Biology subjects

Friese, M. A.

Publications and source records attributed to Friese, M. A..

3 recordsLinked to original sources

bioRxiv2026

HIV-1 promotes cell-to-cell interactions enabling spread from CD4+ T cells to microglia

HIV-1 infection of the brain occurs early in acute infection and results in neuroinflammation and - when untreated - in cognitive impairment, yet the mechanisms by which microglia become infected remain poorly defined. Evidence from simian immunodeficiency virus (SIV) studies supports a model in which infected CD4+ T cells disseminate HIV-1 to tissue macrophages, but this has not yet been confirmed for human microglia. Here, we used human monocyte-derived microglia (MDMi) and autologous HIV-1-infected primary CD4+ T cells to investigate viral transmission and immune cell interactions. Transcriptional profiling of MDMi confirmed microglia signature genes such as CX3CR1, P2RY12 and C1QB, and surface staining showed expression of CD4 and the HIV-1 coreceptor CCR5. Compared to cell-free infection, direct cell-to-cell contact between MDMi and HIV-1-infected CD4+ T cells markedly enhanced productive infection of MDMi. HIV-1 infection downmodulated the "dont-eat-me" signal CD47 and increased phosphatidylserine on the surface of primary CD4+ T cells. Consequently, HIV-1 infection of primary CD4+ T cells increased microglia-CD4+ T cell interactions and resulted in enhanced phagocytosis by MDMi. Together, this supports a mechanism where HIV-1 facilitates cell-to-cell spread from primary CD4+ T cells to microglia, which has important implications for therapeutic targeting of HIV-1 brain reservoir seeding.

immunology↗

bioRxiv2020

Enhancing mitochondrial activity in neurons protects against neurodegeneration in CNS inflammation

Central nervous system (CNS) inflammation in multiple sclerosis (MS) drives neuro-axonal loss resulting in irreversible disability. While transcripts of mitochondrial genes are strongly suppressed in neurons during CNS inflammation, it is unknown whether this results in mitochondrial dysfunction and whether interventions that increase mitochondrial function can rescue neurodegeneration. Here we show that suppression of mitochondrial gene transcripts in inflamed neurons was predominantly affecting genes of the electron transport chain resulting in impaired mitochondrial complex IV activity. This was associated with posttranslational inactivation of the transcriptional co-regulator peroxisome proliferator-activated receptor gamma co-activator 1- (PGC-1). Neuronal overexpression of Pgc-1 led to increased numbers of mitochondria, complex IV activity and elevated maximum respiratory capacity. Moreover, Pgc-1- overexpressing neurons showed a higher mitochondrial membrane potential that related to an improved calcium buffering capacity. Accordingly, neuronal deletion of Pgc-1 aggravated neurodegeneration during experimental autoimmune encephalomyelitis (EAE), while neuronal overexpression of Pgc-1 ameliorated EAE disease course and preserved neurons. Our study provides systemic insights into mitochondrial dysfunction in neurons during inflammation and commends elevation of mitochondrial activity as a promising neuroprotective strategy.

neuroscience↗

bioRxiv2020

A P2rx7 passenger mutation affects the vitality and function of immune cells in P2X4ko and other transgenic mice

Among laboratory mouse strains many genes are differentially expressed in the same cell population. As consequence, gene targeting in 129-derived embryonic stem cells (ESCs) and backcrossing the modified mice onto the C57BL/6 (B6) background can introduce passenger mutations in the close proximity of the targeted gene. Here, we demonstrate that several 129-originating transgenic mice in which P2rx7-neighboring genes were targeted carry a P2rx7 passenger mutation that affects the vitality and function of T cells. By the example of P2rx4tm1Rass we demonstrate that CD4+ and CD8+ T cells derived from these mice express higher levels of P2X7 when compared to corresponding cell populations in B6-WT mice. The increased T cell sensitivity towards the P2X7 activators adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD+) rendered these cells more vulnerable towards NAD-induced cell death (NICD) compared to their B6-WT counterparts. The enhanced NICD sensitivity significantly affected the outcome of functional assays e.g. cytokine production and cell migration. For P2rx4tm1Rass, we demonstrate that the expression of P2X7 is diminished in several innate immune cell populations, possibly as a side effect of P2rx4 targeting, and independent of the P2rx7 passenger mutation. These results need to be considered when working with P2rx4tm1Rass mice or other 129-based transgenic strains that target P2rx7 neighboring genes and might have implications for other mouse models.

immunology↗