The goal of this research project is to understand the molecular mechanisms responsible for the opposing functions of Type I versus Type II interferon (IFN) in controlling the replication of and the pathogenesis associated with the intracellular pathogen Mycobacterium leprae (mLEP) in skin. The disease associated with mLEP varies in different patients with a large spectrum from self-limited, tuberculoid (T-lep) patients with expression of the Th1 cytokine IFN-gamma (Type II) in lesions to disseminated lepromatous (L-lep) patients with expression of immunosuppressive cytokines such as IL-10 in lesions. We were among the first groups made the initial discovery that, while Type II IFN is required for, Type I IFN (mainly IFN-alpha-s and IFN-Beta) plays a detrimental role in host defense against bacterial infections. However, the molecular mechanisms responsible for the effects of Type I and Type II IFNs on mLEP infection and disease development remain to be elucidated. Through close collaboration with Dr. Robert Modlin's group over the past ten years, it became clear that Type I IFN inducible genes are preferentially upregulated in L-lep lesions whereas Type II IFN inducible genes are preferentially upregulated in T-lep lesions. More importantly, we have identified a subset of Type II IFN inducible genes in T-lep lesions that have potential antimicrobial activities and a subset of Type I IFN inducible genes in L-lep lesions that may not only suppress immune responses but also promote pathogenesis of leprosy. We hypothesize that Type ll and Type I IFNs play opposite roles in controlling the mLEP infection and associated diseases by differentially inducing antimicrobial and immunosuppressive gene programs, respectively. We propose to : 1) identify the Type I vs. Type II IFN gene programs in leprosy lesions;2) determine the anti-mLEP activities of type II interferon inducible genes upregulated in T-lep;3) define type I IFN inducible gene programs in suppressing host immunity against mLEP and promoting pathogenesis. We believe our proposed studies will not only help us understand the molecular mechanisms responsible for the opposing functions of Type I and II IFN in controlling mLEP but also provide insight for novel therapeutic tools for skin and systemic inflammatory associated diseases.
The goal of this research project is to understand the molecular mechanisms responsible for the opposing functions of Type I versus Type II interferons in controlling the growth of the bacteria that causes the skin disease leprosy. We found that the expression of Type I and Type II interferons in leprosy skin lesions correlates with the clinical presentation of the disease. Our proposed studies should provide insight for novel therapeutic tools for skin and systemic inflammatory associated diseases.
|Nielson, Carrie M; Jones, Kerry S; Bouillon, Roger et al. (2016) Role of Assay Type in Determining Free 25-Hydroxyvitamin D Levels in Diverse Populations. N Engl J Med 374:1695-6|
|Nielson, Carrie M; Jones, Kerry S; Chun, Rene F et al. (2016) Free 25-Hydroxyvitamin D: Impact of Vitamin D Binding Protein Assays on Racial-Genotypic Associations. J Clin Endocrinol Metab 101:2226-34|
|Lam, Larry; Chin, Lydia; Halder, Ramesh C et al. (2016) Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients. FASEB J 30:3461-3473|
|Tong, Ann-Jay; Liu, Xin; Thomas, Brandon J et al. (2016) A Stringent Systems Approach Uncovers Gene-Specific Mechanisms Regulating Inflammation. Cell 165:165-79|
|Srikanth, P; Chun, R F; Hewison, M et al. (2016) Associations of total and free 25OHD and 1,25(OH)2D with serum markers of inflammation in older men. Osteoporos Int 27:2291-300|
|Busch, Martin; Herzmann, Christian; Kallert, Stephanie et al. (2016) Lipoarabinomannan-Responsive Polycytotoxic T Cells Are Associated with Protection in Human Tuberculosis. Am J Respir Crit Care Med 194:345-55|
|Cunningham, Cameron R; Champhekar, Ameya; Tullius, Michael V et al. (2016) Type I and Type II Interferon Coordinately Regulate Suppressive Dendritic Cell Fate and Function during Viral Persistence. PLoS Pathog 12:e1005356|
|Inkeles, Megan S; Teles, Rosane M B; Pouldar, Delila et al. (2016) Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy. JCI Insight 1:e88843|
|Jenkinson, Carl; Taylor, Angela E; Hassan-Smith, Zaki K et al. (2016) High throughput LC-MS/MS method for the simultaneous analysis of multiple vitamin D analytes in serum. J Chromatogr B Analyt Technol Biomed Life Sci 1014:56-63|
|Cappuccio, Antonio; Zollinger, RaphaÃ«l; Schenk, Mirjam et al. (2015) Combinatorial code governing cellular responses to complex stimuli. Nat Commun 6:6847|
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