Ebola virus disease (EVD) represents a global health threat. The etiological agents of EVD are 6 species of Orthoebolaviruses, with Orthoebolavirus zairense (EBOV) having the greatest public health and medical significance. EVD disease pathogenesis occurs as a result of broad cellular tropism of the virus, robust viral replication and a potent and dysregulated production of cytokines. In vivo, tissue macrophages are some of the earliest cells infected and contribute significantly to virus load and cytokine production. While EBOV is known to infect macrophages and to generate high titer virus in the liver, EBOV infection of liver macrophages, Kupffer cells, has not previously been examined in tissue culture or experimentally manipulated in vivo. Here, we employed primary murine Kupffer cells (KC) and an immortalized murine Kupffer cell line (ImKC) to assess EBOV-eGFP replication in liver macrophages. KCs and ImKCs were highly permissive for EBOV infection and IFN-γ polarization of these cells suppressed their permissiveness to infection. The kinetics of IFN-γ-elicited antiviral responses were examined using a biologically-contained model of EBOV infection termed EBOV ΔVP30. The antiviral activity of IFN-γ was transient, but a modest ~3-fold reduction of infection persisted for as long as 6 days post treatment. To assess the interferon stimulated gene products (ISGs) responsible for protection, the efficacy of secreted ISGs induced by IFN-γ were evaluated. Secreted ISGs blocked recombinant VSV expressing EBOV GP (rVSV/EBOV GP) infection, but failed to block EBOV ΔVP30. Our studies define new cellular tools for the study of EBOV infection that can potentially aid the development of new antiviral therapies. Furthermore, our data underscore the importance of macrophages in EVD pathogenesis and those IFN-γ-elicited ISGs that help to control EBOV infection.

Abstract: Sickle cell disease (SCD) is an autosomal recessive monogenic disorder caused by a homozygous mutation in the β-globin gene, which leads to erythrocyte sickling, hemolysis, vaso-occlusion and sterile inflammation. Oral l-glutamine administration has been shown to reduce the frequency of pain crisis in SCD patients, however, the long-term effect of l-glutamine in SCD remains to be determined. To understand the long-term effect of l-glutamine administration in SCD liver we used quantitative liver intravital microscopy and biochemical analysis in humanized SCD mice. We here show that chronic l-glutamine administration reduces hepatic hemoglobin-heme-iron level, but fails to ameliorate ischemic liver injury. Remarkably, we find that this failure in resolution of hepatobiliary injury and persistent liver fibrosis is associated with reduced expression of hepatic Kupffer cells post l-glutamine treatment. These findings establish the importance to investigate the long-term effects of l-glutamine therapy on liver pathophysiology in SCD patients.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses metabolic dysfunction-associated fatty liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), with MASH posing a risk of progression to cirrhosis and hepatocellular carcinoma (HCC). The global prevalence of MASLD is estimated at approximately a quarter of the population, with significant healthcare costs and implications for liver transplantation. The pathogenesis of MASLD involves intrahepatic liver cells, extrahepatic components, and immunological aspects, particularly the involvement of macrophages. Hepatic macrophages are a crucial cellular component of the liver and play vital roles in liver function, contributing significantly to tissue homeostasis and swift responses during pathophysiological conditions. Recent advancements in technology have revealed the remarkable heterogeneity and plasticity of hepatic macrophage populations and their activation states in MASLD, challenging traditional classification methods like the M1/M2 paradigm and highlighting the coexistence of harmful and beneficial macrophage phenotypes that are dynamically regulated during MASLD progression. This complexity underscores the importance of considering macrophage heterogeneity in therapeutic targeting strategies, including their distinct ontogeny and functional phenotypes. This review provides an overview of macrophage involvement in MASLD progression, combining traditional paradigms with recent insights from single-cell analysis and spatial dynamics. It also addresses unresolved questions and potential therapeutic targets in this area.

Compelling epidemiologic data support the critical role of dietary fructose in the epidemic of obesity, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). The metabolic effects of fructose on the development of metabolic syndrome and NAFLD are not completely understood. High fructose intake impairs copper status, and copper-fructose interactions have been well documented in rats. Altered copper-fructose metabolism leads to exacerbated experimental metabolic syndrome and NAFLD. A growing body of evidence has demonstrated that copper levels are low in NAFLD patients. Moreover, hepatic and serum copper levels are inversely correlated with the severity of NAFLD. Thus, high fructose consumption and low copper availability are considered two important risk factors in NAFLD. However, the causal effect of copper-fructose interactions as well as the effects of fructose intake on copper status remain to be evaluated in humans. The aim of this review is to summarize the role of copper-fructose interactions in the pathogenesis of the metabolic syndrome and discuss the potential underlying mechanisms. This review will shed light on the role of copper homeostasis and high fructose intake and point to copper-fructose interactions as novel mechanisms in the fructose induced NAFLD.