da Silva Prata RB, Mendes MA, Soares VC, França-Costa J, Sales AM, Duppré NC, de Matos Borges V, da Silva TP, Bozza PT, Bozza MT, Sarno EN, Moraes MO, Sperandio da Silva GM, Pinheiro RO. Arginase 1 is a marker of protection against illness in contacts of leprosy patients. Sci Rep. 2022 May 12;12(1):7850.
DOI: 10.1038/s41598-022-11944-9
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Leprosy household contacts are generally more prone to develop the disease compared to the general population. Previous studies have demonstrated that genes related to the alternative activation (M2) profile in macrophages are associated with the increased bacillary load in multibacillary leprosy patients (MB), and that contacts of MB patients have a higher risk of contracting the disease. In addition, positive serological responses to PGL-1 or LID-1 are associated with a higher risk of disease. We performed a 5-year follow-up of contacts of leprosy patients and evaluated the pattern of gene and protein expression in cells from contacts that developed leprosy during this period. Leprosy household contacts had decreased soluble CD163 and heme oxygenase 1 (HO-1) serum levels when compared with healthy donors and leprosy patients. In contrast, arginase 1 activities were higher in contacts when compared with both healthy donors and leprosy patients. Of the contacts, 33 developed leprosy during the follow-up. Gene expression analysis revealed reduced ARG1 expression in these contacts when compared with contacts that did not develop disease. Arginase activity was a good predictive marker of protection in contacts (sensitivity: 90.0%, specificity: 96.77%) and the association with serology for anti-PGL-1 and anti-LID-1 increased the sensitivity to 100%. Altogether, the data presented here demonstrate a positive role of arginase against leprosy and suggest that the evaluation of arginase activity should be incorporated into leprosy control programs in order to aid in the decision of which contacts should receive chemoprophylaxis.
Meuren LM, Coelho SVA, de Arruda LB. Evaluation of DENV-Induced Endothelial Cell Permeability by Measurements of Transendothelial Electrical Resistance (TEER) and Extravasation of Proteins and Virus. Methods Mol Biol. 2022;2409:207-222.
DOI: 10.1007/978-1-0716-1879-0_14
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This chapter will discuss reliable and relatively easy and fast strategies to evaluate the integrity of endothelial cell monolayers when infected by dengue virus (DENV). Human brain microvascular endothelial cells (HBMEC) were exploited here as general model of vessel wall core, but it may also be used as an in vitro simplified model of blood brain barrier (BBB). The integrity of endothelial cells monolayer can be inferred using a transwell culture system by: (1) measuring transendothelial electrical resistance (TEER) using a Voltohmmeter; (2) analyzing the monolayer permeability to fluorescent-conjugated proteins and fluorimetric assay; (3) investigating virus extravasation by quantitative RT-PCR and plaque conventional assay. The rational to use those strategies is that vascular alterations are often observed during dengue infection, being associated to disease severity. The vasculature core consists of a barrier of endothelial cells, which are tightly adhered by the expression of adhesion molecules and tight junctions. This structure must be preserved in order to control the flux of cells and metabolites from the circulation to the tissues and to maintain vascular homeostasis. Therefore, experimental assays that allow evaluation of endothelial integrity can be useful platforms to further understand disease pathogenesis and screen pharmaceutical interventions to control vascular disturbance.
Keywords: Endothelial cells, Blood brain barrier, Transendothelial electrical resistance, Endothelial permeability, Transwell
Kiarely Souza E, Pereira-Dutra FS, Rajão MA, Ferraro-Moreira F, Goltara-Gomes TC, Cunha-Fernandes T, Santos JDC, Prestes EB, Andrade WA, Zamboni DS, Bozza MT, Bozza PT. Lipid droplet accumulation occurs early following Salmonella infection and contributes to intracellular bacterial survival and replication. Mol Microbiol. 2022 Feb;117(2):293-306.
DOI: 10.1111/mmi.14844
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Salmonellosis is a public health problem caused by Salmonella sp., a highly adapted facultative intracellular pathogen. After internalization, Salmonella sp. Manipulates several host processes, mainly through the activation of the type III secretion system (T3SS), including modification of host lipid metabolism and lipid droplet (LD) accumulation. LDs are dynamic and complex lipid-rich organelles involved in several cellular processes. The present study investigated the mechanism involved in LD biogenesis in Salmonella-infected macrophages and its role in bacterial pathogenicity. Here, we reported that S. Typhimurium induced a rapid time-dependent increase of LD formation in macrophages. The LD biogenesis was demonstrated to depend on Salmonella's viability and SPI1-related T3SS activity, with the participation of Toll-Like Receptor (TLR) signaling. We also observed that LD accumulation occurs through TLR2-dependent signaling and is counter-regulated by TLR4. Last, the pharmacologic modulation of LD formation by inhibiting diacylglycerol O-acyltransferase 1 (DGAT1) and cytosolic phospholipase A2 (cPLA2) significantly reduced the intracellular bacterial proliferation and impaired the prostaglandin E2 (PGE2) synthesis. Collectively, our data suggest the role of LDs on S. typhimurium intracellular survival and replication in macrophages. This data set provides new perspectives for future investigations about LDs in host–pathogen interaction.
Keywords: PGE2; Salmonella Typhimurium; TLRs; lipid droplets; lipid metabolism
Costa-da-Silva AC, Nascimento DO, Ferreira JRM, Guimarães-Pinto K, Freire-de-Lima L, Morrot A, Decote-Ricardo D, Filardy AA, Freire-de-Lima CG. Immune Responses in Leishmaniasis: An Overview. Trop Med Infect Dis. 2022 Mar 31;7(4):54.
DOI: 10.3390/tropicalmed7040054
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Leishmaniasis is a parasitic, widespread, and neglected disease that affects more than 90 countries in the world. More than 20 Leishmania species cause different forms of leishmaniasis that range in severity from cutaneous lesions to systemic infection. The diversity of leishmaniasis forms is due to the species of parasite, vector, environmental and social factors, genetic background, nutritional status, as well as immunocompetence of the host. Here, we discuss the role of the immune system, its molecules, and responses in the establishment, development, and outcome of Leishmaniasis, focusing on innate immune cells and Leishmania major interactions.
Keywords: immunology; immunomodulation; immunoparasitology; infection; leishmaniasis.
Prat-Luri B, Neal C, Passelli K, Ganga E, Amore J, Firmino-Cruz L, Petrova TV, Müller AJ, Tacchini-Cottier F. The C5a-C5aR1 complement axis is essential for neutrophil recruitment to draining lymph nodes via high endothelial venules in cutaneous leishmaniasis. Cell Rep. 2022 May 3;39(5):110777.
DOI: 10.1016/j.celrep.2022.110777
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Neutrophils are specialized innate immune cells known for their ability to fight pathogens. However, the mechanisms of neutrophil trafficking to lymph nodes are not fully clear. Using a murine model of dermal infection with Leishmania parasites, we observe a transient neutrophil influx in draining lymph nodes despite sustained recruitment to the infection site. Cell-tracking experiments, together with intravital two-photon microscopy, indicate that neutrophil recruitment to draining lymph nodes occurs minimally through lymphatics from the infected dermis, but mostly through blood vessels via high endothelial venules. Mechanistically, neutrophils do not respond to IL-1β or macrophage-derived molecules. Instead, they are guided by the C5a-C5aR1 axis, using L-selectin and integrins, to extravasate into the draining lymph node parenchyma. We also report that C5, the C5a precursor, is locally produced in the draining lymph node by lymphatic endothelial cells. Our data establish and detail organ-specific mechanisms of neutrophil trafficking.
Keywords: neutrophils, migration, lymph node, lymphatics, blood vessels, complement, Leishmania, cutaneous leishmaniasis, swarming.
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