Atherosclerosis remains a major challenge to global healthcare despite decades of research and constant trials of novel therapeutic approaches. One feature that makes atherosclerosis treatment so elusive is an insufficient understanding of its origins and the early stages of the pathological process, which limits our means of effective prevention of the disease. Macrovascular pericytes are cells with distinct shapes that are located in the arterial wall of larger vessels and are in many aspects similar to microvascular pericytes that maintain the functionality of small vessels and capillaries. This cell type combines the residual contractile function of smooth muscle cells with a distinct stellar shape that allows these cells to make numerous contacts between themselves and the adjacent endothelial layer. Moreover, pericytes can take part in the immune defense and are able to take up lipids in the course of atherosclerotic lesion development. In growing atherosclerotic plaques, the morphology and function of pericytes change dramatically due to phagocytic and synthetic phenotypes that are actively involved in lipid accumulation and extracellular matrix synthesis. In this review, we summarize our knowledge of this less-studied cell type and its role in atherosclerosis.

Gasdermins (GSDMs) are proteins cleaved by caspase (CASP) to trigger pyroptosis. In teleosts, pyroptosis is mediated by gasdermin E (GSDME). The Pufferfish, Takifugu rubripes, possesses two GSDME orthologs: named TrGSDMEa and TrGSDMEb. TrGSDMEa is cleaved by CASP3/7 to liberate the N-terminal (NT) domain that can trigger pyroptosis in mammalian cells. However, the biological function of TrGSDMEa in pufferfish is unknown, and TrGSDMEb is poorly studied. We found that TrGSDMEb was cleaved by CASP1/3/6/7/8, but the resulting NT domain, despite its similarity to TrGSDMEa-NT domain in sequence and structure, failed to induce pyroptosis. TrGSDMEa and TrGSDMEb exhibited similar expression patterns in pufferfish under normal physiological conditions but were up- and downregulated, respectively, in expression during Vibrio harveyi and Edwardsiella tarda infection. Bacterial infection induced the activation of TrGSDMEa and CASP3/7 in pufferfish cells, resulting in pyroptosis accompanied with IL-1β production and maturation. Inhibition of TrGSDMEa-mediated pyroptosis via TrCASP3/7 reduced the death of pufferfish cells and augmented bacterial dissemination in fish tissues. Structure-oriented mutagenesis identified 16 conserved residues in teleost GSDMEa that were required for the pore formation or auto-inhibition of GSDMEa. This study illustrates the role of GSDMEa-mediated pyroptosis in teleost defense against bacterial pathogens and provides new insights into the structure-based function of vertebrate GSDME.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s42995-024-00237-x.

Infections are one of the most significant healthcare and economic burdens across the world as underscored by the recent coronavirus pandemic. Moreover, with the increasing incidence of antimicrobial resistance, there is an urgent need to better understand host-pathogen interactions to design effective treatment strategies. The complement system is a key arsenal of the host defense response to pathogens and bridges both innate and adaptive immunity. However, in the contest between pathogens and host defense mechanisms, the host is not always victorious. Pathogens have evolved several approaches, including co-opting the host complement regulators to evade complement-mediated killing. Furthermore, deficiencies in the complement proteins, both genetic and therapeutic, can lead to an inefficient complement-mediated pathogen eradication, rendering the host more susceptible to certain infections. On the other hand, overwhelming infection can provoke fulminant complement activation with uncontrolled inflammation and potentially fatal tissue and organ damage. This review presents an overview of critical aspects of the complement-pathogen interactions during infection and discusses perspectives on designing therapies to mitigate complement dysfunction and limit tissue injury.

Interleukin (IL)-18 is synthesized as a precursor that requires intracellular processing to become functionally active. In human, IL-18 is processed by caspase 1 (CASP1). In teleost, the maturation and signal transduction mechanisms of IL-18 are unknown. We identified two IL-18 variants, IL-18a and IL-18b, in turbot. IL-18a, but not IL-18b, was processed by CASP6/8 cleavage. Mature IL-18a bound specifically to IL-18 receptor (IL-18R) α-expressing cells and induced IL-18Rα-IL-18Rβ association. Bacterial infection promoted IL-18a maturation in a manner that required CASP6 activation and correlated with gasdermin E activation. The mature IL-18a induced proinflammatory cytokine expression and enhanced bacterial clearance. IL-18a-mediated immune response was suppressed by IL-18 binding protein (IL-18BP), which functioned as a decoy receptor for IL-18a. IL-18BP also functioned as a pathogen pattern recognition receptor and directly inhibited pathogen infection. Our findings revealed unique mechanism of IL-18 maturation and conserved mechanism of IL-18 signaling and regulation in turbot, and provided new insights into the regulation and function of IL-18 related immune signaling.

The aim of this study was to investigate the effects of melatonin (MT) feed supplementation on the antioxidant capacity, immune defense, and intestinal flora in Procambarus clarkii (P. clarkii). Six groups of P. clarkii were fed test feeds containing different levels of MT: 0 mg/kg (control), 22.5, 41.2, 82.7, 165.1, and 329.2 mg/kg for a duration of 2 months. The specific growth rate, hepatosomatic index, and condition factor were recorded highest in the test group of shrimp fed an MT concentration of 165.1 mg/kg. Compared to the control group, the rate of apoptosis was lower in hepatopancreas cells of P. clarkii supplemented with high concentrations of MT. Analyses of antioxidant capacity and immune-response-related enzymes in the hepatopancreas indicated that dietary supplementation of MT significantly augmented both the antioxidant system and immune responses. Dietary MT supplementation significantly increased the expression levels of antioxidant-immunity-related genes and decreased the expression levels of genes linked to apoptosis. Dietary MT was associated with an elevation in the abundance of the Firmicutes and a reduction in the abundance of the Proteobacteria in the intestines; besides, resulting in an increase in the abundance of beneficial bacteria, such as Lactobacilli. The broken-line model indicated that the suitable MT concentration was 154.09-157.09 mg/kg. MT supplementation enhanced the growth performance of P. clarkii, exerting a positive influence on the intestinal microbiota, and bolstered both immune response and disease resistance. Thus, this study offered novel perspectives regarding the application of dietary MT supplementation within the aquaculture field.

In this article for the Highlights of 2023 Series, we consider the growing understanding of mast cell heterogeneity and interactions that has developed from single cell RNA sequencing studies. We also discuss novel concepts concerning mast cell interactions with the central nervous system and evidence for their role in host defense against SARS-CoV-2 infection.

In this study, we present the first cloning and identification of perforin (MsPRF1) in largemouth bass (Micropterus salmoides). The full-length cDNA of MsPRF1 spans 1572 base pairs, encoding a 58.88 kDa protein consisting of 523 amino acids. Notably, the protein contains MACPF and C2 structural domains. To evaluate the expression levels of MsPRF1 in various healthy largemouth bass tissues, real-time quantitative PCR was employed, revealing the highest expression in the liver and gut. After the largemouth bass were infected by Nocardia seriolae, the mRNA levels of MsPRF1 generally increased within 48 h. Remarkably, the recombinant protein MsPRF1 exhibits inhibitory effects against both Gram-negative and Gram-positive bacteria. Additionally, the largemouth bass showed a higher survival rate in the N. seriolae challenge following the intraperitoneal injection of rMsPRF1, with observed reductions in the tissue bacterial loads. Moreover, rMsPRF1 demonstrated a significant impact on the phagocytic and bactericidal activities of largemouth bass MO/MΦ cells, concurrently upregulating the expression of pro-inflammatory factors. These results demonstrate that MsPRF1 has a potential role in the immune response of largemouth bass against N. seriolae infection.

The stingless bee Melipona scutellaris performs buzz pollination, effectively pollinating several wild plants and crops with economic relevance. However, most research has focused on honeybees, leaving a significant gap in studies concerning native species, particularly regarding the impacts of pesticide combinations on these pollinators. Thus, this study aimed to evaluate the sublethal effects of imidacloprid (IMD), pyraclostrobin (PYR), and glyphosate (GLY) on the behavior and fat body cell morphology and physiology of M. scutellaris. Foragers were orally exposed to the different pesticides alone and in combination for 48 h. Bees fed with contaminated solution walked less, moved slower, presented morphological changes in the fat body, including vacuolization, altered cell shape and nuclei morphology, and exhibited a higher count of altered oenocytes and trophocytes. In all exposed groups, alone and in combination, the number of cells expressing caspase-3 increased, but the TLR4 number of cells expressing decreased compared to the control groups. The intensity of HSP70 immunolabeling increased compared to the control groups. However, the intensity of the immunolabeling of HSP90 decreased in the IMD, GLY, and I + G (IMD + GLY) groups but increased in I + P-exposed bees (IMD + PYR). Alternatively, exposure to PYR and P + G (PYR + GLY) did not affect the immunolabeling intensity. Our findings demonstrate the hazardous effects and environmental consequences of isolated and combined pesticides on a vital neotropical pollinator. Understanding how pesticides impact the fat body can provide crucial insights into the overall health and survival of native bee populations, which can help develop more environmentally friendly approaches to agricultural practices.

The ability of Aedes aegypti mosquitoes to transmit vertebrate pathogens depends on multiple factors, including the mosquitoes\' life history traits, immune response, and microbiota (i.e., the microbes associated with the mosquito throughout its life). The microsporidium Edhazardia aedis is an obligate intracellular parasite that specifically infects Ae. aegypti mosquitoes and severely affects mosquito survival and other life history traits critical for pathogen transmission. In this work, we investigated how E. aedis impacts bacterial infection with Serratia marcescens in Ae. aegypti mosquitoes. We measured development, survival, and bacterial load in both larval and adult stages of mosquitoes. In larvae, E. aedis exposure was either horizontal or vertical and S. marcescens was introduced orally. Regardless of the route of transmission, E. aedis exposure resulted in significantly higher S. marcescens loads in larvae. E. aedis exposure also significantly reduced larval survival but subsequent exposure to S. marcescens had no effect. In adult females, E. aedis exposure was only horizontal and S. marcescens was introduced orally or via intrathoracic injection. In both cases, E. aedis infection significantly increased S. marcescens bacterial loads in adult female mosquitoes. In addition, females infected with E. aedis and subsequently injected with S. marcescens suffered 100% mortality which corresponded with a rapid increase in bacterial load. These findings suggest that exposure to E. aedis can influence the establishment and/or replication of other microbes in the mosquito. This has implications for understanding the ecology of mosquito immune defense and potentially disease transmission by mosquito vector species.
OBJECTIVE: The microsporidium Edhazardia aedis is a parasite of the yellow fever mosquito, Aedes aegypti. This mosquito transmits multiple viruses to humans in the United States and around the world, including dengue, yellow fever, and Zika viruses. Hundreds of millions of people worldwide will become infected with one of these viruses each year. E. aedis infection significantly reduces the lifespan of Ae. aegypti and is therefore a promising novel biocontrol agent. Here, we show that when the mosquito is infected with this parasite, it is also significantly more susceptible to infection by an opportunistic bacterial pathogen, Serratia marcescens. This novel discovery suggests the mosquito\'s ability to control infection by other microbes is impacted by the presence of the parasite.