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

Abstract

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...

Disruption of Zika Virus xrRNA1-Dependent sfRNA1 Production Results in Tissue-Specific Attenuated Viral Replication

“…Previous studies have also shown that type II and type III IFN responses are critical to the control of acute RNA virus infections in the brain and placenta, respectively [ 23 , 24 , 25 , 26 ]. Recent studies investigating the antiviral response to alphavirus infection of the central nervous system (CNS) have identified IFN-γ and the type II IFN response as being vital for the control of RNA viruses [ 23 , 24 , 25 , 26 , 27 ]. Given that we found differences in type I IFN deficient mice, future studies evaluating the interactions between xrRNA1 mutant ZIKV and type II and III IFN responses will be critical to fully understand the mechanisms of the sfRNA1 function in different tissues.…”

“…Previous studies have shown that sfRNA1 deficiency does not alter the growth of WNV or DENV in cultured host cells but does result in reduced cytopathic effect and plaque size [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. Differential expression of sfRNA isotypes assists in host adaptation for some flaviviruses [ 35 , 36 , 37 , 38 ].…”

“…Differential expression of sfRNA isotypes assists in host adaptation for some flaviviruses [ 35 , 36 , 37 , 38 ]. However, ZIKV consistently produces equal amounts of sfRNA1 and 2 in both mosquito and mammalian host cells, suggesting that the production of a specific sfRNA species is not crucial for survival in different hosts [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. We show that xrRNA1 mutant ZIKV maintains a loss of sfRNA1 expression in splenic tissue following infection.…”

Evaluation in Swine of a Recombinant African Swine Fever Virus Lacking the MGF-360-1L Gene

“…InterPro sequence analysis [ 26 ] of MGF360-1L revealed that amino acids 99-309 are those that distinguish MGF360-1L as a member of the MGF360 family. Furthermore, MGF360-1L is not detected in the proteome of ASFV viral particles, which would be expected of genes involved in viral DNA replication [ 27 ]. These predicted domains and locations in the genome are shown in Figure 1 .…”

Disruption of Zika virus xrRNA1-dependent sfRNA1 production results in tissue-specific attenuated viral replication

“…We utilized the ZIKV xrRNA1 tertiary structure to construct a mutant with a single nucleotide change that disrupts xrRNA1 structure and eliminates sfRNA1 production without significantly altering the sequence of the ZIKV 3'UTR. We show for the first time that targeted have identified IFN-γ and the type II IFN response as being vital for the control of RNA viruses [20,24]. Given, that we found differences in type 1 IFN deficient mice, future studies evaluating the interactions between xrRNA1 mutant ZIKV and type II and III IFN responses will be critical to fully understand the mechanisms of the sfRNA1 function in different tissues.…”