Despite the ubiquity of invasive organisms and their often deleterious effects on native flora and fauna, the consequences of biological invasions for human health and the ecological mechanisms through which they occur are rarely considered. Here we demonstrate that a widespread invasive shrub in North America, Amur honeysuckle ( Lonicera maackii ), increases human risk of exposure to ehrlichiosis, an emerging infectious disease caused by bacterial pathogens transmitted by the lone star tick ( Amblyomma americanum ). Using large-scale observational surveys in natural areas across the St. Louis, Missouri region, we found that white-tailed deer ( Odocoileus virginianus) , a preeminent tick host and pathogen reservoir, more frequently used areas invaded by honeysuckle. This habitat preference translated into considerably greater numbers of ticks infected with pathogens in honeysuckle-invaded areas relative to adjacent honeysuckle-uninvaded areas. We confirmed this biotic mechanism using an experimental removal of honeysuckle, which caused a decrease in deer activity and infected tick numbers, as well as a proportional shift in the blood meals of ticks away from deer. We conclude that disease risk is likely to be reduced when honeysuckle is eradicated, and suggest that management of biological invasions may help ameliorate the burden of vector-borne diseases on human health.

Blood meal analysis identified white-tailed deer as hosts for ticks that carry zoonotic pathogens.

Iron-regulatory proteins (IRPs) recognize and bind to specific RNA structures called iron-responsive elements. Mediation of these binding interactions by iron and iron-containing compounds regulates several posttranscriptional events relevant to iron metabolism. There are two known IRPs, IRP1 and IRP2, both of which can respond to iron fluxes in the cell. There is ample evidence that IRP1 is converted by iron to cytoplasmic aconitase in vivo. It has also been shown that, under certain conditions, a significant fraction of IRP1 is degraded in cells exposed to iron or heme. Studies have shown that the degradation of IRP1 that is induced by iron can be inhibited by either desferrioxamine mesylate (an iron chelator) or succinyl acetone (an inhibitor of heme synthesis), whereas the degradation induced by heme cannot. This suggests that heme rather than iron is responsible for this degradation.Several laboratories have shown that IRP2 is also degraded in cells treated with iron salts. We now show evidence suggesting that this IRP2 degradation may be mediated by heme. Thus, in experiments analogous to those used previously to study IRP1, we find that IRP2 is degraded in rabbit fibroblast cells exposed to heme or iron salts. However, as shown earlier with IRP1, both desferrioxamine mesylate and succinyl acetone will inhibit the degradation of IRP2 induced by iron but not that induced by heme.

Induction of ferritin synthesis in cultured cells by heme or iron is accompanied by degradation of the ferritin repressor protein (FRP). Intermediates in the degradative pathway apparently include FRP covalently linked in larger aggregates. The effect of iron on FRP degradation is enhanced by porphyrin precursors but is decreased by inhibitors of porphyrin synthesis, which implies that heme is an active agent. These results suggest that translational induction in this system may be caused by enhanced repressor degradation. While unique among translational regulatory systems, this process is common to a variety of other biosynthetic control mechanisms.

Background Coxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through coxsackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critical window of gestation. Methods and Results We infected C57Bl/6 pregnant mice with CVB3 during time points in early gestation (embryonic day [E] 5, E7, E9, and E11). We used different viral titers to examine possible dose‐response relationship and assessed viral loads in various fetal organs. Provided viral exposure occurred between E7 and E9, we observed characteristic features of ventricular septal defect (33.6%), abnormal myocardial architecture resembling noncompaction (23.5%), and double‐outlet right ventricle (4.4%) among 209 viable fetuses examined. We observed a direct relationship between viral titers and severity of congenital heart defects, with apparent predominance among female fetuses. Infected dams remained healthy; we did not observe any maternal heart or placental injury suggestive of direct viral effects on developing heart as likely cause of congenital heart defects. We examined signaling pathways in CVB3‐exposed hearts using RNA sequencing, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and immunohistochemistry. Signaling proteins of the Hippo, tight junction, transforming growth factor‐β1, and extracellular matrix proteins were the most highly enriched in CVB3‐infected fetuses with ventricular septal defects. Moreover, cardiomyocyte proliferation was 50% lower in fetuses with ventricular septal defects compared with uninfected controls. Conclusions We conclude prenatal CVB3 infection induces congenital heart defects. Alterations in myocardial proliferate capacity and consequent changes in cardiac architecture and trabeculation appear to account for most of observed phenotypes.

Structural congenital heart disease (CHD) has not previously been linked to autoimmunity. In our study, we developed an autoimmune model of structural CHD that resembles hypoplastic left heart syndrome (HLHS), a life-threatening CHD primarily affecting the left ventricle. Because cardiac myosin (CM) is a dominant autoantigen in autoimmune heart disease, we hypothesized that immunization with CM might lead to transplacental passage of maternal autoantibodies and a prenatal HLHS phenotype in exposed fetuses. Elevated anti-CM autoantibodies in maternal and fetal sera, and IgG reactivity in fetal myocardium were correlated with structural CHD that included diminished left ventricular cavity dimensions in the affected progeny. Further, fetuses that developed a marked HLHS phenotype had elevated serum titers of anti-β adrenergic receptor antibodies as well as increased protein kinase A activity, suggesting a potential mechanism for the observed pathological changes. Our maternal-fetal model presents a new concept linking autoimmunity against CM and cardiomyocyte proliferation with cardinal features of HLHS. This report shows the first evidence to support a novel immune-mediated mechanism for pathogenesis of structural CHD that may have implications in its future diagnosis and treatment.

Word Count -7635All authors have read and agree with the submission of the manuscript.The manuscript is not submitted or under consideration for publication elsewhere. ABSTRACT 1 Aims: Coxsackievirus B (CVB), the most common cause of viral myocarditis, targets 2 cardiomyocytes through Coxsackie and Adenovirus Receptor, which is highly expressed in the 3 fetal heart. We hypothesized CVB3, a well-recognized culprit for viral myocarditis, can precipitate 4 congenital heart defects (CHD), when fetal infection occurs during critical window of gestation. 5

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