection against the few capsule types that commonly cause disease. However, this strategy is now being eroded by the selection for and replacement by non-vaccine types. The initial step in the interaction of the pneumococcus with its host is colonization of the nasopharynx. Experience with conjugate vaccines has demonstrated that interrupting colonization results in herd immunity that amplifies prevention of disease in the population. To better understand the biology of colonization, during the prior funding period, we utilized a murine model to characterize bacterial and host factors that allow for pneumococcal persistence and its eventual clearance from the mucosal surface. These studies show that carriage, much like infection in normally sterile sites, induces acute inflammation. However, opsonophagocytic killing by this neutrophil-dominated response is not completely effective in clearing colonizing organisms. Complete clearance of carriage requires cellular immunity, and is mediated by the gradual Th17-dependent influx of tissue macrophages into the nasal lumen. The key to the success of the pneumococcus in colonization (and disease), therefore, is its ability to evade the initial inflammatory response it elicits. In specific aim#1, we will identify and characterize the complete set of pneumococcal genes and gene products contributing to evasion of opsonization and phagocytic killing by neutrophils in vitro and in vivo. The key to resolution of pneumococcal carriage appears to be recognition and uptake by macrophages. It remains unclear how the unique population of upper respiratory tract macrophages recognizes colonizing pneumococci. In specific aim#2, we will identify the macrophage receptor(s) (including scavenger receptors and C-type lectins) required for non-opsonic clearance during colonization. Finally, in specific aim#3, we will examine the role of capsule type in colonization and whether type-specific differences are explained by i) evasion of opsonophagocytic clearance by neutrophils and ii) recognition and uptake by upper respiratory tract macrophages. Together these studies will provide mechanistic insight into the three main features of pneumococcal carriage;why it is common, why it is transient, and why it varies greatly among isolates by capsule type.
Funding Period: 1996-04-01 - 2015-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Deglycosylation of human glycoconjugates by the sequential activities of exoglycosidases expressed by Streptococcus pneumoniae
    Samantha J King
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Mol Microbiol 59:961-74. 2006
  2. pmc Within-host competition drives selection for the capsule virulence determinant of Streptococcus pneumoniae
    Elena S Lysenko
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Curr Biol 20:1222-6. 2010
  3. pmc Modifications to the peptidoglycan backbone help bacteria to establish infection
    Kimberly M Davis
    Department of Microbiology, University of Pennsylvania School of Medicine, 3610 Hamilton Walk, Philadelphia, PA 19104 6076, USA
    Infect Immun 79:562-70. 2011
  4. pmc Molecular basis of increased serum resistance among pulmonary isolates of non-typeable Haemophilus influenzae
    Shigeki Nakamura
    Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
    PLoS Pathog 7:e1001247. 2011
  5. ncbi Invasive bacterial pathogens exploit TLR-mediated downregulation of tight junction components to facilitate translocation across the epithelium
    Thomas B Clarke
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Cell Host Microbe 9:404-14. 2011
  6. pmc Klebsiella pneumoniae yersiniabactin promotes respiratory tract infection through evasion of lipocalin 2
    Michael A Bachman
    Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    Infect Immun 79:3309-16. 2011
  7. pmc Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice
    Shigeki Nakamura
    Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 6076, USA
    J Clin Invest 121:3657-65. 2011
  8. pmc Nod2 sensing of lysozyme-digested peptidoglycan promotes macrophage recruitment and clearance of S. pneumoniae colonization in mice
    Kimberly M Davis
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6076, USA
    J Clin Invest 121:3666-76. 2011
  9. pmc Minimization of bacterial size allows for complement evasion and is overcome by the agglutinating effect of antibody
    Ankur B Dalia
    Department of Microbiology, University of Pennsylvania, Philadelphia, 19104, USA
    Cell Host Microbe 10:486-96. 2011
  10. pmc Phosphorylcholine allows for evasion of bactericidal antibody by Haemophilus influenzae
    Sarah E Clark
    Department of Microbiology, University of Pennsylvania, Philadelphia, PA, United States of America
    PLoS Pathog 8:e1002521. 2012

Detail Information

Publications39

  1. ncbi Deglycosylation of human glycoconjugates by the sequential activities of exoglycosidases expressed by Streptococcus pneumoniae
    Samantha J King
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Mol Microbiol 59:961-74. 2006
    ..pneumoniae to deglycosylate human targets and suggest that in addition to NanA, BgaA and StrH also contribute to pneumococcal colonization and/or pathogenesis...
  2. pmc Within-host competition drives selection for the capsule virulence determinant of Streptococcus pneumoniae
    Elena S Lysenko
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Curr Biol 20:1222-6. 2010
    ..pneumoniae type during competition. Our findings demonstrate that competition between microbes during their commensal state may underlie selection for characteristics that allow invasive disease...
  3. pmc Modifications to the peptidoglycan backbone help bacteria to establish infection
    Kimberly M Davis
    Department of Microbiology, University of Pennsylvania School of Medicine, 3610 Hamilton Walk, Philadelphia, PA 19104 6076, USA
    Infect Immun 79:562-70. 2011
    ..This review will focus specifically on peptidoglycan modifications, their role in lysozyme resistance, and downstream effects on the host immune response to infection...
  4. pmc Molecular basis of increased serum resistance among pulmonary isolates of non-typeable Haemophilus influenzae
    Shigeki Nakamura
    Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
    PLoS Pathog 7:e1001247. 2011
    ....
  5. ncbi Invasive bacterial pathogens exploit TLR-mediated downregulation of tight junction components to facilitate translocation across the epithelium
    Thomas B Clarke
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Cell Host Microbe 9:404-14. 2011
    ..These data support a general mechanism for epithelial opening exploited by invasive pathogens to facilitate movement across the epithelium to initiate disease...
  6. pmc Klebsiella pneumoniae yersiniabactin promotes respiratory tract infection through evasion of lipocalin 2
    Michael A Bachman
    Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    Infect Immun 79:3309-16. 2011
    ..However, Lcn2 retained partial protection against disseminated disease. In summary, Ybt is a virulence factor that is prevalent among KPC-producing K. pneumoniae isolates and promotes respiratory tract infections through evasion of Lcn2...
  7. pmc Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice
    Shigeki Nakamura
    Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 6076, USA
    J Clin Invest 121:3657-65. 2011
    ....
  8. pmc Nod2 sensing of lysozyme-digested peptidoglycan promotes macrophage recruitment and clearance of S. pneumoniae colonization in mice
    Kimberly M Davis
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6076, USA
    J Clin Invest 121:3666-76. 2011
    ..pneumoniae colonization event...
  9. pmc Minimization of bacterial size allows for complement evasion and is overcome by the agglutinating effect of antibody
    Ankur B Dalia
    Department of Microbiology, University of Pennsylvania, Philadelphia, 19104, USA
    Cell Host Microbe 10:486-96. 2011
    ..These observations have broad implications for how cell size and morphology can affect virulence among pathogenic microbes...
  10. pmc Phosphorylcholine allows for evasion of bactericidal antibody by Haemophilus influenzae
    Sarah E Clark
    Department of Microbiology, University of Pennsylvania, Philadelphia, PA, United States of America
    PLoS Pathog 8:e1002521. 2012
    ..Collectively, these data suggest that ChoP expression provides a selective advantage during colonization through ChoP-mediated effects on the accessibility of bactericidal antibody to the cell surface...
  11. pmc Co-infection subverts mucosal immunity in the upper respiratory tract
    Rebeccah S Lijek
    Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
    Curr Opin Immunol 24:417-23. 2012
    ..The complex microbial ecology of mucosal sites must be considered to fully understand how immune responses in a natural setting influence the outcome of host-pathogen interactions...
  12. pmc Increased chain length promotes pneumococcal adherence and colonization
    Jesse L Rodriguez
    Departments of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    Infect Immun 80:3454-9. 2012
    ..Together, our results demonstrate that morphological heterogeneity in the pneumococcus may promote colonization of the upper respiratory tract by enhancing the ability of the organism to bind to the epithelial surface...
  13. pmc Pneumococcal surface protein A inhibits complement deposition on the pneumococcal surface by competing with the binding of C-reactive protein to cell-surface phosphocholine
    Reshmi Mukerji
    Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 24294, USA
    J Immunol 189:5327-35. 2012
    ..The combined data reveal a novel mechanism of complement inhibition by a bacterial protein: inhibition of CRP surface binding and, thus, diminution of CRP-mediated complement deposition...
  14. pmc MARCO is required for TLR2- and Nod2-mediated responses to Streptococcus pneumoniae and clearance of pneumococcal colonization in the murine nasopharynx
    Michael G Dorrington
    Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8N 3Z5, Canada
    J Immunol 190:250-8. 2013
    ..Thus, MARCO is an important component of anti-S. pneumoniae responses in the murine nasopharynx during colonization...
  15. pmc Microbial modulation of host immunity with the small molecule phosphorylcholine
    Sarah E Clark
    Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA
    Infect Immun 81:392-401. 2013
    ..In this minireview, we discuss several benefits of ChoP expression during infection as well as how the immune system fights back against ChoP-expressing pathogens...
  16. pmc The battle with the host over microbial size
    Jeffrey N Weiser
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States
    Curr Opin Microbiol 16:59-62. 2013
    ..Some successful pathogens in turn are able to prevent immune mediated clearance by expressing virulence factors that block agglutination. Thus, microbial size is one of the battlegrounds between microbial survival and host defense...
  17. ncbi Pneumococcal IgA1 protease subverts specific protection by human IgA1
    E N Janoff
    Mucosal and Vaccine Research Colorado MAVRC, Division of Infectious Diseases, University of Colorado Denver, Aurora, Colorado, USA
    Mucosal Immunol 7:249-56. 2014
    ..pneumoniae by human IgA. Acquisition of IgA1 protease-neutralizing IgG after infection directs attention to IgA1 protease both as a determinant of successful colonization and infection and as a potential vaccine candidate. ..
  18. pmc The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice
    Hitesh S Deshmukh
    1 Division of Neonatology, Children s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA 2 Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
    Nat Med 20:524-30. 2014
    ..These data support a role for the intestinal microbiota in regulation of granulocytosis, neutrophil homeostasis and host resistance to sepsis in neonates. ..
  19. pmc Three surface exoglycosidases from Streptococcus pneumoniae, NanA, BgaA, and StrH, promote resistance to opsonophagocytic killing by human neutrophils
    Ankur B Dalia
    Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Infect Immun 78:2108-16. 2010
    ..These results demonstrate that deglycosylation of a human serum glycoconjugate(s) by the combined effects of NanA, BgaA, and StrH, is important for resistance to complement deposition and subsequent phagocytic killing of S. pneumoniae...
  20. ncbi Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity
    Thomas B Clarke
    Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Nat Med 16:228-31. 2010
    ..These data establish a mechanism for systemic immunomodulation by the microbiota and highlight potential adverse consequences of microbiota disruption by broad-spectrum antibiotics on innate immune defense to infection...
  21. pmc Streptococcus pneumoniae resistance to complement-mediated immunity is dependent on the capsular serotype
    Catherine Hyams
    Centre for Respiratory Research, Department of Medicine, University College Medical School, Rayne Institute, 5 University Street, London WC1E 6JJ, United Kingdom
    Infect Immun 78:716-25. 2010
    ..This might be one mechanism by which the capsular serotype can affect the relative invasiveness of different S. pneumoniae strains...
  22. pmc Epithelial cells are sensitive detectors of bacterial pore-forming toxins
    Adam J Ratner
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 281:12994-8. 2006
    ..Osmosensing may thus represent a novel innate immune response to a common bacterial virulence strategy...
  23. ncbi The atypical amino-terminal LPNTG-containing domain of the pneumococcal human IgA1-specific protease is required for proper enzyme localization and function
    Matthew H Bender
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Mol Microbiol 61:526-43. 2006
    ..This amino-terminal motif is shared among the other zinc metalloproteinases in streptococci and suggests a novel conserved mechanism for the surface localization of protease activity...
  24. pmc The blp bacteriocins of Streptococcus pneumoniae mediate intraspecies competition both in vitro and in vivo
    Suzanne Dawid
    Department of Microbiology, University of Pennsylvania, 402A Johnson Pavilion, Philadelphia, PA 19104 6076, USA
    Infect Immun 75:443-51. 2007
    ....
  25. pmc Capsule enhances pneumococcal colonization by limiting mucus-mediated clearance
    Aaron L Nelson
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6076, USA
    Infect Immun 75:83-90. 2007
    ..In conclusion, our findings demonstrate that capsule confers an advantage to mucosal pathogens distinct from its role in inhibition of opsonophagocytosis--escape from entrapment in lumenal mucus...
  26. pmc Impact of the molecular form of immunoglobulin A on functional activity in defense against Streptococcus pneumoniae
    Claudine E Fasching
    Division of Infectious Diseases and International Medicine, Veterans Affairs Medical Center, University of Minnesota, Minneapolis, MN, USA
    Infect Immun 75:1801-10. 2007
    ..In summary, the polymeric forms of IgA (both pIgA and SIgA) provide a substantial advantage in binding, agglutination, and OPC of the organism...
  27. pmc Live attenuated Streptococcus pneumoniae strains induce serotype-independent mucosal and systemic protection in mice
    Aoife M Roche
    Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104 6076, USA
    Infect Immun 75:2469-75. 2007
    ..Thus, colonization by live attenuated S. pneumoniae is a potentially safe and less complex vaccine strategy that may offer broad protection...
  28. pmc Interleukin-8 secretion in response to aferric enterobactin is potentiated by siderocalin
    Aaron L Nelson
    Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104 6076, USA
    Infect Immun 75:3160-8. 2007
    ..This may be a novel mechanism for the mucosa to respond to metabolic signals of expanding microbial communities...
  29. pmc Identifying mutator phenotypes among fluoroquinolone-resistant strains of Streptococcus pneumoniae using fluctuation analysis
    Carolyn V Gould
    Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
    Antimicrob Agents Chemother 51:3225-9. 2007
    ....
  30. pmc Nod1 signaling overcomes resistance of S. pneumoniae to opsonophagocytic killing
    Elena S Lysenko
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
    PLoS Pathog 3:e118. 2007
    ..These observations offer insight into mechanisms of microbial competition and demonstrate the importance of Nod1 in neutrophil-mediated clearance of bacteria in vivo...
  31. ncbi Neutrophil-toxin interactions promote antigen delivery and mucosal clearance of Streptococcus pneumoniae
    Kathryn A Matthias
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    J Immunol 180:6246-54. 2008
    ..This study demonstrates how microbial-host interactions affect Ag delivery and the effectiveness of mucosal immunity...
  32. ncbi Mucosal clearance of capsule-expressing bacteria requires both TLR and nucleotide-binding oligomerization domain 1 signaling
    Tracey A Zola
    Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA
    J Immunol 181:7909-16. 2008
    ..In addition, this study provides an example of a microbial virulence determinant that alters the requirements for host signaling to provide effective protection...
  33. pmc Resistance to mucosal lysozyme compensates for the fitness deficit of peptidoglycan modifications by Streptococcus pneumoniae
    Kimberly M Davis
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    PLoS Pathog 4:e1000241. 2008
    ....
  34. pmc Natural antibody to conserved targets of Haemophilus influenzae limits colonization of the murine nasopharynx
    Tracey A Zola
    Departments of Microbiology, University of Pennsylvania, Philadelphia, USA
    Infect Immun 77:3458-65. 2009
    ..The broad effect of natural IgG against genetically diverse isolates suggests the presence of conserved species-wide protective targets of antibody...
  35. pmc Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice
    Zhe Zhang
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6076, USA
    J Clin Invest 119:1899-909. 2009
    ..Our findings demonstrate that monocyte/macrophages and neutrophils recruited to the mucosal surface are key effectors in clearing primary and secondary bacterial colonization, respectively...
  36. ncbi Human neutrophils kill Streptococcus pneumoniae via serine proteases
    Alistair J Standish
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Immunol 183:2602-9. 2009
    ..Our findings show that Gram-positive pathogens are killed by human neutrophils via different mechanisms involving serine proteases...
  37. pmc Mucosal lipocalin 2 has pro-inflammatory and iron-sequestering effects in response to bacterial enterobactin
    Michael A Bachman
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    PLoS Pathog 5:e1000622. 2009
    ..Therefore, Lcn2 may represent a novel mechanism of sensing microbial metabolism to modulate the host response appropriately...
  38. ncbi The pneumococcus: why a commensal misbehaves
    Jeffrey N Weiser
    Department of Microbiology and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA
    J Mol Med (Berl) 88:97-102. 2010
    ..This review summarizes current understanding of how these characteristics may contribute to the commensal lifestyle of the pneumococcus...
  39. ncbi Antibody blocks acquisition of bacterial colonization through agglutination
    A M Roche
    Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Mucosal Immunol 8:176-85. 2015
    ..Our findings highlight the importance of agglutinating antibodies in mucosal defense and reveal how successful pathogens evade this effect. ..

Research Grants30

  1. Bacterial and host factors in pneumococcal competition
    JEFFREY NEAL WEISER; Fiscal Year: 2013
    ..abstract_text> ..
  2. Immune Regulation of Virus Clearance and Tissue Injury at Sites of Infection
    Thomas J Braciale; Fiscal Year: 2013
    ..To determine the impact of viral infection on the production of Te-derived IL- 10. The proposed studies are designed to complement ongoing related studies in Projects 2, 3 and 4. ..
  3. Novel immunotherapeutics for the management of otitis media due to H. influenzae
    Steven D Goodman; Fiscal Year: 2013
    ..e. hearing loss due to OM), a goal of Strategic Plan Priority Area I. ..
  4. Mechanisms of Haemophilus influenzae pathogenesis in the lung
    Hao Shen; Fiscal Year: 2013
    ....
  5. Identification of protective pneumococcal antigens from a surface protein library
    Yingjie Lu; Fiscal Year: 2013
    ....
  6. Zinc-binding lipoproteins of S. pneumoniae regulate invasiveness
    Justin A Thornton; Fiscal Year: 2013
    ..These studies hold potential to identify a new mechanism regulating bacterial invasion, which could be manipulated pharmacologically to decrease or prevent progression of IPD. ..
  7. Oklahoma Center for Respiratory and Infectious Diseases
    Lin Liu; Fiscal Year: 2013
    ..The completion of the goals of the present COBRE will have a major impact on research programs on respiratory infectious diseases in the State of Oklahoma. ..
  8. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  9. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  10. Southeast Regional Centers of Excellence for Biodefense &Emerging Infectious Di
    Philip Frederick Sparling; Fiscal Year: 2013
    ..SERCEB brings new investigators to the biodefense effort through a combination of educational programs, support of innovative new projects, and the synergistic interactions among its world-class investigators. ..
  11. Otitis media-associated pneumococcal genes
    Honggao Yan; Fiscal Year: 2013
    ..pneumoniae. The bacterial genes identified in this project can be targeted to treat and prevent S. pneumoniae disease by disarming the immune evasion arsenals of S. pneumoniae through novel anti-bacterial drugs and vaccines. ..
  12. Effect of the Middle Ear Inflammation On the Inner Ear
    STEVEN SUNG KYUN JUHN; Fiscal Year: 2013
    ..To achieve our goal we have assembled a group of PIs who have collaborated in recent years, and who are uniquely qualified to address this challenge with their combined expertise. ..
  13. Impact of PCV on disease and colonization among Native American communities
    KATHERINE LOUISE O'BRIEN; Fiscal Year: 2013
    ..This information will allow us to design vaccine strategies to meet these new patterns of pneumococcal disease and stay at least one step ahead of the organism changes. ..
  14. Linking the physical and chemical characteristics of Qdots to their toxicity
    TERRANCE JAMES KAVANAGH; Fiscal Year: 2013
    ..These advances can then be used in safe design and manufacturing of nanomaterials so as to maximize their utility for many applications. ..
  15. Integrating Structive Activity, Biokinetics and Response for ENP Risk Assessment
    Brian D Thrall; Fiscal Year: 2013
    ....
  16. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..