Biology subjects

Goodman, A. G.

Publications and source records attributed to Goodman, A. G..

3 recordsLinked to original sources

bioRxiv2020

Natural Genetic Variation in Drosophila melanogaster Reveals Genes Associated with Coxiella burnetii Infection

The gram-negative bacterium Coxiella burnetii is the causative agent of Query (Q) fever in humans and coxiellosis in livestock. Association between host genetic background and Coxiella burnetii pathogenesis has been demonstrated both in humans and animals; however, specific genes associated with severity of infection remain unknown. We employed the Drosophila Genetics Reference Panel to perform a genome-wide association study and identify host genetic variants that affect Coxiella burnetii infection outcome. The analysis resulted in 64 genome-wide suggestive (P < 10-5) single nucleotide polymorphisms or gene variants in 25 unique genes. We examined the role of each gene in Coxiella burnetii infection using flies carrying a null mutation or RNAi knockdown of each gene and monitoring survival. Of the 25 candidate genes, 15 validated using at least one method. For many, this is the first report establishing involvement of these genes or their homologs with Coxiella burnetii susceptibility in any system. Among the validated genes, FER and tara play roles in the JAK-STAT, JNK, and decapentaplegic/TGF-{beta} signaling pathways that are associated with the innate immune response to Coxiella burnetii infection. Two other two validated genes, CG42673 and DIP-{varepsilon}, play roles in bacterial infection and synaptic signaling but no previous association with Coxiella burnetii pathogenesis. Furthermore, since the mammalian ortholog of CG13404 (PLGRKT) is an important regulator of macrophage function, CG13404 could play a role in Coxiella burnetii susceptibility through hemocyte regulation. These insights provide a foundation for further investigation of genetics of Coxiella burnetii susceptibility across a wide variety of hosts.

genetics↗

bioRxiv2019

Insulin potentiates JAK/STAT signaling to broadly inhibit flavivirus replication in insect vectors

The World Health Organization estimates that over half of the worlds population is at risk for vector-borne diseases, such as those caused by arboviral infection. Because many arboviruses are mosquito-borne, investigation of the insect immune response will help identify targets that could reduce the spread of these viruses by the mosquito. In this study, we used a genetic screening approach to identify insulin-like receptor as a novel component of the immune response to arboviral infection. We determined that vertebrate insulin reduces West Nile virus (WNV) replication in Drosophila melanogaster as well as WNV, Zika, and dengue virus titers in mosquito cells. Mechanistically, we showed that insulin signaling activates the JAK/STAT, but not RNAi, pathway to control infection. Finally, we validated that insulin priming of adult female Culex mosquitoes through a blood meal reduces WNV infection, demonstrating an essential role for insulin signaling in insect antiviral responses to emerging human pathogens.

microbiology↗

bioRxiv2019

Natural genetic variation screen in Drosophila identifies Wnt signaling, mitochondrial metabolism, and redox homeostasis genes as modifiers of apoptosis

Apoptosis is the primary cause of degeneration in a number of neuronal, muscular, and metabolic disorders. These diseases are subject to a great deal of phenotypic heterogeneity in patient populations, primarily due to differences in genetic variation between individuals. This creates a barrier to effective diagnosis and treatment. Understanding how genetic variation influences apoptosis could lead to the development of new therapeutics and better personalized treatment approaches. In this study, we examine the impact of the natural genetic variation in the Drosophila Genetic Reference Panel (DGRP) on two models of apoptosis-induced retinal degeneration: overexpression of p53 or reaper (rpr). We identify a number of known apoptotic, neural, and developmental genes as candidate modifiers of degeneration. We also use Gene Set Enrichment Analysis (GSEA) to identify pathways that harbor genetic variation that impact these apoptosis models, including Wnt signaling, mitochondrial metabolism, and redox homeostasis. Finally, we demonstrate that many of these candidates have a functional effect on apoptosis and degeneration. These studies provide a number of avenues for modifying genes and pathways of apoptosis-related disease.

genetics↗