CBC 18th Annual Symposium: POSTER SESSION

Alzheimer’s Disease (AD) involves disruption of the immune system and has a disproportionate impact on African Americans. AD is known to damage the hippocampus, a key structure within the brain responsible for encoding and storing new information, and to be closely linked with a deterioration in the aging process. Both AD and aging, have been associated with expansions of senescent T cells- a critical component of the adaptive immune response system. The Bocarsly lab recently reported that compared to younger individuals, older individuals have an increasing accumulation of senescent CD8+ T cells, and to a lesser extent, senescent CD4+ T cells. T cells become senescent due to age-related dysfunction in telomeres, and outside factors that induce cellular stress, including immune response to infections. This leads us to ask whether higher levels of CD8+ T-cell senescence, the aging of the immune system is associated with the risk and progression of AD. Therefore, it might serve as an immune biomarker for AD. To test this, we recruited 29 COVID-19 vaccinated older African Americans (ages 60 and above) who underwent immunological, cognitive, behavioral, and neural assessments as part of the ongoing longitudinal study of Pathways to Healthy Aging in African Americans at Rutgers University. Our preliminary data showed that peripheral blood mononuclear cells (PBMCs) isolated from African Americans display high CD8+ T cells with high senescence-associated -galactosidase (SA-Gal) activity in participants with lower levels of P-Tau 231 (a measure of AD pathology), and a increase in dynamic flexibility of the Medial Temporal Lobe network from fMRI resting-state measures of connectivity. Moreover, a deeper understanding of the neuroimmunological linkages between cellular senescence and AD may result in better treatments and advances in the field of AD and related dementias.

Diana Grass <Diana.grass@rutgers.edu>

Rutgers University Newark

Center for Molecular and Behavioral Neuroscience

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Background: The COVID-19 mRNA-based vaccines, while proven to be efficacious in the general population, still require detailed assessments of immune protection in vulnerable patient populations. End-stage renal disease patients experience uremia-driven immune compromise including high vaccination failure rates. This immune compromise, coupled with greater risk of exposure to infectious disease at maintenance hemodialysis (HD) centers, necessitate an examination of vaccine efficacy in the HD population.

Methods: The humoral immune response to the Covid-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. Anti-Spike IgG titers and antibody neutralization assays were quantified prior to the first vaccination dose (V1D0) and seven days after the second dose (V2D7). Anti-Spike IgG titers were additionally quantified six months after initial vaccination. Clinical history and lab values in HD patients were obtained to identify baseline and early predictors of vaccination response.

Results: Anti-Spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with only a slight reduction in titers in HD groups (p < 0.05). Anti-Spike IgG remained elevated above baseline at six months in both subject groups. Anti-Spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Additionally, baseline serum ferritin values in the intermediate range and log-fold change in WBCs were predictive of antibody development.

Conclusion: We show that patients on maintenance HD develop a substantial humoral immune response to the BNT162b2 mRNA COVID-19 vaccine, and that antibodies to the SARS-CoV-2 spike protein are persistently elevated six months after initial vaccination.

Jessica Lee

University of Illinois at Chicago, Departments of Microbiology and Immunology, Bioengineering, and Medicine

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Diabetes mellitus is a condition in which either the pancreas does not produce enough insulin, or the cells of the body do not respond properly to the insulin produced, resulting in high levels of sugar in the bloodstream. We hypothesized that epigenetic changes in pancreatic beta cells in the pancreas, the main insulin-producing cells in the body, may contribute to the etiology of diabetes. To test this hypothesis, we treated human pancreatic beta cells derived from induced pluripotent stem cells (iPSCs) with either high (20 mM) or low (2mM) glucose for 14 days. We found epigenetic changes in several hundred genes, including those involved in many signaling pathways, especially glucose metabolism and insulin secretion. Other pathways affected were those involved in oxytocin metabolism, gastric acid secretion, calcium signaling, and adrenergic signaling. Our study suggests that diabetes may, at least in part, be caused by epigenetic changes in pancreatic beta cells.

Rasha Alhazzaa <rasha.alhazzaa@bison.howard.edu>

Howard University

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The Accelerator Award program supports translational research and provide university researchers with “early commercial guidance.” Accelerator Awards intend to support the initial, and therefore highest risk, stage of commercially-directed research focused on the development of a therapeutic or an associated biomarker or diagnostic. The program encourages interactions between academic researchers and industry/pharmaceutical experts early in the development of projects and provides advice to award recipients in setting and progressing toward commercialization milestones. Award recipients will be mentored by faculty, industry experts, tech transfer officers and CBC personnel. Accelerator awardees will provide project updates at CBCAN meetings.

The CBC Accelerator Network (CBCAN) program brings together industry experts, university tech transfer officers, researchers and others from the local and extended biomedical ecosystem with discoveries that may have commercial potential. The aim is to move promising discoveries into and forward in the pipeline towards commercialization, providing early commercial guidance that universities and university-based researchers need.

Nancy Tyrell

Chicago Biomedical Consortium

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Rationale: Individuals with COPD who develop COVID-19 are at increased risk of hospitalization, ICU admission and death. COPD is associated with increased airway epithelial expression of ACE2, that binds and mediates SARS-CoV-2 entry into cells. Hypercapnia, elevation of CO2 in blood and tissue, commonly develops in advanced COPD and is associated with frequent and potentially fatal pulmonary infections. We previously showed that hypercapnia alters expression of viral response genes and increases cholesterol bio-synthesis genes in primary human bronchial epithelial (HBE) cells. Interestingly, cellular cholesterol is involved in virus entry. Thus, in the current study, we explored whether hypercapnia increases ACE2 expression and uptake of a Pseudo-SARS-CoV-2 baculovirus into the cells and if the master regulator of cholesterol metabolism, sterol-regulatory element binding protein 2 (SREBP2), is involved in these effects.

Methods: Differentiated HBE cells, BEAS-2B or VERO cells were incubated in normocapnia (5% CO2, PCO2 36 mmHg) or hypercapnia (15% CO2, PCO2 108 mmHg). ACE2 protein expression was assessed by immunoblot or immunofluorescence, and cholesterol by Amplex red assay. Also, cells pre-exposed to normocapnia or hypercapnia were infected with Pseudo SARS-CoV-2. For in vivo studies, C57BL/6 mice were pre-exposed to normoxic hypercapnia (10% CO2/21% O2) for 7 days, or air, and ACE2 expression in airways was assessed by immunofluorescence. SREBP2 was blocked using betulin or AM580.

Results: Hypercapnia increased cellular cholesterol and ACE2 protein expression in epithelial cells in vivo and in vitro. This effect was reversed by blocking SREBP2. Additionally, hypercapnia augmented Pseudo SARS-CoV-2 entry into cells, effect reduced by SREBP2 inhibitors.

Conclusion: Hypercapnia creates a high-cholesterol cellular environment that induces increased ACE2 expression and Pseudo-SARS-CoV-2 entry. This may lead to a greater burden of SARS-CoV-2 infection in patients with hypercapnia, and in part account for worse clinical outcomes of COVID-19 pneumonia in advanced COPD and other severe lung diseases.

Marina Casalino-Matsuda

Northwestern University

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