Tate, M. D. | bioRxiv Science

bioRxiv2023

Network analysis reveals strain-dependent response to misfolded tau aggregates

Mouse genetic backgrounds have been shown to modulate amyloid accumulation and propagation of tau aggregates. Previous research into these effects has highlighted the importance of studying the impact of genetic heterogeneity on modeling Alzheimers disease. However, it is unknown what mechanisms underly these effects of genetic background on modeling Alzheimers disease, specifically tau aggregate-driven pathogenicity. In this study, we induced tau aggregation in wild-derived mice by expressing MAPT (P301L). To investigate the effect of genetic background on the action of tau aggregates, we performed RNA sequencing with brains of 6-month-old C57BL/6J, CAST/EiJ, PWK/PhJ, and WSB/EiJ mice (n=64). We also measured tau seeding activity in the cortex of these mice. We identified three gene signatures: core transcriptional signature, unique signature for each wild-derived genetic background, and tau seeding-associated signature. Our data suggest that microglial response to tau seeds is elevated in CAST/EiJ and PWK/PhJ mice. Together, our study provides the first evidence that mouse genetic context influences the seeding of tau. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/526029v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1c99217org.highwire.dtl.DTLVardef@965522org.highwire.dtl.DTLVardef@1af4105org.highwire.dtl.DTLVardef@d5ea98_HPS_FORMAT_FIGEXP M_FIG C_FIG SUMMARYSeeding of tau predates the phosphorylation and spreading of tau aggregates. Acri and colleagues report transcriptomic responses to tau and elevated tau seeds in wild-derived mice. This paper creates a rich resource by combining genetics, tau biosensor assays, and transcriptomics.

neuroscience↗

bioRxiv2022

Constitutive expression and distinct properties of IFN-epsilon protect the female reproductive tract from Zika virus infection

The immunological surveillance factors controlling vulnerability of the female reproductive tract (FRT) to sexually transmitted viral infections are not well understood. Interferon-epsilon (IFN{varepsilon}) is a distinct, immunoregulatory type-I IFN that is constitutively expressed by FRT epithelium and is not induced by pathogens like other antiviral IFNs , {beta} and {lambda}. We show the necessity of IFN{varepsilon} for Zika Virus (ZIKV) protection by: increased susceptibility of IFN{varepsilon}-/- mice; their "rescue" by intravaginal recombinant IFN{varepsilon} treatment and blockade of protective endogenous IFN{varepsilon} by neutralising antibody. Complementary studies in human FRT cell lines showed IFN{varepsilon} had potent anti-ZIKV activity, associated with transcriptome responses similar to IFN{lambda} but lacking the proinflammatory gene signature of IFN. IFN{varepsilon} activated STAT1/2 pathways similar to IFN and {lambda} that were inhibited by ZIKV-encoded non-structural (NS) proteins, but not if IFN{varepsilon} exposure preceded infection. This scenario is provided by the constitutive expression of endogenous IFN{varepsilon}. However, the IFN{varepsilon} expression was not inhibited by ZIKV NS proteins despite their ability to antagonise the expression of IFN{beta} or {lambda}. Thus, the constitutive expression of IFN{varepsilon} provides cellular resistance to viral strategies of antagonism and maximises the antiviral activity of the FRT. These results show that the unique spatiotemporal properties of IFN{varepsilon} provides an innate immune surveillance network in the FRT that is a significant barrier to viral infection with important implications for prevention and therapy. Author SummaryThe female reproductive tract (FRT) is vulnerable to sexually transmitted infections and therefore a well-tuned immune surveillance system is crucial for maintaining a healthy FRT. However, our understanding of the factors that impact viral infection of the FRT and the host response are not well understood. In this work we investigate the role of a hormonally regulated type I interferon, IFN epsilon (IFN{varepsilon}) in control of Zika virus (ZIKV) infection of the FRT. IFN{varepsilon} is unique compared to other canonical type-I IFNs in that it is constitutively expressed by epithelial cells of the FRT with expression levels controlled by progesterone and not in response to viral infection. We demonstrate that IFN{varepsilon} has anti-ZIKV properties using a combination of IFN{varepsilon} KO mice, blockade of endogenous IFN{varepsilon} by neutralising Abs and rescue of IFN{varepsilon} KO mice by recombinant IFN{varepsilon} administered directly to the FRT. Furthermore, we complemented our in vivo studies using human FRT derived cell lines. Importantly, ZIKV NS proteins did not block IFN{varepsilon} expression despite their ability to antagonise the expression of IFN{beta} or {lambda}. Collectively this work implicates IFN{varepsilon} as a key type-I IFN that provides a distinct homeostatic antiviral environment in the FRT.

immunology↗