Biology subjects

Monogue, B.

Publications and source records attributed to Monogue, B..

4 recordsLinked to original sources

bioRxiv2025

Myeloid cell IL-15 production in the brain supports Bystander CD8+ T-Cell Neuropathic Immune Responses following Virus infection

The central nervous system (CNS) includes a uniquely regulated immune response that supports homeostasis, response to injury, and response to pathogens. Recent work has shown that virus-associated immune responses in the CNS may contribute to neuronal injury and long-term outcomes such as neurocognitive decline. However, the fundamental mechanisms that regulate acute infiltration of immune cells from vascular compartments into the CNS are not well defined. Using an attenuated Venezuelan equine encephalitis virus TC83 (referred to as TC83) to inoculate using olfactory and intracranial injections, we show that infection in the CNS and olfactory pathways results in rapid infiltration of both CD4+ and CD8+ T-cells as early as 3- and 5-days post-infection. CNS-infiltrating CD8+ T-cells exhibit a bystander, memory phenotype (CD49d+, Tbet+, NKG2D+, Eomes+), are cytotoxic, and are recruited independent of antigen specific responses. We show that infiltration of CD8+ bystander T-cells is supported by microglia and infiltrating macrophage expression of IL-15 and interferon expression in the CNS. These innate antiviral immune signals support activation of bystander CD8+ T-cells in the CNS that contribute to tissue injury independent of virus replication at early time points post-infection. These data support a mechanism by IL-15 stimulates bystander memory CD8+ T-cells to enter the CNS and contribute to injury independent of antigen-specific stimulation. ImportancePrior studies have shown that virus infections in the respiratory and olfactory nerve pathways can result in long term injury in the brain. However, the mechanisms that link virus infection in the olfactory neurons and brain injury are not understood. We show that virus infection of olfactory neurons results in immune stimulation in the brain of resident immune cells to release a cytokine called IL-15 and interferon. This results in infiltration and activation of non-specific T-cells that cause injury of neurons in the brain. This may be an important mechanism by which respiratory viruses and other viruses cause inflammation and injury in the brain.

immunology↗

bioRxiv2020

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

Zika virus (ZIKV), like other flaviviruses, produces several species of sub-genomic RNAs (sfRNAs) during infection, corresponding to noncoding RNA fragments of different lengths derived from the viral 3 untranslated region (UTR). Over the course of infection, these sfRNAs accumulate in the cell as a result of incomplete viral genome degradation of the 3UTR by host 5 to 3 exoribonuclease (Xrn1). The halting of Xrn1 in the 3UTR is due to two RNA pseudoknot structures in the 3UTR termed exoribonuclease-resistant RNA1 and 2 (xrRNA1&2). Studies with related flaviviruses have shown that sfRNAs are important for pathogenicity and inhibiting both mosquito and mammalian host defense mechanisms. However, these investigations have not included ZIKV and there is very limited data addressing how sfRNAs impact infection in a whole animal model or specific tissues. In this study, we rescued a sfRNA1-deficient ZIKV (X1) by targeted mutation in the xrRNA1 3 UTR structure. We found that virus which lacks the production of the largest ZIKV sfRNA species, sfRNA1. Using the X1 virus to infect adult IFNAR1-/- mice, we found that while the lack of sfRNA1 does not alter ZIKV replication in the spleen, there is a significant reduction of ZIKV genome replication in the brain and placenta compared to WT ZIKV infection. Despite thee attenuated phenotype of the X1 ZIKV, mice develop a robust neutralizing antibody response. We conclude that targeted disruption of xrRNA1 results in tissue-specific attenuation while still supporting robust neutralizing antibody responses. Future studies will need to investigate the tissue-specific mechanisms by which ZIKV sfRNAs influence infection and may utilize targeted xrRNA mutations to develop novel attenuated flavivirus vaccine approaches.

microbiology↗

bioRxiv2020

Alpha-synuclein expression supports interferon stimulated gene expression in neurons

The protein alpha-synuclein (asyn) is predominantly expressed in neurons and is associated with neurodegenerative diseases like Parkinsons disease (PD); yet, a functional role for asyn in neurons is not clearly established. We have previously shown that asyn expression is up-regulated following viral infection in neurons and is critical for host immune responses to RNA virus infections. Here, we investigate the mechanisms underlying asyn-dependent immune responses to RNA virus infection in the brain. Using asyn knock-out (KO) mice and human neuronal models, we show that asyn is required for expression of the full repertoire of interferon-stimulated genes (ISGs) in neurons following acute RNA virus infection. Furthermore, treatment of asyn KO human neurons with poly I:C or type I interferon also fail to induce expression of the full complement of ISGs suggesting that asyn plays an important role in modulating neuronal innate immune responses. In brain tissue, asyn-dependent ISG expression is independent of microglia activation and supports activation of infiltrating lymphocytes following viral challenge. We also show that virus infections lead to accumulation of phosphorylated S129 asyn in human and non-human primate neuronal tissues. In a model of pS129 asyn pathology, we found that infection with West Nile virus increases microglia activation but does not significantly alter pS129 asyn pathology in the mouse model. Taken together, our results establish asyn as a novel, neuron-specific modulator of innate immunity by a mechanism that promotes interferon-stimulated gene expression and links responses to virus infection with formation of phosphorylated S129-asyn in neuronal tissue.

neuroscience↗

bioRxiv2019

Parallel genomics uncover novel enterococcal-bacteriophage interactions

Bacteriophages (phages) have been proposed as alternative therapeutics for the treatment of multidrug resistant bacterial infections. However, there are major gaps in our understanding of the molecular events in bacterial cells that control how bacteria respond to phage predation. Using the model organism Enterococcus faecalis, we employed two distinct genomic approaches, transposon (Tn) library screening and RNA sequencing, to investigate the interaction of E. faecalis with a virulent phage. We discovered that a transcription factor encoding a LytR family response regulator controls the expression of enterococcal polysaccharide antigen (epa) genes that are involved in phage infection and bacterial fitness. In addition, we discovered that DNA mismatch repair mutants rapidly evolve phage adsorption deficiencies, underpinning a molecular basis for epa mutation during phage infection. Transcriptomic profiling of phage infected E. faecalis revealed broad transcriptional changes influencing viral replication and progeny burst size. We also demonstrate that phage infection alters the expression of bacterial genes associated with intra and inter-bacterial interactions, including genes involved in quorum sensing and polymicrobial competition. Together our results suggest that phage predation has the potential to influence complex microbial behavior and may dictate how bacteria respond to external environmental stimuli. These responses could have collateral effects (positive or negative) on microbial communities such as the host microbiota during phage therapy. ImportanceWe lack fundamental understanding of how phage infection influences bacterial gene expression and consequently how bacterial responses to phage infection affect the assembly of polymicrobial communities. Using parallel genomic approaches, we have discovered novel transcriptional regulators and metabolic genes that influence phage infection. The integration of whole genome transcriptomic profiling during phage infection has revealed the differential regulation of genes important for group behaviors and polymicrobial interactions. Our work suggests that therapeutic phages could more broadly influence bacterial community composition outside of their intended host targets.

microbiology↗