De Silva, A. | bioRxiv Science

bioRxiv2021

Intergenerational Stress Transmission is Associated with Brain Metabotranscriptome Remodeling andMitochondrial Dysfunction

Intergenerational stress increases lifetime susceptibility to depression and other psychiatric disorders. Whether intergenerational stress transmission is a consequence of in utero neurodevelopmental disruptions vs early-life mother-infant interaction is largely unknown. Here, we demonstrated that exposure to traumatic stress in mice during pregnancy, through predator scent exposure, induces in the offspring social deficits and depressive-like behavior. We found, through cross-fostering experiments, that raising of normal pups by traumatized mothers produced a similar behavioral phenotype to that induced in pups raised by their biological traumatized mothers. Good caregiving (by non-traumatized mothers), however, did not completely protect against the prenatal trauma-induced behavioral deficits. These findings support a two-hit stress mechanism of both in utero and early-life parenting (poor caregiving by the traumatized mothers) environments. Associated with the behavioral deficits, we found profound changes in brain metabolomics and transcriptomic (metabotranscriptome). Striking increases in the mitochondrial hypoxia marker and epigenetic modifier 2-hydroxyglutaric acid, in the brains of neonatal and adult pups whose mothers were exposed to stress during pregnancy, indicated mitochondrial metabolism dysfunctions and epigenetic mechanisms. Bioinformatic analyses revealed mechanisms involving stress- and hypoxia-response metabolic pathways in the brains of the neonatal mice, which appear to lead to long-lasting alterations in mitochondrial-energy metabolism, and epigenetic processes pertaining to DNA and chromatin modifications. Most strikingly, we demonstrated that an early pharmacological intervention that can correct mitochondria metabolism - lipid metabolism and epigenetic modifications with acetyl-L-carnitine (ALCAR) supplementation - produces long-lasting protection against the behavioral deficits associated with intergenerational transmission of traumatic stress. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/438868v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1fb2500org.highwire.dtl.DTLVardef@13a5c6forg.highwire.dtl.DTLVardef@8aa512org.highwire.dtl.DTLVardef@5b6906_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Defining levels of dengue virus serotype-specific neutralizing antibodies induced by a live attenuated tetravalent dengue vaccine (TAK-003)

The four dengue virus serotypes (DENV1-4) infect several hundred million people each year living in tropical and sub-tropical regions. Clinical development of DENV vaccines is difficult because immunity to a single serotype increases risk of severe disease during a second infection with a new serotype. Leading vaccines are based on tetravalent formulations to induce simultaneous and balanced protective immunity to all 4 serotypes. TAK-003 is a tetravalent live attenuated dengue vaccine candidate developed by Takeda Vaccines Inc, which is currently being evaluated in phase 3 efficacy trials. Here, we use antibody depletion methods and chimeric, epitope transplant DENVs to characterize the specificity of neutralizing antibodies in dengue-naive adults and non-human primates immunized with TAK-003. Our results demonstrate that TAK-003 induced high levels of DENV2 neutralizing antibodies that recognized unique (type-specific) epitopes on DENV2. In contrast, most vaccinated subjects developed lower levels of DENV1, DENV3 and DENV4 neutralizing antibodies that mainly targeted epitopes that were conserved (cross-reactive) between serotypes. We conclude that the DENV2 component in the vaccine is immunodominant because of the high levels of serum neutralizing antibodies targeting type-specific epitopes. We also conclude that DENV1, 3 and 4 vaccine components are less immunogenic because most study subjects did not develop type-specific serum neutralizing antibodies to these serotypes. While DENV vaccine development has been guided by the presence of neutralizing antibodies to each serotype as a benchmark, our results indicate that the presence of neutralizing antibodies alone are not a reliable indicator of the immunogenicity of each vaccine component. Author summaryThe development of tetravalent dengue vaccines has been guided by neutralizing antibodies to each serotype as a correlate of safe and effective vaccine induced immunity. However, the absolute levels of neutralizing antibodies to each serotype has proven to be an unreliable correlate of protection. Levels of antibodies to epitopes that are unique to each serotype, which are measures of immunity independently stimulated by each vaccine component, rather than total quantity of neutralizing antibodies, are likely to be better correlates of protection. Here, we mapped the specificity of antibodies induced by the Takeda tetravalent dengue vaccine TAK-003 in monkeys and humans with no prior immunity to dengue. The TAK-003 vaccine induces high levels of serotype 2 specific neutralizing antibodies that map to known protective epitopes. In contrast, the serotype 1, 3 and 4 neutralizing antibody responses are lower and mainly consist of cross-reactive antibodies binding to epitopes conserved between serotypes. These heterotypic antibodies, which are most likely derived from the serotype 2 component, may not provide long term protection in vivo.

immunology↗