Persistent Adaptive Response Research Articles

Persistence of Integrase-Deficient Lentiviral Vectors Correlates with the Induction of STING-Independent CD8+ T Cell Responses

Lentiviruses are among the most promising viral vectors for invivo gene delivery. To overcome the risk of insertional mutagenesis, integrase-deficient lentiviral vectors (IDLVs) have been developed. We show here that strong and persistent specific cytotoxic Tcell (CTL) responses are induced by IDLVs, which persist several months after a single injection. These responses were associated with the induction of mild and transient maturation of dendritic cells (DCs) and with the production of low levels of inflammatory cytokines and chemokines. They were independent of the IFN-I, TLR/MyD88, interferon regulatory factor (IRF), retinoic acid induced gene I (RIG-I), and stimulator of interferon genes (STING) pathways but require NF-κB signaling in CD11c+ DCs. Despite the lack of integration of IDLVs, the transgene persists for 3months in the spleen and liver of IDLV-injected mice. These results demonstrate that the capacity of IDLVs to trigger persistent adaptive responses is mediated by a weak and transient innate response, along with the persistence of the vector in tissues.

Emergent memory in cell signaling: Persistent adaptive dynamics in cascades can arise from the diversity of relaxation time-scales

The mitogen-activated protein kinase (MAPK) signaling cascade, an evolutionarily conserved motif present in all eukaryotic cells, is involved in coordinating crucial cellular functions. While the asymptotic dynamical behavior of the pathway stimulated by a time-invariant signal is relatively well-understood, we show using a computational model that it exhibits a rich repertoire of transient adaptive responses to changes in stimuli. When the signal is switched on, the response is characterized by long-lived modulations in frequency as well as amplitude. On withdrawing the stimulus, the activity decays over long timescales, exhibiting reverberations characterized by repeated spiking in the activated MAPK concentration. The long-term persistence of such post-stimulus activity suggests that the cascade retains memory of the signal for a significant duration following its removal. The molecular mechanism underlying the reverberatory activity is related to the existence of distinct relaxation rates for the different cascade components. This results in the imbalance of fluxes between different layers of the cascade, with the reuse of activated kinases as enzymes when they are released from sequestration in complexes. The persistent adaptive response, indicative of a cellular “short-term” memory, suggests that this ubiquitous signaling pathway plays an even more central role in information processing by eukaryotic cells.

RAGE and TLRs as Key Targets for Antiatherosclerotic Therapy.

Receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs) are the key factors indicating a danger to the organism. They recognize the microbial origin pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). The primary response induced by PAMPs or DAMPs is inflammation. Excessive stimulation of the innate immune system occurs in arterial wall with the participation of effector cells. Persistent adaptive responses can also cause tissue damage and disease. However, inflammation mediated by the molecules innate responses is an important way in which the adaptive immune system protects us from infection. The specific detection of PAMPs and DAMPs by host receptors drives a cascade of signaling that converges at nuclear factor-κB (NF-κB) and interferon regulatory factors (IRFs) and induces the secretion of proinflammatory cytokines, type I interferon (IFN), and chemokines, which promote direct killing of the pathogen. Therefore, signaling of these receptors' pathways also appear to present new avenue for the modulation of inflammatory responses and to serve as potential novel therapeutic targets for antiatherosclerotic therapy.

Maternal fructose consumption programs gene expression pattern in intestine of male offspring

Metabolic programming of insulin‐sensitive processes by maternal diet has been demonstrated for liver, pancreas, and muscle of offspring, but has not been evaluated for small intestine. To determine the effects of maternal (MAT) and postweaning diet (PWT) on intestinal programming, male offspring of Sprague Dawley females fed either a 60% starch diet (CON), 60% fructose diet (FRU) or protein restricted diet (LP) throughout pregnancy and lactation were weaned to either a CON, FRU or a 30% fat diet (FAT). Intestinal mRNA expression was evaluated at 18 weeks for all nine MAT×PWT groups. Glucose 6 phosphatase (G6Pase) was elevated in FRUFAT compared with FRUCON offspring (3.98 ± 0.70 vs. 1.16 ± 0.53, P < 0.05) with a similar tendency for PEP carboxykinase (PCK1) (2.95 ± 0.62 vs. 1.53 ± 0.47, P=0.07). G6Pase and PCK1 mRNA levels in offspring from CON and LP dams were not affected by the FAT diet (G6Pase: CONFAT vs. CONCON, 0.46 ± 0.50 vs. 1.17 ± 0.64, LPFAT vs. LPCON, 0.84 ± 0.56 vs. 1.92 ± 0.56, PCK1: CONFAT vs. CONCON, 0.57 ± 0.44 vs. 1.33 ± 0.53, LPFAT vs. LPCON, 0.95 ± 0.53 vs. 0.82 ± 0.53). Collectively, offspring from FRU dams had more (P < 0.05) PCG‐1α mRNA compared with offspring of CON or LP dams (1.31 ± 0.14 vs. 0.89 ± 0.13 or 0.85 ± 0.14, respectively). These data indicate a persistent adaptive response for intestinal gene expression in offspring that is sensitive to maternal fructose consumption and amplified with postweaning fat intake.Grant Funding Source: NIH DK077581