MSTPublications: September 2017
MSTPublications: September 2017
Congratulations to all of our MSTP students on their successful publications! Take a look at the great work our students are doing.
First Author Original Research:
Dietary Manganese Promotes Staphylococcal Infection of the Heart.
Juttukonda LJ, Berends ETM, Zackular JP, Moore JL, Stier MT, Zhang Y, Schmitz JE, Beavers WN, Wijers CD, Gilston BA, Kehl-Fie TE, Atkinson J, Washington MK, Peebles RS, Chazin WJ, Torres VJ, Caprioli RM, Skaar EP.
Cell Host Microbe. 2017 Sep 20. pii: S1931-3128(17)30342-6. doi: 10.1016/j.chom.2017.08.009. [Epub ahead of print]
Read more about this paper in the VUMC Reporter here.
Bacterial pathogens must acquire nutrients from the host during infection. However, the impact of host nutritional status on bacterial acquisition of micronutrients remains poorly understood. For this project, we investigated how dietary intake of a single trace metal influences the pathogenesis of Staphylococcus aureus infection. We found that mice fed a high manganese diet are more susceptible to S. aureus infection, and higher tissue manganese levels enhance S. aureus abscess formation specifically in the heart. The mechanism for enhanced disease in the heart is multifactorial. We determined that excess manganese is bioavailable to S. aureus in the heart and demonstrated that S. aureus is protected from reactive oxygen species and neutrophil killing in a manganese-dependent manner. Thus, excess supplementation with manganese counteracts two major antibacterial strategies of the vertebrate innate immune response. From a training perspective, this was a fun project to work on because it combined immunology, bacteriology, mouse models, and mass spectrometry. This paper wouldn’t have happened without multiple awesome collaborators. If you find the topic interesting, I invite you to check out the paper or ask me about it. (By Lillian Juttukonda, M3)
Money KM, Barke TL, Serezani A, Gannon M, Garbett KA, Aronoff DM, Mirnics K.
Mol Psychiatry. 2017 Sep 26. doi: 10.1038/mp.2017.191. [Epub ahead of print]
Maternal inflammation and diabetes increase the risk for psychiatric disorders in offspring. We hypothesized that these co-occurring risk factors may potentiate each other. To test this, we maternally exposed developing mice in utero to gestational diabetes mellitus (GDM) and/or maternal immune activation (MIA). Fetal mouse brains were exposed to either vehicle, GDM, MIA or GDM+MIA. At gestational day (GD) 12.5, GDM produced a hyperglycemic, hyperleptinemic maternal state, whereas MIA produced significant increases in proinflammatory cytokines and chemokines. Each condition alone resulted in an altered, inflammatory and neurodevelopmental transcriptome profile. In addition, GDM+MIA heightened the maternal inflammatory state and gave rise to a new, specific transcriptional response. This exacerbated response was associated with pathways implicated in psychiatric disorders, including dopamine neuron differentiation and innate immune response. Based on these data, we hypothesize that children born to GDM mothers and exposed to midgestation infections have an increased vulnerability to psychiatric disorder later in life, and this should be tested in follow-up epidemiological studies. (By Kelli Money, M4)
Host Expression of the CD8 Treg/NK Cell Restriction Element Qa-1 is Dispensable for Transplant Tolerance.
Stocks BT, Wilson CS, Marshall AF, Brewer LA, Moore DJ.
Sci Rep. 2017 Sep 11;7(1):11181. doi: 10.1038/s41598-017-11780-2.
Disruption of the non-classical Major Histocompatibility Complex (MHC) Ib molecule Qa-1 impairs CD8 Treg and natural killer (NK) cell function and promotes a lupus-like autoimmune disease. This immune perturbation would be expected to enhance anti-transplant responses and impair tolerance induction, but the effect of Qa-1 deficiency on the transplant response has not been previously reported. Qa-1 deficiency enhanced CD4 TFH and germinal center (GC) B cell numbers in naïve mice and hastened islet allograft rejection. Despite enhanced immunity in B6.Qa-1-/- mice, these mice did not generate an excessive primary CD4 TFH cell response nor an enhanced alloantibody reaction. Both CD8 Tregs and NK cells, which often regulate other cells through host Qa-1 expression, were targets of anti-CD45RB therapy that had not been previously recognized. However, B6.Qa-1-/- mice remained susceptible to anti-CD45RB mediated suppression of the alloantibody response and transplant tolerance induction to mismatched islet allografts. Overall, despite enhanced immunity as demonstrated by augmented CD4 TFH/GC B cell numbers and hastened islet allograft rejection in naïve 12-week old Qa-1 deficient mice, the CD8 Treg/NK cell restriction element Qa-1 does not regulate the primary cellular or humoral alloresponse and is not required for long-term transplant tolerance. (By Blair Stocks, M4)
Co-authorships, Clinical Studies, and Reviews:
Mouse pancreatic islet macrophages use locally released ATP to monitor beta cell activity.
Weitz JR, Makhmutova M, Almaça J, Stertmann J, Aamodt K, Brissova M, Speier S, Rodriguez-Diaz R, Caicedo A.
Diabetologia. 2017 Sep 7. doi: 10.1007/s00125-017-4416-y. [Epub ahead of print]
Signals in the pancreatic islet microenvironment influence β-cell proliferation.
Aamodt KI, Powers AC.
Diabetes Obes Metab. 2017 Sep;19 Suppl 1:124-136. doi: 10.1111/dom.13031. Review.
Emerging biomarkers for cancer immunotherapy in melanoma.
Axelrod ML, Johnson DB, Balko JM.
Semin Cancer Biol. 2017 Sep 13. pii: S1044-579X(17)30121-9. doi: 10.1016/j.semcancer.2017.09.004. [Epub ahead of print] Review.
Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction.
Gaskill CF, Carrier EJ, Kropski JA, Bloodworth NC, Menon S, Foronjy RF, Taketo MM, Hong CC, Austin ED, West JD, Means AL, Loyd JE, Merryman WD, Hemnes AR, De Langhe S, Blackwell TS, Klemm DJ, Majka SM.
J Clin Invest. 2017 Jun 1;127(6):2262-2276. doi: 10.1172/JCI88629. Epub 2017 May 2.
Clinical and In Vitro Evidence That Subclinical Hemolysis Contributes to LVAD Thrombosis.
Bartoli CR, Zhang D, Kang J, Hennessy-Strahs S, Restle D, Howard J, Redline G, Bermudez C, Atluri P, Acker MA.
Ann Thorac Surg. 2017 Sep 21. pii: S0003-4975(17)30795-6. doi: 10.1016/j.athoracsur.2017.05.060. [Epub ahead of print]
Longitudinal cell-free DNA analysis in patients with small cell lung cancer reveals dynamic insights into treatment efficacy and disease relapse.
Almodovar K, Iams WT, Meador CB, Zhao Z, York S, Horn L, Yan Y, Hernandez J, Chen H, Shyr Y, Lim LP, Raymond CK, Lovly CM.
J Thorac Oncol. 2017 Sep 22. pii: S1556-0864(17)32705-3. doi: 10.1016/j.jtho.2017.09.1951. [Epub ahead of print]
Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium.
Weng LC, Lunetta KL, Müller-Nurasyid M, Smith AV, Thériault S, Weeke PE, Barnard J, Bis JC, Lyytikäinen LP, Kleber ME, Martinsson A, Lin HJ, Rienstra M, Trompet S, Krijthe BP, Dörr M, Klarin D, Chasman DI, Sinner MF, Waldenberger M, Launer LJ, Harris TB, Soliman EZ, Alonso A, Paré G, Teixeira PL, Denny JC, Shoemaker MB, Van Wagoner DR, Smith JD, Psaty BM, Sotoodehnia N, Taylor KD, Kähönen M, Nikus K, Delgado GE, Melander O, Engström G, Yao J, Guo X, Christophersen IE, Ellinor PT, Geelhoed B, Verweij N, Macfarlane P, Ford I, Heeringa J, Franco OH, Uitterlinden AG, Völker U, Teumer A, Rose LM, Kääb S, Gudnason V, Arking DE, Conen D, Roden DM, Chung MK, Heckbert SR, Benjamin EJ, Lehtimäki T, März W, Smith JG, Rotter JI, van der Harst P, Jukema JW, Stricker BH, Felix SB, Albert CM, Lubitz SA.
Sci Rep. 2017 Sep 12;7(1):11303. doi: 10.1038/s41598-017-09396-7.