Desmond Edwards

All Publications

• Soluble Factors and Mechanisms Regulated by Sialylated IgG Signaling. Immunological reviews Edwards, D. L., Huang, M., Wang, T. T. 2025; 330 (1): e70021

  Abstract

  Inflammation is a complex biological response that can be both induced and actively suppressed by IgG-Fc gamma receptor (FcgammaR) interactions. This review explores the role of IgG sialylation in reducing or blocking inflammatory responses. We first revisit foundational studies that established the anti-inflammatory properties of sialylated IgG1 Fc. These early investigations revealed that the sialylated fraction is crucial for intravenous immunoglobulin's (IVIg's) ability to reduce inflammation in many autoinflammatory diseases and defined a paracrine signaling mechanism underlying this activity. Next, we discuss a recently identified mechanism whereby sialylated IgG directly induces RE1-Silencing Transcription Factor (REST) which functions as a transcriptional repressor of NF-kappaB1. This mechanism suggests a very broad role for sialylated IgG signaling in inflammation control since NF-kappaB is a central mediator of responses downstream of diverse activating receptors on both adaptive and innate immune cells. Finally, we review a set ofsoluble factors that are suppressedby sialylated IgG signaling in the murine airway and in purified human macrophages, providing additional insight into mechanisms by which sialylated IgG contributes to broad inflammatory control.

  View details for DOI 10.1111/imr.70021

  View details for PubMedID 40084926

• Sialylated IgG induces the transcription factor REST in alveolar macrophages to protect against lung inflammation and severe influenza disease. Immunity Chakraborty, S., Cheng, B. Y., Edwards, D. L., Gonzalez, J. C., Chiu, D. K., Zheng, H., Scallan, C., Guo, X., Tan, G. S., Coffey, G. P., Conley, P. B., Hume, P. S., Janssen, W. J., Byers, D. E., Mudd, P. A., Taubenberger, J., Memoli, M., Davis, M. M., Chua, K. F., Diamond, M. S., Andreakos, E., Khatri, P., Wang, T. T. 2024

  Abstract

  While most respiratory viral infections resolve with little harm to the host, severe symptoms arise when infection triggers an aberrant inflammatory response that damages lung tissue. Host regulators of virally induced lung inflammation have not been well defined. Here, we show that enrichment for sialylated, but not asialylated immunoglobulin G (IgG), predicted mild influenza disease in humans and was broadly protective against heterologous influenza viruses in a murine challenge model. Mechanistic studies show that sialylated IgG mediated this protection by inducing the transcription factor repressor element-1 silencing transcription factor (REST), which repressed nuclear factor kappaB (NF-kappaB)-driven responses, preventing severe lung inflammation and protecting lung function during influenza infection. Therapeutic administration of a recombinant, sialylated Fc molecule in clinical development similarly activated REST and protected against severe influenza disease, demonstrating that this pathway could be clinically harnessed. Overall, induction of REST through sialylated IgG signaling is a strategy to limit inflammatory disease sequelae in infections caused by antigenically distinct influenza strains.

  View details for DOI 10.1016/j.immuni.2024.10.002

  View details for PubMedID 39541970

• An expanded genetic toolkit for inducible expression and targeted gene silencing in Rickettsia parkeri. Journal of bacteriology McGinn, J., Wen, A., Edwards, D. L., Brinkley, D. M., Lamason, R. L. 2024; 206 (7): e0009124

  Abstract

  Pathogenic species within the Rickettsia genus are transmitted to humans through arthropod vectors and cause a spectrum of diseases ranging from mild to life-threatening. Despite rickettsiae posing an emerging global health risk, the genetic requirements of their infectious life cycles remain poorly understood. A major hurdle toward building this understanding has been the lack of efficient tools for genetic manipulation, owing to the technical difficulties associated with their obligate intracellular nature. To this end, we implemented the Tet-On system to enable conditional gene expression in Rickettsia parkeri. Using Tet-On, we show inducible expression of antibiotic resistance and a fluorescent reporter. We further used this inducible promoter to screen the ability of R. parkeri to express four variants of the catalytically dead Cas9 (dCas9). We demonstrate that all four dCas9 variants can be expressed in R. parkeri and used for CRISPR interference (CRISPRi)-mediated targeted gene knockdown. We show targeted knockdown of an antibiotic resistance gene as well as the endogenous virulence factor sca2. Altogether, we have developed systems for inducible gene expression and CRISPRi-mediated gene knockdown for the first time in rickettsiae, laying the groundwork for more scalable, targeted mechanistic investigations into their infectious life cycles.IMPORTANCEThe spotted fever group of Rickettsia contains vector-borne pathogenic bacteria that are neglected and emerging threats to public health. Due to the obligate intracellular nature of rickettsiae, the development of tools for genetic manipulation has been stunted, and the molecular and genetic underpinnings of their infectious lifecycle remain poorly understood. Here, we expand the genetic toolkit by introducing systems for conditional gene expression and CRISPR interference (CRISPRi)-mediated gene knockdown. These systems allow for relatively easy manipulation of rickettsial gene expression. We demonstrate the effectiveness of these tools by disrupting the intracellular life cycle using CRISPRi to deplete the sca2 virulence factor. These tools will be crucial for building a more comprehensive and detailed understanding of rickettsial biology and pathogenesis.

  View details for DOI 10.1128/jb.00091-24

  View details for PubMedID 38842342

  View details for PubMedCentralID PMC11270864