CD4 + T cells require either B cells or CD8 + T cells to control spread and pathogenesis of a neurotropic infection

Solomos, Andreas C.; O'Regan, Kevin J.; Rall, Glenn F.

doi:10.1016/j.virol.2016.09.013

Cited by 9 publications

(10 citation statements)

References 29 publications

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“…Both T cells and IFNγ are critical to the survival of adult CD46+ mice. CD46+ adult mice lacking mature T and B cells (CD46+/RAG2-KO) experience 100% mortality during infection, whereas CD46+ adult mice lacking only B cells do not succumb to the infection (Solomos et al, 2016). CD46+ adult mice that lack IFNγ (CD46+/IFNγ-KO) do not clear the virus, with ~50% of the mice succumbing to the infection within 21 dpi (O’Donnell, Conway, 2012).…”

Section: Resultsmentioning

confidence: 99%

The neonatal anti-viral response fails to control measles virus spread in neurons despite interferon-gamma expression and a Th1-like cytokine profile

Ganesan

Chandwani

Creisher

et al. 2018

Journal of Neuroimmunology

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Neonates are highly susceptible to viral infections in the periphery, potentially due to deviant cytokine responses. Here, we investigated the role of interferon-gamma (IFNγ), a key anti-viral in the neonatal brain. We found that (i) IFNγ, which is critical for viral control and survival in adults, delays mortality in neonates, (ii) IFNγ limits infiltration of macrophages, neutrophils, and T cells in the neonatal brain, (iii) neonates and adults differentially express pathogen recognition receptors and Type I interferons in response to the infection, (iv) both neonates and adults express IFNγ and other Th1-related factors, but expression of many cytokines/chemokines and IFNγ-responsive genes is age-dependent, and (v) administration of IFNγ extends survival and reduces CD4 T cell infiltration in the neonatal brain. Our findings suggest age-dependent expression of cytokine/chemokine profiles in the brain and distinct dynamic interplays between lymphocyte populations and cytokines/chemokines in MV-infected neonates.

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Section: Resultsmentioning

confidence: 99%

The neonatal anti-viral response fails to control measles virus spread in neurons despite interferon-gamma expression and a Th1-like cytokine profile

Ganesan

Chandwani

Creisher

et al. 2018

Journal of Neuroimmunology

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“…While there is a role of type I IFNs in limiting viral replication in neurons, there are open questions about the mechanisms used by T cells to target these cells. For example, the non-cytolytic clearance of Measles (the cause of sub-acute sclerosing panencephalitis) and Sindbis from neurons is IFN-γ dependent ( Binder and Griffin, 2001 , Patterson et al., 2002 ) and there appears to be a bystander role for CD4 + T cells in some of these events ( Solomos et al., 2016 ). In “carrier mice” that have an established LCMV infection in neurons, there is a literature that identifies “therapeutic” CD8 + T cells as being important in elimination of this virus pool through the production of IFN-γ that licenses microglia to purge virus, present antigen, and amplify the local antiviral T cell response ( Herz et al., 2015 , Oldstone et al., 1986 , Pinschewer et al., 2010 ).…”

Section: Main Textmentioning

confidence: 99%

Protective and Pathological Immunity during Central Nervous System Infections

2017

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The concept of immune privilege of the central nervous system (CNS) has dominated the study of inflammatory processes in the brain. However, clinically relevant models have highlighted the innate pathways that limit pathogen invasion of the CNS and that adaptive immunity mediates control of many neural infections. Because protective responses can result in bystander damage there are regulatory mechanisms that balance protective and pathological inflammation but which may also allow microbial persistence. The focus of this review is to consider the host-pathogen interactions that influence neurotropic infections and to highlight advances in understanding of innate and adaptive mechanisms of resistance as key determinants of the outcome of CNS infection. Advances in these areas have broadened our comprehension of how the immune system functions in the brain and can readily overcome immune privilege.

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“…Studies using the herpesviruses VZV and HSV have shown that T rm lymphocytes are necessary to maintain viral latency (14-21, 23, 30). Considering that T cells are paramount for controlling acute neuronal MV infection in our model (31,32), coupled with the knowledge that T rm lymphocytes prevent viral RT-qPCR data were generated using randomhexamer priming for cDNA generation, followed by qPCR using primers specific for the MV nucleoprotein and cyclophilin B as a standard. Data were analyzed using the ΔΔC T method.…”

Section: Nse-cd46mentioning

confidence: 99%

Immune-Mediated Control of a Dormant Neurotropic RNA Virus Infection

Miller

Matullo

Milora

et al. 2019

J Virol

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Genomic material from many neurotropic RNA viruses (e.g., measles virus [MV], West Nile virus [WNV], Sindbis virus [SV], rabies virus [RV], and influenza A virus [IAV]) remains detectable in the mouse brain parenchyma long after resolution of the acute infection. The presence of these RNAs in the absence of overt central nervous system (CNS) disease has led to the suggestion that they are viral remnants, with little or no potential to reactivate. Here we show that MV RNA remains detectable in permissive mouse neurons long after challenge with MV and, moreover, that immunosuppression can cause RNA and protein synthesis to rebound, triggering neuropathogenesis months after acute viral control. Robust recrudescence of viral transcription and protein synthesis occurs after experimental depletion of cells of the adaptive immune response and is associated with a loss of T resident memory (Trm) lymphocytes within the brain. The disease associated with loss of immune control is distinct from that seen during the acute infection: immune cell-depleted, long-term-infected mice display severe gait and motor problems, in contrast to the wasting and lethal disease that occur during acute infection of immunodeficient hosts. These results illuminate the potential consequences of noncytolytic, immune-mediated viral control in the CNS and demonstrate that what were once considered “resolved” RNA viral infections may, in fact, induce diseases later in life that are distinct from those caused by acute infection. IMPORTANCE Viral infections of neurons are often not cytopathic; thus, once-infected neurons survive, and viral RNAs can be detected long after apparent viral control. These RNAs are generally considered viral fossils, unlikely to contribute to central nervous system (CNS) disease. Using a mouse model of measles virus (MV) neuronal infection, we show that MV RNA is maintained in the CNS of infected mice long after acute control and in the absence of overt disease. Viral replication is suppressed by the adaptive immune response; when these immune cells are depleted, viral protein synthesis recurs, inducing a CNS disease that is distinct from that observed during acute infection. The studies presented here provide the basis for understanding how persistent RNA infections in the CNS are controlled by the host immune response, as well as the pathogenic consequences of noncytolytic viral control.

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CD4 + T cells require either B cells or CD8 + T cells to control spread and pathogenesis of a neurotropic infection

Cited by 9 publications

References 29 publications

The neonatal anti-viral response fails to control measles virus spread in neurons despite interferon-gamma expression and a Th1-like cytokine profile

The neonatal anti-viral response fails to control measles virus spread in neurons despite interferon-gamma expression and a Th1-like cytokine profile

Protective and Pathological Immunity during Central Nervous System Infections

Immune-Mediated Control of a Dormant Neurotropic RNA Virus Infection

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