Assistant Professor
MD 1996 George Washington University
MPH 1992 UCLA
RESEARCH
Project 1: Innate Immune Responses to Filaria and Wolbachia. One focus of current research is to define the role of the filarial symbiont Wolbachia and innate toll-like receptors (TLRs) in the pathogenesis of filarial diseases, including onchocerciasis (River Blindness) and human lymphatic filariasis. Wolbachia are obligate endosymbiotic gram negative bacteria related to Rickettsia and are required for embryogenesis and development in filarial nematodes (Figure 1). We have found a critical role for TLR2/1 in Wolbachia induced inflammation. Polymorphisms (SNPs) in key TLR and signaling molecule genes will be assayed in populations from filarial endemic areas (CWRU study site in Papua New Guinea) using high throughput multiplexed analysis. This work will help characterize host immunogenetic factors that play a role in the pathogenesis of filarial diseases and extend earlier studies of limited TLR2 and TLR4 polymorphisms in human filariasis (Hise, Genes and Immun, 2003).
Project 2: Host Responses to Oral Microbes. A second area of investigation is to define the regulation of IL-1β in oral candidiasis. We have developed a murine model of oropharyngeal candidiasis (OPC) to define the innate immune pathways involved in susceptibility to oral colonization, dissemination of infection, and persistence of infection. In this funded project, critical innate receptors involved in the pathogenesis of localized and disseminated infection in OPC will be identified, including TLRs and dectin-1 (R01DE018279, start date 04/07). The synthesis, processing and release of IL-1β are tightly regulated and require at least three distinct stimuli. An inflammatory stimulus causes accumulation of large intracellular stores of the 31-kDa pro-IL-1β (step 1), while a second stimulus activates a multiprotein complex, commonly referred to as the “inflammasome”, which controls the activation of caspase-1 and cleavage of the pro-IL-1β (step 2) followed by release of the active mature 17-kDa IL-1β (step 3). The activation of caspase-1 (step 2) is controlled by the inflammasome, which consists of one or more NALP proteins. This project will define the role of TLRs, dectin-1 and adaptors in the transcriptional regulation of pro-IL-1β (signal 1) as well as examine the contribution of the NALP3/ASC inflammasome complex in the activation of caspase-1 and the processing of proIL-1β (signal 2) in response to Candida albicans.
Other projects. Additionally my lab is investigating innate immune receptors and pathways in viral infections including Rift Valley Fever Virus (RVFV), a Category A biodefense pathogen, with collaborators Dr. Charles King and Dr. Desiree LaBeaud (CWRU) and Dr. CJ Peters (UTMB, Galveston, TX). Our goal is to elucidate critical receptors, including TLRs, RIGi and Mda-5 and signaling pathways in host protective type-I IFN responses to RVFV. Future directions will include field-based studies in order to define TLR responses of individuals with and without RVFV-related clinical diseases, and to correlate polymorphisms in key TLR and innate response genes with variations in clinical outcome and vaccine response.
SELECT PUBLICATIONS
Gillette-Ferguson I, Daehnel K, Hise AG, Sun Y, Carlson E, Diaconu E, McGarry HF, Taylor MJ, Pearlman E. TLR2 regulates CXC chemokine production and neutrophil recruitment to the cornea in Onchocerca volvulus/Wolbachia keratitis (river blindness). Infect Immun. 2007 Sep 17; [Epub ahead of print]
Daehnel, K., et al., Filaria/Wolbachia activation of dendritic cells and development of Th1-associated responses is dependent on Toll-like receptor 2 in a mouse model of ocular onchocerciasis (river blindness). Parasite Immunol, 2007. 29(9): p. 455-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17727569
Gillette-Ferguson, I., et al., TLR2 regulates CXC chemokine production and neutrophil recruitment to the cornea in Onchocerca volvulus/Wolbachia keratitis (river blindness). Infect Immun, 2007.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17875630
Gillette-Ferguson, I., et al., Wolbachia- and Onchocerca volvulus-induced keratitis (river blindness) is dependent on myeloid differentiation factor 88. Infect Immun, 2006. 74(4): p. 2442-5.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16552075
Hise, A.G., et al., Innate immune responses to endosymbiotic Wolbachia bacteria in Brugia malayi and Onchocerca volvulus are dependent on TLR2, TLR6, MyD88, and Mal, but not TLR4, TRIF, or TRAM. J Immunol, 2007. 178(2): p. 1068-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17202370
Hise, A.G., I. Gillette-Ferguson, and E. Pearlman, Immunopathogenesis of Onchocerca volvulus keratitis (river blindness): a novel role for TLR4 and endosymbiotic Wolbachia bacteria. J Endotoxin Res, 2003. 9(6): p. 390-4.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14733727
Hise, A.G., et al., Polymorphisms of innate immunity genes and susceptibility to lymphatic filariasis. Genes Immun, 2003. 4(7): p. 524-7.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14551607
Saint Andre, A., et al., The role of endosymbiotic Wolbachia bacteria in the pathogenesis of river blindness. Science, 2002. 295(5561): p. 1892-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11884755
CONTACT INFORMATION
Phone: 216-368-5036
FAX: 216-368-4825
Email: axh48@case. edu
PUBLICATIONS
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