Rajeev Aurora, Ph.D.
Molecular Microbiology and Immunology
Our long term goal is to understand the mechanisms that lead to chronic inflammation. Acute inflammation is a healthy response to infection or trauma. In contrast, chronic inflammation leads to, or exacerbates, most disease states. The process of acute inflammation has a initiation, maintenance and resolution phase. Either persistent initiation, or lack of resolution of acute inflammation can lead to a chronic activation of the immune system. To understand the genetic, epigenetic and environmental factors we use both mouse models and human studies employing both computational and laboratory tools.
Osteoimmunology: Osteoimmunology is the emerging field of the crosstalk between the immune and skeletal systems. Osteoclasts are bone resorbing cells, derived from the myeloid cell lineage, that play a key role in remodeling and maintaining bone density. We discovered that osteoclasts produce chemokines that recruit T-cells and act as antigen-presenting cells to the CD8 T-cells. Cross-presentation of antigens leads to induction of interferon-γ, IL-2, IL-6, IL-10 and CD25, FoxP3 in the CD8 T-cells. These FoxP3+ CD25+ CD-8 T-cells (TcREG) are immunosuppressive and also limit osteoclast activity. Chronic exposure to proinflammatory effector T-cells (TEFF) that produce TNFα or IL-17 can lead to bone loss, as observed in osteoporosis or arthritis. Our laboratory has demonstrated that adoptive transfer of TcREG or induction of TcREG in mice with osteoporosis can decrease bone loss and lower the levels of TEFF and to increased levels of bone formation. Our current efforts are focused on the signals that osteoclasts induce in the CD8 T-cells to induce FoxP3 and the regulatory phenotype.
Microbiome and chronic inflammation: Our laboratory is also interested in how the microbiota modulates the immune system and potentially the effect on bone homeostasis. In particular, we have examined the microbiota in patients with chronic rhinosinusitis (CRS) and control subjects. CRS is the chronic inflammation of the sinus and paranasal tissue lasting over three months. It is believed that CRS is caused by changes in the configuration of the bacterial microbiota. Surprisingly, these studies demonstrate that patients with acute rhinosinusitis have an altered sinus microbiota. In contrast, the sinus microbiota from patients with CRS was indistinguishable from control subjects. Based on these and other ongoing studies, we hypothesize that the microbiota is an epigenetic factor that contributes to maintaining health and response to disease.
Systems and population biology: An important measure of biological fitness is robustness, the ability to respond to and survive in diverse environmental conditions. One important feature of robustness is the ability to maintain homeostasis at the biochemical, cellular, organ and organismal level. Maintaining homeostasis at each of these levels requires complex network of (regulatory) interactions that are arranged as positive and negative feedback loops. In some cases, feedforward anticipatory loops are also observed. In addition to developing tools for network inference and analysis of networks, our laboratory is interested in how the regulatory loops are used in biology in general, and specifically in immune response to infections to restore homeostasis and in response to vaccinations. For instance, chronic inflammation arises due to genetic and epigenetic dysfunction(s) caused by environmental insults where the immune systems is unable to restore homeostasis. As different chronic inflammatory diseases may arise in individuals from various dysfunctions, we are also using tools of population biology to understand the contribution of genetics, epigenetics and environmental factors to disease states.
Labs and Facilities
Elena Shashkova, Ph.D.
Rajeev Aurora, Ph.D.
Cline-Smith A, Gibbs J, Shashkova E, Buchwald ZS, Novack DV, Aurora R
Pulsed low-dose RANKL as a potential therapeutic for postmenopausal osteoporosis.
JCI Insight. 2016 Aug 18;1(13). Pii:e88839.
Pubmed Abstract Link: 27570837
Shashkova EV, Trivedi J, Cline-Smith AB, Ferris C, Bushwald ZS, Gibbs J, Novack D, Aurora R
Osteoclast-Primed Foxp3+ CD8 T Cells Induce T-bet, Eomesodermin, and IFN-γ To Regulate Bone Resorption.
J Immunol. 2016 Aug 1;197(3):726-35. doi: 10.4049/jimmunol.1600253. Epub 2016 June 20.
Pubmed Abstract Link: 27324129
Anderson M, Stokken J, Sanford T, Aurora R, Sindwani R
A systematic review of the sinonasal microbiome in chronic rhinosinusitis.
Am J Rhinol Allergy. 2016 May;30(3):161-6. doi: 10.2500/ajra.2016.30.4320. Review.
Pubmed Abstract Link: 27216345
Z. Buchwald, C. Yang, S. Nellore, E. Shashkova, J. Davis, A. Cline, J. Ko, D. Novack,
R. DiPaolo, R. Aurora
A Bone Anabolic Effect of RANKL in a Murine Model of Osteoporosis Mediated Through FoxP3+ CD8 T Cells.
J Bone Miner Res. 2015 Aug;30(8):1508-22. doi: 10.1002/jbmr.2472.
Pubmed Abstract Link: 25656537
Aurora R, Sanford T.
Host Microbiota Contributes to Health and Response to Disease.
Mo Med. 2015 Jul-Aug;112(4):317-22.
Pubmed Abstract Link: 26455065
Duerr MA, Aurora R, Ford DA
Identification of glutathione adducts of α-chlorofatty aldehydes produced in activated neutrophils.
J Lipid Res. 2015 May;56(5):1014-24. doi: 10.1194/jlr.M058636. Epub 2015 Mar 26.
Pubmed Abstract Link: 25814023
M. Anderson*, Z. Buchwald*, J. Ko, R. Aurora1, T. Sanford1
Pediatric Obstructive Sleep Apnea Patients Show Altered T-Cell Populations With A Dominant TH17 Profile.
Otolaryngol Head Neck Surg. 2014 150:880-6. doi: 10.1177/01945998145217802013 * Equal contribution; 1Corresponding authors
Pubmed Abstract Link: 24486778
R. Aurora, D. Chatterjee, J. Hentzleman, G. Prasad, R. Sindwani, T. Sanford
Contrasting the Microbiomes From Healthy Volunteers and Patients With Chronic Rhinosinusitis.
JAMA Otolaryngology 2013 10.1001/jamaoto.2013.5465.
Pubmed Abstract Link: 24177790
Z. Buchwald, and R. Aurora.
Osteoclasts and CD8 T cells form a negative feedback loop that contributes to homeostasis of both the skeletal and immune systems.
Clin Dev Immunol 2013: 429373.
Pubmed Abstract Link: 23840242
Z. Buchwald, J. Kiesel, C. Yang, R. DiPaolo, D. Novack, R. Aurora
Osteoclast-induced Foxp3+ CD8 T-cells limit bone loss in mice.
Bone, 2013 56: 163-73.
Pubmed Abstract Link: 23756229
T. Zhu, J. Chappel, F. Hsu, J. Turk, R. Aurora, K. Hyrc, P. De Camilli, T. Broekelmann, R. Mecham, S. Teitelbaum, W. Zou
Type I phosphotidylinosotol 4-phosphate 5-kinase gamma regulates osteoclasts in a bifunctional manner.
J Biol Chem, 2013 288: 5268-77.
Pubmed Abstract Link: 23300084
Buchwald ZA, Kiesel JR, DiPaolo R, Pagadama MS, Aurora R
Osteoclast activated FoxP3+ CD8+ T-cells suppress bone resorption in vitro.
PLoS One 2012 Jun 6; 7(6):e38199.
Pubmed Abstract Link:22701612
Donlin MJ, Szeto B, Gohara DW, Aurora R, Tavis JE
Genome-wide networks of amino acid covariances are common among viruses.
J. Virol. 2012 Mar 86(6):3050-3063.
Pubmed Abstract Link: 22238298
Tavis JE, Donlin MJ, Aurora R, Fan X, Di Bisceglie AM.
Prospects for personalizing antiviral therapy for hepatitis C virus with pharmacogenetics.
Genome Med. 2011 Feb 8;3(2):8.
Pubmed Abstract Link: 21345258
Singh AK, Bhattacharyya-Pakrasi M, Elvitigala T, Ghosh B, Aurora R, Pakrasi HB.
A systems-level analysis of the effects of light quality on the metabolism of a cyanobacterium.
Plant Physiol. 2009 Nov;151(3):1596-608. Epub 2009 Sep 16.
Pubmed Abstract Link: 19759342
Kiesel JR, Buchwald ZS, Aurora R.
Cross-presentation by osteoclasts induces FoxP3 in CD8+ T cells.J Immunol. 2009 May 1;182(9):5477-87.
Pubmed Abstract Link: 19380796
Aurora R, Donlin MJ, Cannon NA, Tavis JE.
Genome-wide hepatitis C virus amino acid covariance networks can predict response to antiviral therapy in humans.
J Clin Invest. 2009 Jan;119(1):225-36. doi: 10.1172/JCI37085. Epub 2008 Dec 22.
Pubmed Abstract Link: 19104147
Welsh EA, Liberton M, Stöckel J, Loh T, Elvitigala T, Wang C, Wollam A, Fulton RS, Clifton SW, Jacobs JM, Aurora R, Ghosh BK, Sherman LA, Smith RD, Wilson RK, Pakrasi HB.
The genome of Cyanothece 51142, a unicellular diazotrophic cyanobacterium important in the marine nitrogen cycle.
Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):15094-9. Epub 2008 Sep 23.
Pubmed Abstract Link: 18812508
Dubec SJ, Aurora R, Zassenhaus HP.
Mitochondrial DNA mutations may contribute to aging via cell death caused by
peptides that induce cytochrome c release.
Rejuvenation Res. 2008 Jun;11(3):611-9.
Pubmed Abstract link: 18593279
Cannon NA, Donlin MJ, Fan X, Aurora R, Tavis JE; Virahep-C Study Group.
Hepatitis C virus diversity and evolution in the full open-reading frame during antiviral therapy.
PLoS ONE. 2008 May 7;3(5):e2123.
Pubmed Abstract link: 18463735
Stöckel J, Welsh EA, Liberton M, Kunnvakkam R, Aurora R, Pakrasi HB.
Global transcriptomic analysis of Cyanothece 51142 reveals robust diurnal
oscillation of central metabolic processes.
Proc Natl Acad Sci U S A. 2008 Apr 22;105(16):6156-61. Epub 2008 Apr 21.
Pubmed Abstract link: 18427117
Aurora R, Hihara Y, Singh AK, Pakrasi HB.
A network of genes regulated by light in cyanobacteria.
OMICS. 2007 Summer;11(2):166-85.
Pubmed Abstract link: 17594236
Kiesel J, Miller C, Abu-Amer Y, Aurora R.
Systems level analysis of osteoclastogenesis reveals intrinsic and extrinsic regulatory interactions.
Dev Dyn. 2007 Aug;236(8):2181-97.
Pubmed Abstract link: 17584858
Donlin MJ, Cannon NA, Yao E, Li J, Wahed A, Taylor MW, Belle SH, Di Bisceglie AM, Aurora R, Tavis JE; Virahep-C Study Group.
Pretreatment sequence diversity differences in the full-length hepatitis C virus open reading frame correlate with early response to therapy.
J Virol. 2007 Aug;81(15):8211-24.
Pubmed Abstract link: 17522222
R01AR064821-01A1. Role: PI
04/01/2014 - 03/31/2020
National Institute of Arthritis And Musculoskeletal and Skin Diseases of the NIH entitled: “A Negative Feedback Loop between Osteoclasts and CD8 T-cells”
R01AR068438-01. Role: Co-I (PI: Griggs)
08/01/2015 - 07/31/2019
National Institute of Arthritis And Musculoskeletal and Skin Diseases of the NIH entitled: “High Throughput Screening To Identify Small Molecule Rank Agonists”
05/01/2005 - 06/30/2011
U.S. Department of Energy's Biological and Environmental Research Program
Membrane Biology EMSL Scientific Grand Challenge Project
09/01/2004 - 08/31/2010
NSF Frontiers in Integrative Biological Research Program
A Systems Approach to Study Redox Regulation of Functions of Photosynthetic Organisms
Missouri Life Sciences Trust Fund
01/01/2008 - 06/30/2010
Discovery & Utilization of Enzymes for Renewable Biofuels Production