Microsporidia are important protozoan parasites in human immunodeficiency (HIV) infected patients. A recent study showed up to 40% of patients with AIDS associated diarrheas were shedding microsporidia. These parasites have also been recently implicated in causing illness to non-HIV-infected travelers and immunocompetent elderly individuals. The host immune response generated against these pathogens remains understudied. The limited studies available with Enc. cuniculi, a microsporidia that can be easily cultured in the laboratory, have emphasized the importance of T cells in the protection against the parasite. T cell deficient mice, unlike the immunocompetent animals are unable to resolve the infection. Our laboratory has demonstrated that among the T cell subsets, CD8+ cytotoxic T lymphocytes play a dominant role in protection against E.cuniculi administered via intraperitoneal route. However, during an oral infection both CD4 and CD8+ T cells contribute to protective immunity against the parasites. As microsporidia are acquired orally, it is critical that the gut immune response evoked against the infection be characterized and mechanism of protection understood. Recent studies from our laboratory have shown that per oral Enc.cuniculi infection induces a strong and prolonged intraepithelial lymphocyte (IEL) response in the gut. IELs isolated from the infected animals exhibit strong antigen-specific cytotoxicity and cytokine response. Thus IELs appear to play an important role in mucosal immune response against the parasite. Understanding the kinetics and mechanism of IEL mediated protection will form a basis for generating immunotherapeutic agents against these pathogens. The proposal comprises of three specific aims. In the first specific aim the induction of IEL response to Enc. Cuniculi infection will be evaluated. Role of dendritic cells (DCs) from the Peyer's patches in priming IEL response in the gut will be assayed. Finally the mechanism by which Peyer's patch DCs and IEL response will be studied. In the second specific aim, the role of different IEL subsets in the regulation of mucosal immunity against Enc. cuniculi infection will be assayed. The mechanism of IEL mediated protection against the parasite will be evaluated. In the third specific aim long-term IEL response against the pathogen will be analyzed. Our preliminary data suggests that immune IELs in the Enc.cuniculi infected mice persist for a long period. Development and mechanism of persistence of long-term antigen specific IELs (memory IELs) in the infected animals will be evaluated. ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-AARR-B (04))
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Wali, Tonu M
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George Washington University
Schools of Medicine
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Moretto, Magali M; Khan, Imtiaz A; Weiss, Louis M (2012) Gastrointestinal cell mediated immunity and the microsporidia. PLoS Pathog 8:e1002775
Moretto, Magali M; Lawlor, Elizabeth M; Khan, Imtiaz A (2010) Lack of interleukin-12 in p40-deficient mice leads to poor CD8+ T-cell immunity against Encephalitozoon cuniculi infection. Infect Immun 78:2505-11
Moretto, Magali M; Lawlor, Elizabeth M; Xu, Yanji et al. (2010) Purified PTP1 protein induces antigen-specific protective immunity against Encephalitozoon cuniculi. Microbes Infect 12:574-9
Lawlor, Elizabeth M; Moretto, Magali M; Khan, Imtiaz A (2010) Optimal CD8 T-cell response against Encephalitozoon cuniculi is mediated by Toll-like receptor 4 upregulation by dendritic cells. Infect Immun 78:3097-102
Moretto, Magali M; Lawlor, Elizabeth M; Khan, Imtiaz A (2008) Aging mice exhibit a functional defect in mucosal dendritic cell response against an intracellular pathogen. J Immunol 181:7977-84
Moretto, Magali M; Weiss, Louis M; Combe, Crescent L et al. (2007) IFN-gamma-producing dendritic cells are important for priming of gut intraepithelial lymphocyte response against intracellular parasitic infection. J Immunol 179:2485-92
Moretto, Magali; Weiss, Louis M; Khan, Imtiaz A (2004) Induction of a rapid and strong antigen-specific intraepithelial lymphocyte response during oral Encephalitozoon cuniculi infection. J Immunol 172:4402-9
Bacchi, Cyrus J; Weiss, Louis M; Lane, Schenella et al. (2002) Novel synthetic polyamines are effective in the treatment of experimental microsporidiosis, an opportunistic AIDS-associated infection. Antimicrob Agents Chemother 46:55-61
Moretto, M; Durell, B; Schwartzman, J D et al. (2001) Gamma delta T cell-deficient mice have a down-regulated CD8+ T cell immune response against Encephalitozoon cuniculi infection. J Immunol 166:7389-97
Moretto, M; Casciotti, L; Durell, B et al. (2000) Lack of CD4(+) T cells does not affect induction of CD8(+) T-cell immunity against Encephalitozoon cuniculi infection. Infect Immun 68:6223-32

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