Opportunistic infections of the central nervous system are common complication in acquired immunodeficiency syndrome (AIDS) patients. Cryptococcus neoformans (Cne) is an encapsulated yeast that causes often fatal cryptococcal meningoencephalitis (CM) in 7-30% of AIDS patients. While highly active anti-retroviral therapy has successfully decreased the incidence of many opportunistic infections, it is less effective in decreasing the incidence of opportunistic fungal infections in advanced AIDS patients. The host's response to Cne is a complex interplay between the innate and adaptive immunities. In animal models, the inability to increase the brain levels of proinflammatory cytokines or promote leukocyte migration into the brain is typically associated with lethal CM. Thus, """"""""proinflammatory"""""""" responses are required to contain Cne infection in the central nervous system. Epidemiological studies show that cigarette smoking is a significant risk factor in cryptococcosis and other opportunistic fungal infections, and >85% of AIDS patients with cryptococcosis are cigarette smokers. However, the mechanism by which smoking affects the pathogenesis of Cne is totally unknown. We have demonstrated that cigarette smoke suppresses the immune system, and nicotine (NT) is a major immunosuppressive component of cigarette smoke that causes T cell anergy and inhibits the inflammatory responses. Our preliminary studies suggest that chronic NT treatment inhibits chemokinesis/chemotaxis and the migration of leukocytes to the site of inflammation, decreases brain IL-1beta expression in response to an inflammatory stimuli such as turpentine and Cne, and promotes growth and early dissemination of Cne into the brain. Therefore, we hypothesize that cigarette smoke/NT modulates both the innate and adaptive immune responses to Cne, thus facilitating its dissemination to the brain and the development CM. To test this hypothesis and to identify mechanism(s) by which NT facilitates brain infection by Cne, the following studies are proposed: 1. To investigate the effects of NT on Cne-induced innate immunity, including the expression of proinflammatory cytokines/chemokines in the brain and the response of leukocytes to cytokines/chemokines that are affected by Cne, to establish the kinetics of Cne and leukocyte migration into the brain and the development of CM, and to examine the effects of NT on the Cne-induced fever response. 2. To ascertain the effects on the adaptive immune responses including generation of anti-Cne antibodies, proliferative and delayed-type hypersensitivity responses to cryptococcal antigens, and generation of cytotoxic T cells to immunodominant epitopes of Cne proteins, as well as to evaluate the protective function of T cells that migrate into the brain after Cne infection. 3. To investigate the mechanisms by which NT suppresses the migration of leukocytes toward the site of infection. These studies, we believe, will delineate the mechanism(s) by which smoking/NT encourages dissemination of Cne and, perhaps, other fungal infections into the brain of AIDS patients, and identify potential therapeutic targets for treatment of CM.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA017003-04
Application #
7071172
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Purohit, Vishnudutt
Project Start
2003-09-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
4
Fiscal Year
2006
Total Cost
$390,600
Indirect Cost
Name
Lovelace Biomedical & Environmental Research
Department
Type
DUNS #
045911138
City
Albuquerque
State
NM
Country
United States
Zip Code
87108
Gundavarapu, Sravanthi; Wilder, Julie A; Mishra, Neerad C et al. (2012) Role of nicotinic receptors and acetylcholine in mucous cell metaplasia, hyperplasia, and airway mucus formation in vitro and in vivo. J Allergy Clin Immunol 130:770-780.e11
Singh, Shashi P; Gundavarapu, Sravanthi; Peña-Philippides, Juan C et al. (2011) Prenatal secondhand cigarette smoke promotes Th2 polarization and impairs goblet cell differentiation and airway mucus formation. J Immunol 187:4542-52
Langley, Raymond J; Mishra, Neerad C; Peña-Philippides, Juan Carlos et al. (2011) Fibrogenic and redox-related but not proinflammatory genes are upregulated in Lewis rat model of chronic silicosis. J Toxicol Environ Health A 74:1261-79
Razani-Boroujerdi, Seddigheh; Langley, Raymond J; Singh, Shashi P et al. (2011) The role of IL-1? in nicotine-induced immunosuppression and neuroimmune communication. J Neuroimmune Pharmacol 6:585-96
Mishra, Neerad C; Rir-sima-ah, Jules; Boyd, R Thomas et al. (2010) Nicotine inhibits Fc epsilon RI-induced cysteinyl leukotrienes and cytokine production without affecting mast cell degranulation through alpha 7/alpha 9/alpha 10-nicotinic receptors. J Immunol 185:588-96
Langley, Raymond J; Mishra, Neerad C; Pena-Philippides, Juan Carlos et al. (2010) Granuloma formation induced by low-dose chronic silica inhalation is associated with an anti-apoptotic response in Lewis rats. J Toxicol Environ Health A 73:669-83
Singh, Shashi P; Mishra, Neerad C; Rir-Sima-Ah, Jules et al. (2009) Maternal exposure to secondhand cigarette smoke primes the lung for induction of phosphodiesterase-4D5 isozyme and exacerbated Th2 responses: rolipram attenuates the airway hyperreactivity and muscarinic receptor expression but not lung inflammation and a J Immunol 183:2115-21
Mishra, Neerad C; Rir-Sima-Ah, Jules; Langley, Raymond J et al. (2008) Nicotine primarily suppresses lung Th2 but not goblet cell and muscle cell responses to allergens. J Immunol 180:7655-63
Razani-Boroujerdi, Seddigheh; Behl, Muskaan; Hahn, Fletcher F et al. (2008) Role of muscarinic receptors in the regulation of immune and inflammatory responses. J Neuroimmunol 194:83-8
Razani-Boroujerdi, Seddigheh; Sopori, Mohan L (2007) Early manifestations of NNK-induced lung cancer: role of lung immunity in tumor susceptibility. Am J Respir Cell Mol Biol 36:13-9

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