MSTPublications: October 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:
Cytomegalovirus (CMV) Epitope-Specific CD4+ T Cells Are Inflated in HIV+ CMV+ Subjects.
Abana CO, Pilkinton MA, Gaudieri S, Chopra A, McDonnell WJ, Wanjalla C, Barnett L, Gangula R, Hager C, Jung DK, Engelhardt BG, Jagasia MH, Klenerman P, Phillips EJ, Koelle DM, Kalams SA, Mallal SA.
J Immunol. 2017 Oct 2. pii: ji1700851. doi: 10.4049/jimmunol.1700851. [Epub ahead of print]
CMV infection or latency reactivation is usually asymptomatic except in immune-suppressed hosts such as HIV+ subjects or organ recipients. Conventional (low magnitudes during CMV latency) and memory-inflated (lifelong elevated magnitudes during latency) CMV-specific CD8+ T cell responses have been documented in CMV+ healthy subjects and in seroconverted organ recipients, but CD4+ T cell memory inflation has not adequately investigated. To address this, we used HLA-DR7 tetramers folded with the immunogenic DYSNTHSTRYV (DYS) epitope of CMV glycoprotein B to determine the magnitude and phenotypes of DYS+ CD4+ T cells in DR7+ CMV+ cohorts of HIV+ and HIV- subjects, ex vivo. DYS+ CD4+ T cells were inflated among the HIV+ subjects compared to either the HIV- cohort, or to CD4+ T cells from the same co-infected cohort that were specific for DR7+ epitopes of another CMV protein or other pathogens, including HIV. Importantly, the inflated response persisted for years in the co-infected subjects, documenting the first evidence for CMV-specific CD4+ T cell memory inflation to our knowledge. These cells used highly restricted T cell receptors and nearly monoclonal complementarity determining region-3 containing conserved amino-acids to recognize DYS. They expressed high CX3CR1, granzyme-B, CD38 and HLA-DR, but low CD28. These phenotypes are important for their similarity to phenotypes of CMV-specific CX3CR1+ CD4+ T cells proposed to cause endothelial damage in cardiovascular disease, indicating a potential role for memory-inflated T cell responses. The inflation mechanism did not involve apoptosis suppression, increased proliferation, or HIV gag cross-reactivity. Instead, the findings suggest that intermittent or chronic expression of epitopes, such as DYS, drive inflation of activated CD4+ T cells that home to endothelial cells and have the potential to mediate cytotoxicity and vascular disease. (By Chike Abana, G3)
Characterization of MC4R Regulation of the Kir7.1 Channel Using the Tl+ Flux Assay.
Litt MJ, Cone RD, Ghamari-Langroudi M
Methods Mol Biol. 2018;1684:211-222. doi: 10.1007/978-1-4939-7362-0_16.
The family of inward rectifying potassium channels (Kir channels) plays crucial roles in the regulation of heart rhythms, renal excretion, insulin release, and neuronal activity. Their dysfunction has been attributed to numerous diseases such as cardiac arrhythmia, kidney failure and electrolyte imbalance, diabetes mellitus, epilepsy, retinal degeneration, and other neuronal disorders. We have recently demonstrated that the melanocortin-4 receptor (MC4R), a Gαs-coupled GPCR, regulates Kir7.1 activity through a mechanism independent of Gαs and cAMP. In contrast to the many other members of the Kir channel family, less is known about the biophysical properties, regulation, and physiological functions of Kir7.1. In addition to using conventional patch clamp techniques, we have employed a high-throughput Tl+ flux assay to further investigate the kinetics of MC4R-Kir7.1 signaling in vitro. Here, we discuss the employment of the Tl+ flux assay to study MC4R -mediated regulation of Kir7.1 activity and to screen compounds for drug discovery. (By Michael Litt, M3)
Thyroid and Glucocorticoid Hormones Promote Functional T-tubule Development in Human-Induced Pluripotent Stem Cell Derived Cardiomyocytes.
Parikh SS, Blackwell DJ, Gomez-Hurtado N, Frisk M, Wang L, Kim K, Dahl CP, Fiane AE, Tønnessen T, Kryshtal DO, Louch WE, Knollmann BC.
Circ Res. 2017 Oct 2. pii: CIRCRESAHA.117.311920. doi: 10.1161/CIRCRESAHA.117.311920. [Epub ahead of print]
The discovery of induced pluripotent stem cells by Yamanaka in 2006 was expected to transform biomedical research by accelerating the development of induced pluripotent cell (iPSC) technology for regeneration of injured tissues. Heart failure often results from cardiomyocyte loss after myocardial infarction. The idea of translating iPSC-CM for repair of this injured myocardium brings great hope for combating this devastating outcome; however, progress has largely been hampered by limitations in iPSC-CM maturation that lead to fatal arrhythmias. Currently, iPSC-CM technology remains a tool and is primarily utilized for modeling cardiac disease and in safety pharmacology for assessing cardiac liability of new drugs. My interest is in maturation of human iPSC-CM, which I hypothesized could be accelerated by simply mirroring environmental conditions to that of postnatal heart development. By adding the critical developmental factors thyroid hormone and glucocorticoid hormone in combination with culturing on an extracellular matrix of physiological stiffness, our lab was able to demonstrate substantial improvement in hiPSC-CM structure and function. (By Shan Parikh, G5)
Leiomyomas in Pregnancy and Spontaneous Abortion: A Systematic Review and Meta-analysis.
Sundermann AC, Velez Edwards DR, Bray MJ, Jones SH, Latham SM, Hartmann KE.
Obstet Gynecol. 2017 Oct 6. doi: 10.1097/AOG.0000000000002313. [Epub ahead of print]
See Alex’s full infographic explaining her methods and results here!
Prior meta-analyses of the relationship between fibroids and miscarriage are restricted to or dominated by studies of women seeking reproductive assistance. In this meta-analysis, we exclude studies limited to women seeking care for recurrent miscarriage, infertility care, or assisted reproductive technologies to determine the association between fibroids and miscarriage in a population more representative of general reproductive-aged populations. We did not document evidence of increased risk of miscarriage among women with fibroids across our pooled sample of twenty thousand participants (risk ratio of 0.83 when comparing women with fibroids to those without [confidence intervals 0.68-0.98]). Of note, only a single study adjusted for critical confounders such as maternal age and race. The paucity of rigorous studies adjusting for pertinent confounders may have perpetuated the common clinical belief that fibroids are risk factors for miscarriage in women of typical reproductive potential though this is not supported by evidence in the literature. Current counseling about fibroids may lead to undue patient anxiety or the recommendation of unnecessary surgeries. (By Alex Sundermann, G3)
Co-authorships, Clinical Studies, and Reviews:
Adipose Tissue is Enriched for Activated and Late-differentiated CD8+ T cells, and Shows Distinct CD8+ Receptor Usage, Compared to Blood in HIV-infected Persons.
Koethe JR, McDonnell W, Kennedy A, Abana CO, Pilkinton M, Setliff I, Georgiev I, Barnett L, Hager CC, Smith R, Kalams SA, Hasty A, Mallal S.
J Acquir Immune Defic Syndr. 2017 Oct 14. doi: 10.1097/QAI.0000000000001573. [Epub ahead of print]
Biofilm Formation by Uropathogenic Escherichia coli Is Favored under Oxygen Conditions That Mimic the Bladder Environment.
Eberly AR, Floyd KA, Beebout CJ, Colling SJ, Fitzgerald MJ, Stratton CW, Schmitz JE, Hadjifrangiskou M.
Int J Mol Sci. 2017 Sep 30;18(10). pii: E2077. doi: 10.3390/ijms18102077.
Murine hepatitis virus nsp14 exoribonuclease activity is required for resistance to innate immunity.
Case JB, Li Y, Elliott R, Lu X, Graepel KW, Sexton NR, Smith EC, Weiss SR, Denison MR.
J Virol. 2017 Oct 18. pii: JVI.01531-17. doi: 10.1128/JVI.01531-17. [Epub ahead of print]