Biology subjects

Hatfield, J. S.

Publications and source records attributed to Hatfield, J. S..

3 recordsLinked to original sources

bioRxiv2026

Pichinde virus models intrauterine infection by hemorrhagic fever-causing arenaviruses

Arenavirus infection during pregnancy can cause severe maternal disease, congenital infection, and fetal demise. Many arenaviruses are endemic in economically disadvantaged areas and must be studied in high containment laboratories, which has limited our understanding of arenavirus pathogenesis in the placenta. Pichinde virus (PICV) is a nonpathogenic arenavirus that recapitulates many aspects of viral hemorrhagic fever in guinea pigs. Using a combination of experiments in human placental cells and guinea pigs, we characterized the tropism and impact of PICV infection during pregnancy. PICV replicated in human trophoblast stem cells (TSCs), TSC-derived trophoblasts, and explanted term placenta. When guinea pigs were infected at mid-gestation, PICV caused fetal demise. High infectious titers were recovered from placenta and decidua, but PICV was infrequently detected in fetal tissues or amniotic fluid. In situ hybridization confirmed that the placenta, decidua, and fetal membranes were all infected by the virus. Transcriptional profiling of PICV-infected human trophoblasts and guinea pig tissues revealed that infection upregulated canonical antiviral responses, which could contribute to placental dysfunction and pregnancy loss. Thus, PICV is safe and tractable model of zoonotic arenavirus infection during pregnancy with utility for preclinical therapeutic and vaccine development.

microbiology↗

bioRxiv2026

Genetics of Cocaine Consumption and Preference in Drosophila melanogaster

Cocaine Use Disorder (CUD) poses a significant public health and socioeconomic challenge. Determining the genetic basis of predisposition for development of CUD is challenging in human populations but can be studied in Drosophila. We assessed cocaine consumption and cocaine preference of 74,875 flies from 598 sequenced, wild-derived, inbred lines from the expanded Drosophila melanogaster Genetic Reference Panel (DGRP3). We found significant genetic variation, sexual dimorphism, and genetic variation in sexual dimorphism for these traits. Whereas most lines showed cocaine avoidance, ~10% of the lines showed innate cocaine preference in at least one sex. Genome-wide association analyses for cocaine consumption, preference, and micro-environmental variance of these traits identified 2,155 polymorphisms in/near 866 genes that were enriched for Gene Ontology terms associated with neurogenesis, development, and behavior. Many of the associated genes had human orthologs with known associations with CUD and other substance use disorders as well as psychiatric and behavioral traits. We confirmed causal associations with cocaine preference for three polymorphisms with large effect sizes by assessing their effects in DGRP3 lines not included in the initial association analyses. Pairwise associations between these polymorphisms exhibited suppressing epistasis. These polymorphisms are in genes with human orthologs that fulfill essential functions in the nervous system, including the glucose transporter SLC2A8; KCNC2, a subunit of the voltage gated potassium channel; and CHRNA7, a nicotinic cholinergic receptor subunit. Thus, studies on Drosophila can provide insights into the genetic and neural mechanisms of CUD.

genetics↗

bioRxiv2024

CD4+ but not CD8+ T cells are required for protection against severe guinea pig cytomegalovirus infections

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus and the leading cause of infectious disease related birth defects worldwide. How the immune response modulates the risk of intrauterine transmission of HCMV after maternal infection remains poorly understood. Maternal T cells likely play a critical role in preventing infection at the maternal-fetal interface and limiting spread across the placenta, but concerns exist that immune responses to infection may also cause placental dysfunction and adverse pregnancy outcomes. This study investigated the role of CD4+ and CD8+ T cells in a guinea pig model of primary cytomegalovirus infection. Monoclonal antibodies specific to guinea pig CD4 and CD8 were used to deplete T cells in non- pregnant and in pregnant guinea pigs after mid-gestation. CD4+ T cell depletion increased the severity of illness, caused significantly elevated viral loads, and increased the rate of congenital guinea pig cytomegalovirus (GPCMV) infection relative to animals treated with control antibody. CD8+ T cell depletion was comparably well tolerated and did not significantly affect the weight of infected guinea pigs or viral loads in their blood or tissue. However, significantly more viral genomes and transcripts were detected in the placenta and decidua of CD8+ T cell depleted dams post-infection. This study corroborates earlier findings made in nonhuman primates that maternal CD4+ T cells play a critical role in limiting the severity of primary CMV infection during pregnancy while also revealing that other innate and adaptive immune responses can compensate for an absent CD8+ T cell response in -CD8-treated guinea pigs. Author SummaryCongenital cytomegalovirus infection is a leading cause of adverse pregnancy outcomes and preventable disability in children. Using guinea pigs, a well-established small animal model of congenital infection and intrauterine development, this study tested how depleting T cells affects the course of primary cytomegalovirus infections. Severe illness and high rates of congenital infection were observed when helper CD4+ T cells were depleted. The depletion of killer CD8+ T cells did not affect the severity of disease or the rate of congenital infection but did increase the amount of virus that was detected in the placenta. A greater understanding how an immune response can prevent the infection of the placenta and developing offspring is needed to inform vaccine and therapeutic development. This study not only describes a new reagent that can be used to study the guinea pig immune system but also sheds new light in how adaptive immunity regulates congenital viral infection.

immunology↗