Infection-mediated priming of phagocytes protects against lethal secondary Aspergillus fumigatus challenge

Phagocytes restrict the germination of Aspergillus fumigatus conidia and prevent the establishment of invasive pulmonary aspergillosis in immunecompetent mice. Here we report that immunecompetent mice recovering from a primary A. fumigatus challenge are protected against a secondary lethal challenge. Using RAGγc knock-out mice we show that this protection is independent of T, B and NK cells. In protected mice, lung phagocytes are recruited more rapidly and are more efficient in conidial phagocytosis and killing. Protection was also associated with an enhanced expression of CXCR2 and Dectin-1 on bone marrow phagocytes. We also show that protective lung cytokine and chemokine responses are induced more rapidly and with enhanced dynamics in protected mice. Our findings support the hypothesis that following a first encounter with a non-lethal dose of A. fumigatus conidia, the innate immune system is primed and can mediate protection against a secondary lethal infection

Etude de la modulation de l'expression de p21WAF1/CAP20/SD11 par des cytokines (application à une lignée d'hépatomes transformés par la protéine core du virus de l'hépatite C humaine et à des monocytes de sujets sains)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Rôles de PPAR et de p21

Les macrophages sont des cellules impliquées dans la réponse immunitaire et inflammatoire. La dérégulation de leurs propriétés physiologiques est associée à plusieurs pathologies telles que l’athérosclérose ou certains cancers. L’action de cytokines sur cette lignée hématopoïétique module l’expression de p21WAF1/CIP1, un inhibiteur du cycle cellulaire. Il semblerait que cette protéine joue un rôle dans la régulation de l’inflammation via les facteurs de transcription de type PPAR (récepteurs nucléaires activés par les proliférateurs de peroxysomes), qui sont fortement liés au métabolisme lipidique. Elle pourrait aussi être engagée dans le contrôle de la prolifération des monocytes/macrophages, bien que ces cellules soient classiquement décrites comme n’ayant aucune capacité proliférative

Effect of ischemia on intestinal CYP-derived eicosanoids production.

<p>Synthesis of eicosanoids from arachidonic acid (AA) was measured by liquid chromatography-tandem mass spectrometry in control mice (naïve and sham operated mice) and following 50 minutes of ischemia. Data represent means ± SEM of 6 to 8 mice per group. *p<0.05, and ***p<0.001 <i>versus</i> the corresponding sham operated group.</p

Effect of ischemia on intestinal docosanoid metabolites production.

<p>Synthesis of docosanoids from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) was measured by liquid chromatography-tandem mass spectrometry in control mice (naïve and sham operated mice) and following 50 minutes of ischemia. Data represent means ± SEM of 6 to 8 mice per group. *p<0.05, and **p<0.01 <i>versus</i> the corresponding sham operated group.</p

Temporal schemes of PUFA-producing enzymes and metabolites upon ischemia-reperfusion.

<p><b>A</b>, Kinetic scheme of COX, LOX and CYP activation based on PUFA metabolites enzymatic biosynthesis. Early ischemia induces LOX metabolite biosynthesis, while COX activation seems to play a major role during the first hours after reperfusion (2 and 5 hours). CYP-derived metabolite synthesis starts immediately during ischemia and up to 5 hours reperfusion. <b>B,</b> Scheme of temporal PUFA metabolites production during intestinal ischemia reperfusion injury. Ischemic episodes (induction of the inflammatory response) lead to a concomitant early production of both the neutrophil chemo-attractant LTB₄ and the vascular-protective LxA₄. Immediate biosynthesis of LxA₄ could assure an appropriate counterbalance role against ischemic damage. From 2 hours and up to 5-h reperfusion, PGE₂ (such as other COX-derived metabolites) production was strongly increased fitting with the concomitant peaks of mucosal damage (2 hours) and granulocyte recruitment (5 hours). LTB₄ (such as other LOX-derived metabolites) again significantly increased after 5 h of reperfusion, suggesting that at this time-point, additional cell source (potentially granulocytes) is responsible for the biosynthesis of LOX metabolites. At 24-h after reperfusion, all PUFA metabolites were decreased, to reach basal levels after 48 h of reperfusion, except for mediators known to take part into the resolution of inflammation: the RvE precursor 18-HEPE and the PPARγ agonist, 15d-PGJ₂.</p

<i>In vivo</i> effects of systemic treatment with the transient receptor potential vanilloid-4 antagonist HC-067047 (50 mg/kg i.p.) or its vehicle.

<p>A, histological damage; B, microscopic damage (white) and MPO activity (grey); C–E chemokine (KC, MCP-1 and IL-6) tissue protein expression. Data in B, C, D and E represent means ± SEM of 6 to 8 mice per group. *p<0.05, **p<0.01, ***p<0.001 <i>versus</i> the corresponding sham operated group +p<0.05 <i>versus</i> the indicated I–R group.</p

Effect of ischemia followed by reperfusion from 2 to 48 hours on intestinal eicosanoids/docosanoid production.

<p><b>A</b>–<b>D</b> Synthesis of eicosanoids derived from COX-(<b>A</b>) LOX-(<b>B</b>) CYP-(<b>C</b>) arachidonic acid (AA) or its precursor the dihomo-γ-linolenic acid (DGLA) metabolism. <b>D,</b> Synthesis of docosanoid derived from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) metabolism. Data are expressed as fold increase <i>versus</i> corresponding sham operated group and represent means ± SEM of 6 to 8 mice per group.</p

Proteomic and Lipidomic Profiling of Calves Experimentally Co-Infected with Influenza D Virus and Mycoplasma bovis : Insights into the Host-Pathogen Interactions

The role of Influenza D virus (IDV) in bovine respiratory disease remains unclear. An in vivo experiment resulted in increased clinical signs, lesions, and pathogen replication in calves co-infected with IDV and Mycoplasma bovis (M. bovis), compared to single-infected calves. The present study aimed to elucidate the host-pathogen interactions and profile the kinetics of lipid mediators in the airways of these calves. Bronchoalveolar lavage (BAL) samples collected at 2 days post-infection (dpi) were used for proteomic analyses by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Additionally, lipidomic analyses were performed by LC-MS/MS on BAL samples collected at 2, 7 and 14 dpi. Whereas M. bovis induced the expression of proteins involved in fibrin formation, IDV co-infection counteracted this coagulation mechanism and downregulated other acute-phase response proteins, such as complement component 4 (C4) and plasminogen (PLG). The reduced inflammatory response against M. bovis likely resulted in increased M. bovis replication and delayed M. bovis clearance, which led to a significantly increased abundance of oxylipids in co-infected calves. The identified induced oxylipids mainly derived from arachidonic acid; were likely oxidized by COX-1, COX-2, and LOX-5; and peaked at 7 dpi. This paper presents the first characterization of BAL proteome and lipid mediator kinetics in response to IDV and M. bovis infection in cattle and raises hypotheses regarding how IDV acts as a co-pathogen in bovine respiratory disease