We propose to continue our studies of the superantigen (Sag) exotoxins produced by pathogenetic strains of Staphylococcus aureus and Streptococcus pyogenes. We will focus primarily on four members of this family, the staphylococcal enterotoxins SEA, SEB and SEE and the related streptococcal superantigen SSA, which we isolated and characterized during the initial period of support. These Sag are chosen for study because of functional and structural properties that make them particularly suitable for answering the questions posed and because of the valuable library of molecular variants of the relevant genes and their products that we have developed. Our overall objective is to enhance understanding of the interaction between bacterial parasites and mammalian hosts and the mechanisms whereby Sag alter this relationship.
Five specific aims are proposed: 1) Definition of those elements of the staphylococcal enterotoxins SEA and SEE and of T cell receptors that determine their interactions with one another; 2) Characterization of class II-independent Sag presentation, including definition of the responsible cell surface ligand; 3) Comparative studies of SEB with SSA and its alleles and mutants, based on structural resolution and functional analysis in order to explore the relationship between Sag potency, MHC class II and TCR interactions; 4) Analysis of the mechanism of interaction between SEA and the affinity ligand red dye A to determine whether definition of the biochemical specificity of this interaction can provide insight into biological activities of bacterial Sag and to extend use of this strategy for the identification of additional novel Sag, e.g., from M. tuberculosis; and 5) Use of SEA insertion and deletion mutants of S. aureus to assess the role of SEA in S. aureus pathogenesis in mice and to determine effects of infection with an enterotoxin-producing strain on host immune responses. We believe that the experiments proposed are conceptually novel and the experiments designed to answer them general decisive. They can be expected to improve understanding of fundamental aspects of mammalian immune response to Sag and Sag-producing bacterial pathogens and to provide insight into pathogenetic mechanisms of Sag-mediated human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI030036-09
Application #
2886661
Study Section
Immunobiology Study Section (IMB)
Program Officer
Ash-Shaheed, Belinda
Project Start
1991-07-01
Project End
2001-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
9
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Lun, Shichun; Miranda, David; Kubler, Andre et al. (2014) Synthetic lethality reveals mechanisms of Mycobacterium tuberculosis resistance to ?-lactams. MBio 5:e01767-14
Maiga, Mamoudou; Ammerman, Nicole C; Maiga, Mariama C et al. (2013) Adjuvant host-directed therapy with types 3 and 5 but not type 4 phosphodiesterase inhibitors shortens the duration of tuberculosis treatment. J Infect Dis 208:512-9
Be, Nicholas A; Bishai, William R; Jain, Sanjay K (2012) Role of Mycobacterium tuberculosis pknD in the pathogenesis of central nervous system tuberculosis. BMC Microbiol 12:7
Pelly, Shaaretha; Bishai, William R; Lamichhane, Gyanu (2012) A screen for non-coding RNA in Mycobacterium tuberculosis reveals a cAMP-responsive RNA that is expressed during infection. Gene 500:85-92
Maiga, Mamoudou; Abaza, Ahmed; Bishai, William R (2012) Current tuberculosis diagnostic tools & role of urease breath test. Indian J Med Res 135:731-6
Maiga, Mamoudou; Lun, Shichun; Guo, Haidan et al. (2012) Risk of tuberculosis reactivation with tofacitinib (CP-690550). J Infect Dis 205:1705-8
Maiga, Mamoudou; Agarwal, Nisheeth; Ammerman, Nicole C et al. (2012) Successful shortening of tuberculosis treatment using adjuvant host-directed therapy with FDA-approved phosphodiesterase inhibitors in the mouse model. PLoS One 7:e30749
Pieroni, Marco; Tipparaju, Suresh K; Lun, Shichun et al. (2011) Pyrido[1,2-a]benzimidazole-based agents active against tuberculosis (TB), multidrug-resistant (MDR) TB and extensively drug-resistant (XDR) TB. ChemMedChem 6:334-42
Olaleye, Omonike; Raghunand, Tirumalai R; Bhat, Shridhar et al. (2011) Characterization of clioquinol and analogues as novel inhibitors of methionine aminopeptidases from Mycobacterium tuberculosis. Tuberculosis (Edinb) 91 Suppl 1:S61-5
Jassal, Mandeep S; Nedeltchev, Gueno G; Osborne, Jonathan et al. (2011) A modified scoring system to describe gross pathology in the rabbit model of tuberculosis. BMC Microbiol 11:49

Showing the most recent 10 out of 40 publications