Macrophage Selenoproteins Restrict Intracellular Replication of Francisella tularensis and Are Essential for Host Immunity

Abstract

The essential micronutrient Selenium (Se) is co-translationally incorporated as selenocysteine into proteins. Selenoproteins contain one or more selenocysteines and are vital for optimum immunity. Interestingly, many pathogenic bacteria utilize Se for various biological processes suggesting that Se may play a role in bacterial pathogenesis. A previous study had speculated that Francisella tularensis, a facultative intracellular bacterium and the causative agent of tularemia, sequesters Se by upregulating Se-metabolism genes in type II alveolar epithelial cells. Therefore, we investigated the contribution of host vs. pathogen-associated selenoproteins in bacterial disease using F. tularensis as a model organism. We found that F. tularensis was devoid of any Se utilization traits, neither incorporated elemental Se, nor exhibited Se-dependent growth. However, 100% of Se-deficient mice (0.01 ppm Se), which express low levels of selenoproteins, succumbed to F. tularensis-live vaccine strain pulmonary challenge, whereas 50% of mice on Se-supplemented (0.4 ppm Se) and 25% of mice on Se-adequate (0.1 ppm Se) diet succumbed to infection. Median survival time for Se-deficient mice was 8 days post-infection while Se-supplemented and -adequate mice was 11.5 and >14 days post-infection, respectively. Se-deficient macrophages permitted significantly higher intracellular bacterial replication than Se-supplemented macrophages ex vivo, corroborating in vivo observations. Since Francisella replicates in alveolar macrophages during the acute phase of pneumonic infection, we hypothesized that macrophage-specific host selenoproteins may restrict replication and systemic spread of bacteria. F. tularensis infection led to an increased expression of several macrophage selenoproteins, suggesting their key role in limiting bacterial replication. Upon challenge with F. tularensis, mice lacking selenoproteins in macrophages (TrspM) displayed lower survival and increased bacterial burden in the lung and systemic tissues in comparison to WT littermate controls. Furthermore, macrophages from TrspM mice were unable to restrict bacterial replication ex vivo in comparison to macrophages from littermate controls. We herein describe a novel function of host macrophage-specific selenoproteins in restriction of intracellular bacterial replication. These data suggest that host selenoproteins may be considered as novel targets for modulating immune response to control a bacterial infection.

Uso del selenio en organismo acuáticos. Una revisión

“…El interés por este mineral inició al ser considerado un elemento tóxico, sin embargo, Schwarz y Foltz (1957) evidenciaron un papel esencial en mamíferos al señalar que su deficiencia producía la enfermedad del "músculo blanco", inmunodeficiencia y distrofias musculares, entre otros. Existen reportes que indican que niveles adecuados de Se influyen en la respuesta inmunitaria (Flohé, 2000;Ryan-Harshman y Aldoori, 2005;Markley et al, 2021;Dalgaard et al, 2018), en la función antioxidante y antiinflamatoria (Liu et al, 2016a), en la disminución del riesgo de tumores (Mahan et al, 2004;Burk y Hill et al, 2015), en la prevención de enfermedades cardiovasculares y en la toxicidad producida por micotoxinas o por contaminantes como el cadmio (Ren, 2020).…”

Oxidative Stress Induced by Selenium Deficiency Contributes to Inflammation, Apoptosis and Necroptosis in the Lungs of Calves

“…The effects of Se on lung function are primarily in the anti-infective, antioxidant, and alveolar development capacities. It has been demonstrated that macrophage-specific host selenoprotein restricts intracellular bacterial proliferation and protects mice from Francisella tularensis infection [ 4 ]. The antioxidant GPX protects respiratory membranes from peroxidative damage [ 5 ].…”

On‐Off Phagocytosis and Switchable Macrophage Activation Stimulated with NIR for Infected Percutaneous Tissue Repair of Polypyrrole‐Coated Sulfonated PEEK

“…[ 11 , 21 , 22 ] Macrophages are important immune cells that play an essential role in innate immune defense and specific immune activation against bacteria. [ 23 , 24 , 25 ] Macrophages can recognize bacteria via cytoplasmic pattern recognition receptors (PRRs). Surface PRRs, such as C‐type lectins and mannose receptors (MR), recognize and bind bacteria to initiate phagocytosis.…”