Reduced pericytes coverage of endothelium in brain is one of the structural changes leading to breach of the Blood Brain Barrier during HIV infection. We previously showed in central memory T (TCM) cells that HIV latency increases cellular susceptibility to DNA damage. In this study we investigated susceptibility of primary brain pericytes infected with HIV-1 to DNA damage in response to glutamate and TNFα, both known to induce neuronal death during chronic inflammatory conditions. To infect pericytes, we used a single-cycle HIV-1 pseudotyped with VSV-G envelope glycoprotein and maintained the cultures until latency was established. Our data indicate that pericytes silence HIV-1 expression at similar rate compared to primary TCM cells. TNFα and IL-1β caused partial reactivation of the virus suggesting that progression of disease and neuroinflammation might facilitate virus reactivation from latency. Significant increases in the level of γH2AX, which reflect DNA damage, were observed in infected cultures exposed to TNFα and glutamate at day 2 post-infection. Glutamate, an excitatory neurologic stimuli, also caused increases in the γH2AX level in latently infected pericytes, whereas PARP and DNA-PK inhibitors caused reductions in cell population suggesting that HIV-1 latency affects repairs of single and double strand DNA breaks. For comparison, we also analyzed latently infected astrocytes and determined that DNA damage response in astrocytes is less affected by HIV-1. In conclusion, our results indicate that productive infection and HIV-1 latency in pericytes interferes with DNA damage response, rendering them vulnerable to the agents that are characteristic of chronic neuroinflammatory disease conditions.
Mexican Americans (MAs) are the fastest-growing Hispanic population segment in the US; as this population increases in age, so will the societal burden of age-related diseases such as Alzheimer’s disease (AD). Mitochondrial DNA (mtDNA) damage may be implicated in MA AD risk since metabolic comorbidities are more prevalent in this group. Oxidative damage to guanosine (8oxoG) is one of the most prevalent DNA lesions and a putative indicator of mitochondrial dysfunction. Testing blood samples from participants of the Texas Alzheimer’s Research and Care Consortium, we found mtDNA 8oxoG mutational load to be significantly higher in MAs compared to non-Hispanic whites and that MA females are differentially affected. Furthermore, we identified specific mtDNA haplotypes that confer increased risk for oxidative damage and suggestive evidence that cognitive function may be related to 8oxoG burden. Our understanding of these phenomena will elucidate population- and sex-specific mechanisms of AD pathogenesis, informing the development of more precise interventions and therapeutic approaches for MAs with AD in the future.
Lung metastasis is a leading cause of cancer-related deaths. Here, we show that intranasal delivery of our engineered CpG-coated tumor antigen (Tag)-encapsulated nanoparticles (NPs)—nasal nano-vaccine—significantly reduced lung colonization by intravenous challenge of an extra-pulmonary tumor. Protection against tumor-cell lung colonization was linked to the induction of localized mucosal-associated effector and resident memory T cells as well as increased bronchiolar alveolar lavage-fluid IgA and serum IgG antibody responses. The nasal nano-vaccine-induced T-cell-mediated antitumor mucosal immune response was shown to increase tumor-specific production of IFN-γ and granzyme B by lung-derived CD8+ T cells. These findings demonstrate that our engineered nasal nano-vaccine has the potential to be used as a prophylactic approach prior to the seeding of tumors in the lungs, and thereby prevent overt lung metastases from existing extra pulmonary tumors.
Oxidative stress, placental mitochondrial morphological alterations, and impaired bioenergetics are associated with hypertensive disorders of pregnancy. Here we examined mitochondrial DNA mutational load in pregnant women with pregnancy-induced hypertension and reanalyzed publicly available high-throughput transcriptomic datasets from maternal and fetal tissues from normotensive and hypertensive pregnancies. Mitochondrial dysregulation was indicated by aberrant mitochondrial gene expression, and putative consequences were examined. Women with hypertensive pregnancy had elevated mitochondrial DNA mutational load. Maternal mitochondrial dysregulation in hypertensive pregnancies was associated with pathways involved in inflammation, cell death/survival, and placental development. In fetal tissues from hypertensive pregnancies, mitochondrial dysregulation was associated with increased extracellular vesicle production. Our study demonstrates mitochondria-mediated maternal-fetal interactions during healthy pregnancy and maternal mitochondrial dysregulation in hypertensive pregnancy development.
Alzheimer’s Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65+) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latinx population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer’s Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk. Our results show that 8oxoG levels in both buffy coat and plasma were significantly associated with population, sex, years of education, and reveal a potential association with AD. Furthermore, MAs are significantly burdened by mtDNA oxidative damage in both blood fractions, which may contribute to their metabolic vulnerability to developing AD.
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