Development and characterization of type I interferon receptor knockout sheep: A model for viral immunology and reproductive signaling

Abstract

Type I interferons (IFNs) initiate immune responses to viral infections. Their effects are mediated by the type I IFN receptor, IFNAR, comprised of two subunits: IFNAR1 and IFNAR2. One or both chains of the sheep IFNAR were disrupted in fetal fibroblast lines using CRISPR/Cas9 and 12 lambs were produced by somatic cell nuclear transfer (SCNT). Quantitative reverse transcription-polymerase chain reaction for IFN-stimulated gene expression showed that IFNAR deficient sheep fail to respond to IFN-alpha. Furthermore, fibroblast cells from an IFNAR2−/− fetus supported significantly higher levels of Zika virus (ZIKV) replication than wild-type fetal fibroblast cells. Although many lambs have died from SCNT related problems or infections, one fertile IFNAR2−/− ram lived to over 4 years of age, remained healthy, and produced more than 80 offspring. Interestingly, ZIKV infection studies failed to demonstrate a high level of susceptibility. Presumably, these sheep compensated for a lack of type I IFN signaling using the type II, IFN-gamma and type III, IFN-lambda pathways. These sheep constitute a unique model for studying the pathogenesis of viral infection. Historical data supports the concept that ruminants utilize a novel type I IFN, IFN-tau, for pregnancy recognition. Consequently, IFNAR deficient ewes are likely to be infertile, making IFNAR knockout sheep a valuable model for studying pregnancy recognition. A breeding herd of 32 IFNAR2+/− ewes, which are fertile, has been developed for production of IFNAR2−/− sheep for both infection and reproduction studies.

Genomic signatures of selection, local adaptation and production type characterisation of East Adriatic sheep breeds

“…It is the Interferon regulatory factor 2 binding protein 2 which acts as a transcriptional coregulator and it was found to be involved in the fleece variation between the hairy/long coat and short/woolly fleece phenotypes [ 123 ]. Also, it was confirmed in another study about the functionality of these genes in relation to immune and reproduction response, where high and low gene signalling variants resulted in different hair phenotypes [ 124 ].…”

Role of Genetic Variants AGT rs699 and ACE2 rs2106809 in Increasing the Risk and Severity of COVID-19 Infection in Iraqi Patients

“…Interferon Tau (IFNT) or ovine trophoblast protein-1 oTP-1 is a pregnancy recognition signal in ruminants, secreted by trophectoderm after embryo elongation on day 10 and ceases after day 21 [5][6][7][8]. In addition to its role in pregnancy recognition, IFNT has other functions such as anti-luteolytic and CL protective [9], preventing rejection and supporting progesterone secretion [10].…”