? A lethal synergism exists between influenza virus and Streptococcus pneumoniae, accounting for excess mortality during influenza epidemics. The recent development of a mouse model recapitulating lethal synergism allows study of potential mechanisms underlying this synergism. The hypothesis that the sialidase activities of the viral and bacterial neuraminidases (NAs) act synergistically to promote adherence and invasion of pneumococcus will be explored. Human viruses of different subtypes and viruses engineered by reverse genetics to have different total NA activities and relative specificities for alpha (2-3) and alpha (2-6) sialic acids will be studied in bacterial adherence assays and in mouse and ferret models of synergism. The concept that differences in excess mortality based on viral subtype can be related to differences in the activity and specificity of the viral NA will be studied by comparison of these results with historical excess mortality related to particular viruses. The utility of viral NA inhibitors for abrogation of synergism will be evaluated. A detailed understanding of the interaction between influenza virus and pneumococcus will provide support for drug and vaccine based interventions aimed at amelioration of human disease and death caused by pneumococcal superinfection following influenza. More broadly, the proposed work addresses evidence that treatment of viral diseases can change the subsequent outcome of bacterial infections. The research proposed is consistent with the purpose of the RFA as it involves an intermicrobial interaction well known to cause significant human mortality, and it makes use of novel technology (reverse genetics for influenza) and novel animal models. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI054802-01
Application #
6604342
Study Section
Special Emphasis Panel (ZAI1-GPJ-M (J1))
Program Officer
Cassetti, Cristina
Project Start
2003-04-01
Project End
2005-03-30
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
1
Fiscal Year
2003
Total Cost
$225,000
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
McCullers, Jonathan A; Iverson, Amy R; McKeon, Raelene et al. (2008) The platelet activating factor receptor is not required for exacerbation of bacterial pneumonia following influenza. Scand J Infect Dis 40:11-7
Smith, Matthew W; Schmidt, Jeffrey E; Rehg, Jerold E et al. (2007) Induction of pro- and anti-inflammatory molecules in a mouse model of pneumococcal pneumonia after influenza. Comp Med 57:82-9
McAuley, Julie L; Hornung, Felicita; Boyd, Kelli L et al. (2007) Expression of the 1918 influenza A virus PB1-F2 enhances the pathogenesis of viral and secondary bacterial pneumonia. Cell Host Microbe 2:240-9
McCullers, Jonathan A (2006) Insights into the interaction between influenza virus and pneumococcus. Clin Microbiol Rev 19:571-82
McCullers, Jonathan A (2006) The clinical need for new antiviral drugs directed against influenza virus. J Infect Dis 193:751-3
Peltola, Ville T; Boyd, Kelli L; McAuley, Julie L et al. (2006) Bacterial sinusitis and otitis media following influenza virus infection in ferrets. Infect Immun 74:2562-7
Peltola, Ville T; Murti, K Gopal; McCullers, Jonathan A (2005) Influenza virus neuraminidase contributes to secondary bacterial pneumonia. J Infect Dis 192:249-57
Alymova, Irina V; Portner, Allen; Takimoto, Toru et al. (2005) The novel parainfluenza virus hemagglutinin-neuraminidase inhibitor BCX 2798 prevents lethal synergism between a paramyxovirus and Streptococcus pneumoniae. Antimicrob Agents Chemother 49:398-405
McCullers, Jonathan A (2004) Effect of antiviral treatment on the outcome of secondary bacterial pneumonia after influenza. J Infect Dis 190:519-26
Peltola, Ville T; McCullers, Jonathan A (2004) Respiratory viruses predisposing to bacterial infections: role of neuraminidase. Pediatr Infect Dis J 23:S87-97