Publications by authors named "Nina J Gao"

4 Publications

  • Page 1 of 1

Immunobiology of the Classical Lancefield Group A Streptococcal Carbohydrate Antigen.

Infect Immun 2021 11 20;89(12):e0029221. Epub 2021 Sep 20.

Biomedical Sciences Graduate Program, UC San Diego, La Jolla, California, USA.

Group A Streptococcus (GAS) is a preeminent human bacterial pathogen causing hundreds of millions of infections each year worldwide. In the clinical setting, the bacterium is easily identified by a rapid antigen test against the group A carbohydrate (GAC), a polysaccharide that comprises 30 to 50% of the GAS cell wall by weight. Originally described by Rebecca Lancefield in the 1930s, GAC consists of a polyrhamnose backbone and a -acetylglucosamine (GlcNAc) side chain. This side chain, the species-defining immunodominant antigen, is potentially implicated in autoreactive immune responses against human heart or brain tissue in poststreptococcal rheumatic fever or rheumatic heart disease. The recent discovery of the genetic locus encoding GAC biosynthesis and new insights into its chemical structure have provided novel insights into the assembly of the polysaccharide, its contribution to immune evasion and virulence, and ideas for safely harnessing its natural immunogenicity in vaccine design. This minireview serves to summarize the emerging new literature on GAC, the eponymous cell well antigen that provides structural integrity to GAS and directly interfaces with host innate and adaptive immune responses.
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http://dx.doi.org/10.1128/IAI.00292-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594609PMC
November 2021

Functional and Proteomic Analysis of Virulence Upon Loss of Its Native Cas9 Nuclease.

Front Microbiol 2019 22;10:1967. Epub 2019 Aug 22.

Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, United States.

The public health impact of (group A , GAS) as a top 10 cause of infection-related mortality in humans contrasts with its benefit to biotechnology as the main natural source of Cas9 nuclease, the key component of the revolutionary CRISPR-Cas9 gene editing platform. Despite widespread knowledge acquired in the last decade on the molecular mechanisms by which GAS Cas9 achieves precise DNA targeting, the functions of Cas9 in the biology and pathogenesis of its native organism remain unknown. In this study, we generated an isogenic serotype M1 GAS mutant deficient in Cas9 protein and compared its behavior and phenotypes to the wild-type parent strain. Absence of Cas9 was linked to reduced GAS epithelial cell adherence, reduced growth in human whole blood , and attenuation of virulence in a murine necrotizing skin infection model. Virulence defects of the GAS Δ strain were explored through quantitative proteomic analysis, revealing a significant reduction in the abundance of key GAS virulence determinants. Similarly, deletion of affected the expression of several known virulence regulatory proteins, indicating that Cas9 impacts the global architecture of GAS gene regulation.
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http://dx.doi.org/10.3389/fmicb.2019.01967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714885PMC
August 2019

Group A streptococcal M protein activates the NLRP3 inflammasome.

Nat Microbiol 2017 Oct 7;2(10):1425-1434. Epub 2017 Aug 7.

Department of Pediatrics, University of California, San Diego, La Jolla, CA, 92093, USA.

Group A Streptococcus (GAS) is among the top ten causes of infection-related mortality in humans. M protein is the most abundant GAS surface protein, and M1 serotype GAS strains are associated with invasive infections, including necrotizing fasciitis and toxic shock syndrome. Here, we report that released, soluble M1 protein triggers programmed cell death in macrophages (Mϕ). M1 served as a second signal for caspase-1-dependent NLRP3 inflammasome activation, inducing maturation and release of proinflammatory cytokine interleukin-1β (IL-1β) and macrophage pyroptosis. The structurally dynamic B-repeat domain of M1 was critical for inflammasome activation, which involved K efflux and M1 protein internalization by clathrin-mediated endocytosis. Mouse intraperitoneal challenge showed that soluble M1 was sufficient and specific for IL-1β activation, which may represent an early warning to activate host immunity against the pathogen. Conversely, in systemic infection, hyperinflammation associated with M1-mediated pyroptosis and IL-1β release could aggravate tissue injury.
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http://dx.doi.org/10.1038/s41564-017-0005-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750061PMC
October 2017

The Activation-Induced Assembly of an RNA/Protein Interactome Centered on the Splicing Factor U2AF2 Regulates Gene Expression in Human CD4 T Cells.

PLoS One 2015 7;10(12):e0144409. Epub 2015 Dec 7.

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America.

Activation of CD4 T cells is a reaction to challenges such as microbial pathogens, cancer and toxins that defines adaptive immune responses. The roles of T cell receptor crosslinking, intracellular signaling, and transcription factor activation are well described, but the importance of post-transcriptional regulation by RNA-binding proteins (RBPs) has not been considered in depth. We describe a new model expanding and activating primary human CD4 T cells and applied this to characterizing activation-induced assembly of splicing factors centered on U2AF2. We immunoprecipitated U2AF2 to identify what mRNA transcripts were bound as a function of activation by TCR crosslinking and costimulation. In parallel, mass spectrometry revealed the proteins incorporated into the U2AF2-centered RNA/protein interactome. Molecules that retained interaction with the U2AF2 complex after RNAse treatment were designated as "central" interactome members (CIMs). Mass spectrometry also identified a second class of activation-induced proteins, "peripheral" interactome members (PIMs), that bound to the same transcripts but were not in physical association with U2AF2 or its partners. siRNA knockdown of two CIMs and two PIMs caused changes in activation marker expression, cytokine secretion, and gene expression that were unique to each protein and mapped to pathways associated with key aspects of T cell activation. While knocking down the PIM, SYNCRIP, impacts a limited but immunologically important set of U2AF2-bound transcripts, knockdown of U2AF1 significantly impairs assembly of the majority of protein and mRNA components in the activation-induced interactome. These results demonstrated that CIMs and PIMs, either directly or indirectly through RNA, assembled into activation-induced U2AF2 complexes and play roles in post-transcriptional regulation of genes related to cytokine secretion. These data suggest an additional layer of regulation mediated by the activation-induced assembly of RNA splicing interactomes that is important for understanding T cell activation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144409PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671683PMC
June 2016
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