The long-term objective of this work is to identify molecular targets on the surface of enterotoxigenic E. coli (ETEC) that could be used in a vaccine. These organisms are globally the most common bacterial cause of serious diarrheal illness, perennially the most main infection associated with diarrhea in travelers, and an emerging cause of diarrheal illness in the US. Despite the relevance of these organisms to global human health, there is presently no broadly protective ETEC vaccine available. These studies will use newly available state-of the-art technology platforms designed specifically for this purpose. These will include both DNA (gene) and protein microarrays made available by the NIAID-sponsored Pathogen Functional Genomic Resource Center. Both the gene and protein microarrays encompass known or potential virulence factors from multiple ETEC strains making them extraordinarily useful tools for vaccine discovery.
The aims of this project are:
Aim 1. Indentify: (a). genes conserved among ETEC strains isolated from cases of severe cholera-like diarrheal illness, (b). virulence factors that are altered in response to infection. Both of sets of studies will use ETEC-specific DNA microarrays made available by the PFGRC.
Aim 2. Indentify proteins that are recognized by antibodies following experimental infections in mice or natural infections in humans. These studies will use immuno-proteomic techniques including mass spectrometry and protein microarrays produced by the PFGRC.
Aim 3. Finally, this project will test the protective efficacy of proteins identified as being both highly conserved (aim 1) and recognized during infection (aim 2) in a recently developed adult mouse model of ETEC infection. Following purification of the proteins, mice will be immunized and challenged with ETEC to test the ability of the candidate vaccine molecules to prevent infection.
Enterotoxigenic Escherichia coli (ETEC) are responsible for millions of infections and hundreds of thousands of deaths due to diarrhea annually. While these infections predominate in developing countries, and are perennially the major cause of traveler's diarrhea, they are also responsible for numerous recent large-scale outbreaks in the United States. The major long-term goal of this research is to prevent these infections by development of an ETEC vaccine.
|Fleckenstein, James M; Rasko, David A (2016) Overcoming Enterotoxigenic Escherichia coli Pathogen Diversity: Translational Molecular Approaches to Inform Vaccine Design. Methods Mol Biol 1403:363-83|
|Luo, Qingwei; Vickers, Tim J; Fleckenstein, James M (2016) Immunogenicity and Protective Efficacy against Enterotoxigenic Escherichia coli Colonization following Intradermal, Sublingual, or Oral Vaccination with EtpA Adhesin. Clin Vaccine Immunol 23:628-37|
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|Kuhlmann, F Matthew; Santhanam, Srikanth; Kumar, Pardeep et al. (2016) Blood Group O-Dependent Cellular Responses to Cholera Toxin: Parallel Clinical and Epidemiological Links to Severe Cholera. Am J Trop Med Hyg 95:440-3|
|Luo, Qingwei; Qadri, Firdausi; Kansal, Rita et al. (2015) Conservation and immunogenicity of novel antigens in diverse isolates of enterotoxigenic Escherichia coli. PLoS Negl Trop Dis 9:e0003446|
|Sahl, Jason W; Sistrunk, Jeticia R; Fraser, Claire M et al. (2015) Examination of the Enterotoxigenic Escherichia coli Population Structure during Human Infection. MBio 6:e00501|
|Luo, Qingwei; Kumar, Pardeep; Vickers, Tim J et al. (2014) Enterotoxigenic Escherichia coli secretes a highly conserved mucin-degrading metalloprotease to effectively engage intestinal epithelial cells. Infect Immun 82:509-21|
|Fleckenstein, James; Sheikh, Alaullah; Qadri, Firdausi (2014) Novel antigens for enterotoxigenic Escherichia coli vaccines. Expert Rev Vaccines 13:631-9|
|Fleckenstein, James M; Sheikh, Alaullah (2014) Designing vaccines to neutralize effective toxin delivery by enterotoxigenic Escherichia coli. Toxins (Basel) 6:1799-812|
|Sheikh, Alaullah; Luo, Qingwei; Roy, Koushik et al. (2014) Contribution of the highly conserved EaeH surface protein to enterotoxigenic Escherichia coli pathogenesis. Infect Immun 82:3657-66|
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