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Alison Eastman
e-mail address: aljoeast@umich.edu

Mentor: Michal Olszewski, D.V.M., Ph.D.


Research Description


Immune modulation by TNFα antagonists during C. neoformans
pulmonary infection

TNF is an encapsulated yeast that causes respiratory infection in over 1 million people and kills over 600,000 people worldwide each year. It is primarily an opportunistic pathogen, infecting immunocompromised populations such as people with AIDS and transplant recipients. A Th1/Th17 T cell mediated immune response is necessary for clearance of the microbe, while a Th2/Treg T cell mediated immune response results in non-protective immunity, persistent infection and/or cryptococcal dissemination to the central nervous system and subsequent death by meningoencephalitis. TNFα is a crucial factor in host defense: hypervirulent strains of C. neoformans causing infection in immunocompetent individuals modulate the host response to produce less TNFα; AIDS patients who can no longer make TNFα are at heightened risk of death from C. neoformans infection; and patients receiving TNFα blocking antibody therapy for autoimmune diseases are at heightened risk for C. neoformans infection and its complications. Previous work with C. neoformans infection during anti-TNFα antibody treatment at day 0 has shown that while TNFα levels recover by day 14, a non-protective immune response persists in the anti-TNFα treated mice through day 28 and beyond. The mechanism by which this occurs is unknown. My thesis project investigates the effect of this TNFα depletion on dendritic cells (DCs) during cryptococcal infection. I hypothesize that TNFα is necessary to promote continuous, stable DC priming of a Th1/Th17 –type immune response by inducing epigenetic modifications promoting classical (DC1) DC activation genes and suppressing alternative (DC2) DC activation genes. I have thoroughly characterized both DCs and T cell immune polarization in a mouse model and found that in infected mice treated with anti-TNFα antibody, DC show a DC2 activation profile throughout 28 days of infection and the T cells express more Th2 and Treg cytokines and transcription factors, while DC from infected and isotype antibody treated mice have a DC1 phenotype accompanied by a robust Th1/Th17 immune response. Modeling these findings in vitro using bone marrow derived DCs (BMDCs) incubated with pro-DC1 IFNγ or pro-DC2 IL-4 in the presence or absence of TNFα, I have found that DC treated with both IFNγ and TNFα have reduced plasticity of key DC1 and DC2 genes when subsequently exposed to IL-4, indicating that the combination if IFNγ and TNFα “stabilizes” the DC1 phenotype. To assess the mechanism by which this may be occurring, I have begun by quantifying histone methyltransferase and demethylase enzyme transcript levels to determine whether any of these enzymes are induced by IFNγ, IL-4, TNFα, or the IFNγ-TNFα combination and found that histone 3 lysine 4 methyltransferase MLL1 and histone 3 lysine 27 demethylase Jmjd3 are differentially regulated between the cytokine conditions above, and further are differentially regulated in vivo. My future studies will involve modulation of epigenetic modifications through specific inhibitors of methyltransferases and demethylases, chromatin immunoprecipitation to determine which key DC1 and DC2 genes are associated with activating or repressing histone modifications, and adoptive transfer studies of “TNFα-stabilized” DCs to anti-TNFα treated, infected mice to investigate whether stabilized DCs are sufficient to confer a protective immune response to C. neoformans.


Publications

Jayadev S, Case A, Alajajian B, Eastman AJ, Möller T, Garden GA. Presenilin 2 influences miR146 level and activity in microglia. Journal of Neurochemistry. 2013 Aug 17. 127,  592-599.

Farnand AW, Eastman AJ, Herrero R, Hanson JF, Mongovin S, Altemeier WA, Matute-Bello G. Fas Activation in Alveolar Epithelial Cells Induces KC (CXCL1) Release by a MyD88-dependent Mechanism. Am J Respir Cell Mol Biol. 2011 Jan 21.

Jayadev S, Case A,
Eastman AJ, Nguyen H, Pollak J, Wiley JC, Möller T, Morrison RS, Garden GA. Presenilin 2 is the predominant γ-secretase in microglia and modulates cytokine release. PLoS One. 2010 Dec 29 ;5(12):e15743.

Lozon TI,
Eastman AJ, Matute-Bello G, Chen P, Hallstrand TS, Altemeier WA. PKR-dependent CHOP induction limits hyperoxia-induced lung injury. Am J Physiol Lung Cell Mol Physiol. 2011 Mar ;300(3):L422-9. Epub 2010 Dec 24.


Abstracts


Alison J. Eastman, Lisa M. Rogers, Katie L. Mason, David M. Aronoff. In vitro innate immune response to spores of the intrauterine pathogen Clostridium sordellii. Autumn Immunology Conference, Poster. Chicago, IL, November 2012.

Alison Eastman
, Lisa M. Rogers, Katie L. Mason, David M. Aronoff. Innate immune response to spores of intrauterine pathogen Clostridium sordellii in vivo and in vitro.
Anita Payne Symposium, Poster. Ann Arbor, MI, November 2012.

Alison J. Eastman, Jacob Carolan, Yafeng Qiu, Michael Davis, Antoni Malachowski, Michal Olszewski. Immune polarization during TNFα blockade in Cryptococcus neoformans infection. Autumn Immunology Conference, Poster. Chicago, IL, November 2013.

Alison Eastman, Jacob Carolan, Yafeng Qiu, Michael Davis, Antoni Malachowski, Michal Olszewski. Assessing the role of TNFα in Cryptococcus neoformans infection in the mouse model. Midwestern Neglected Infectious Disease Conference, Poster. Notre Dame, IN, August 2013

Eastman AJ, Carolan J, Davis M, Malachowski A, Kunkel S, Kryczek I, Olszewski MA. TNF-alpha-induced stability of DC1 programming is required for maintenance of protective Th1/Th17 immune response against Cryptococcus neoformans. 9th International Conference on Cryptococcus and Cryptococcosis, Poster. Amsterdam, Netherlands, May 2014

Eastman, AJ; Potchen, N; Carolan, J; Davis, M; Qiu, Y; Malachowski, A; Kryczek, I; Cavassani De Souza, K; Kunkel, S; Huffnagle, G; Osterholzer, J; Olszewski, M. TNFα-induced epigenetic modifications support a DC1 program in dendritic cells during protective immunity to cryptococcal infection. Midwestern Neglected Infectious Disease Conference, Notre Dame, IN, Oral, August 2014.

Eastman, AJ; He, X; Qiu, Y; Davis, M; Baht, P; Lyons, D; Park, Y; Hardison, S; Malachowski, A; Osterholzer, JJ; Wormley, F; Williamson, P; Olszewski, MA. Cryptococcal HSP70 homologue Ssa1 contributes to pulmonary expansion of C. neoformans during the afferent phase of the immune response by promoting macrophage M2 polarization. Midwestern Neglected Infectious Disease Conference, Poster, Notre Dame, IN, August 2014.

 


Awards

Rackham Predoctoral Fellowship, University of Michigan, 2014-15
Rackham Conference Travel Grant, University of Michigan, 2013
Rackham Conference Travel Grant, University of Michigan, 2012

Benard Maas Fellowship, University of Michigan, 2011


 



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