Oas1b-dependent Immune Transcriptional Profiles of West Nile Virus Infection in the Collaborative Cross

Green, Richard; Wilkins, Courtney; Thomas, Sunil; Sekine, Aimee; Hendrick, Duncan M.; Voss, Kathleen; Ireton, Reneé C.; Mooney, Michael A.; Go, Jennifer T.; Choonoo, Gabrielle; Jeng, Sophia; Villena, Fernando P Pardo Manuel De; Ferris, Martin T.; McWeeney, Shannon K.; Gale, Michael

doi:10.1534/g3.117.041624

Cited by 45 publications

(41 citation statements)

References 61 publications

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“…RNA viruses, including the alphavirus chikungunya virus (CHIKV), target IRGM to promote virus replication [42,43]. Another antiviral protein system highly induced by IFN-γ signaling during SINV infection of neurons was the 2 -5 -oligoadenylate synthetase (OAS) family, a pathway that affects replication of several neurotropic viruses, including rabies virus, canine distemper virus, West Nile virus (WNV), and JEV [29,[44][45][46]. Two other antiviral genes usually more robustly induced by type I than type II IFNs, Rsad2 and Zc3hav1, were induced later and to lesser extents.…”

Section: Discussionmentioning

confidence: 99%

Interferon-Gamma Modulation of the Local T Cell Response to Alphavirus Encephalomyelitis

Baxter

Griffin

2020

Viruses

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Infection of mice with Sindbis virus (SINV) provides a model for examining the role of the immune response to alphavirus infection of the central nervous system (CNS). Interferon-gamma (IFN-γ) is an important component of this response, and we show that SINV-infected differentiated neurons respond to IFN-γ in vitro by induction of antiviral genes and suppression of virus replication.To determine the in vivo effects of IFN-γ on SINV clearance and T cell responses, C57BL/6 mice lacking IFN-γ or IFN-γ receptor-1 were compared to wild-type (WT) mice after intracranial SINV infection. In WT mice, IFN-γ was first produced in the CNS by natural killer cells and then by CD4 + and CD8 + T cells. Mice with impaired IFN-γ signaling initiated clearance of viral RNA earlier than WT mice associated with CNS entry of more granzyme B-producing CD8 + T cells. However, these mice established fewer CD8 + tissue-resident memory T (T RM ) cells and were more likely to experience reactivation of viral RNA synthesis late after infection. Therefore, IFN-γ suppresses the local development of granzyme B-expressing CD8 + T cells and slows viral RNA clearance but promotes CD8 + T RM cell establishment.Viruses 2020, 12, 113 2 of 25 virus is no longer recoverable, but declining levels of viral RNA are still readily detectable. Finally, in Phase 3, from 60 days through at least a year and presumably for the life of the animal, viral RNA persists at a low level [10,11].The immune response to alphavirus infection in the CNS presents a double-edged sword: while local production of antibody and IFN-γ clears infectious virus [6-9], T cell-mediated inflammation is responsible for many of the pathological changes and much of the neurological damage produced [12][13][14]. CD8 + T cells participate in clearance of viral RNA because CD8 and B2m knockout mice clear viral RNA more slowly from the brains and spinal cords than wild-type (WT) mice [3].IFN-γ, an important product of natural killer (NK) cells and CD4 + and CD8 + T cells, exerts its antiviral effects by inducing IFN-stimulated genes (ISGs), but also by modulating the immune response to infection. The IFN-γ receptor is a heterotetramer of ligand-binding IFN-γR1 and signaling IFN-γR2 expressed on many cell types, including neurons [15]. IFN-γ binding to its receptor triggers a Jak/Stat signaling pathway that can induce expression of over 200 ISGs, some of which have direct antiviral activity, while others modulate the immune response [15][16][17]. IFN-γ is particularly important for clearance of infectious virus from spinal cord neurons [7]. IFN-γ-induced immunomodulatory effects include immune cell activation, trafficking, and differentiation, as well as more direct intracellular antiviral activities [18].IFN-γ is detectable in the CNS within 3 days after infection, peaks at 7 days and becomes undetectable by 10-14 days, although IFN-γ mRNA remains elevated for months [9]. Previous studies have shown that mice with impaired IFN-γ signaling produce lower levels of inflammatory cytokines and chemo...

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Section: Discussionmentioning

confidence: 99%

Interferon-Gamma Modulation of the Local T Cell Response to Alphavirus Encephalomyelitis

Baxter

Griffin

2020

Viruses

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“…The CC and its founders have been used to successfully identify genetic association for several traits, including spontaneous colitis and susceptibility to infection by viruses such as Ebola, West Nile, Severe Acute Respiratory Syndrome, and influenza (Ferris et al 2013;Chesler 2014;Rasmussen et al 2014;Gralinski et al 2015Gralinski et al , 2017Green et al 2017). The CC is an ideal population to study fertility since it contains a large amount of genetic diversity, has wide variation in fertility, and has complementary resources to validate discoveries (Threadgill and Churchill 2012;Morgan and Welsh 2015;Morgan et al 2017).…”

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confidence: 99%

Male Infertility Is Responsible for Nearly Half of the Extinction Observed in the Mouse Collaborative Cross

et al. 2017

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The goal of the Collaborative Cross (CC) project was to generate and distribute over 1000 independent mouse recombinant inbred strains derived from eight inbred founders. With inbreeding nearly complete, we estimated the extinction rate among CC lines at a remarkable 95%, which is substantially higher than in the derivation of other mouse recombinant inbred populations. Here, we report genome-wide allele frequencies in 347 extinct CC lines. Contrary to expectations, autosomes had equal allelic contributions from the eight founders, but chromosome had significantly lower allelic contributions from the two inbred founders with underrepresented subspecific origins (PWK/PhJ and CAST/EiJ). By comparing extinct CC lines to living CC strains, we conclude that a complex genetic architecture is driving extinction, and selection pressures are different on the autosomes and chromosome Male infertility played a large role in extinction as 47% of extinct lines had males that were infertile. Males from extinct lines had high variability in reproductive organ size, low sperm counts, low sperm motility, and a high rate of vacuolization of seminiferous tubules. We performed QTL mapping and identified nine genomic regions associated with male fertility and reproductive phenotypes. Many of the allelic effects in the QTL were driven by the two founders with underrepresented subspecific origins, including a QTL on chromosome for infertility that was driven by the PWK/PhJ haplotype. We also performed the first example of cross validation using complementary CC resources to verify the effect of sperm curvilinear velocity from the PWK/PhJ haplotype on chromosome 2 in an independent population across multiple generations. While selection typically constrains the examination of reproductive traits toward the more fertile alleles, the CC extinct lines provided a unique opportunity to study the genetic architecture of fertility in a widely genetically variable population. We hypothesize that incompatibilities between alleles with different subspecific origins is a key driver of infertility. These results help clarify the factors that drove strain extinction in the CC, reveal the genetic regions associated with poor fertility in the CC, and serve as a resource to further study mammalian infertility.

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“…Gralinski et al 2017) and West Nile(Green et al 2017) virus infections to those associated with fertility(Shorter et al 2017) allergensKelada (2016) Morgan et al (2016). andDumont et al (2017) also provide insights into genome structure.…”

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confidence: 99%

Back to the Future: Multiparent Populations Provide the Key to Unlocking the Genetic Basis of Complex Traits

Koning

McIntyre

2017

Genetics

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Oas1b-dependent Immune Transcriptional Profiles of West Nile Virus Infection in the Collaborative Cross

Cited by 45 publications

References 61 publications

Interferon-Gamma Modulation of the Local T Cell Response to Alphavirus Encephalomyelitis

Interferon-Gamma Modulation of the Local T Cell Response to Alphavirus Encephalomyelitis

Male Infertility Is Responsible for Nearly Half of the Extinction Observed in the Mouse Collaborative Cross

Back to the Future: Multiparent Populations Provide the Key to Unlocking the Genetic Basis of Complex Traits

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