Publications by authors named "Louise Jeammet"

9 Publications

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PLA2G1B is involved in CD4 anergy and CD4 lymphopenia in HIV-infected patients.

J Clin Invest 2020 06;130(6):2872-2887

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The precise mechanism leading to profound immunodeficiency of HIV-infected patients is still only partially understood. Here, we show that more than 80% of CD4+ T cells from HIV-infected patients have morphological abnormalities. Their membranes exhibited numerous large abnormal membrane microdomains (aMMDs), which trap and inactivate physiological receptors, such as that for IL-7. In patient plasma, we identified phospholipase A2 group IB (PLA2G1B) as the key molecule responsible for the formation of aMMDs. At physiological concentrations, PLA2G1B synergized with the HIV gp41 envelope protein, which appears to be a driver that targets PLA2G1B to the CD4+ T cell surface. The PLA2G1B/gp41 pair induced CD4+ T cell unresponsiveness (anergy). At high concentrations in vitro, PLA2G1B acted alone, independently of gp41, and inhibited the IL-2, IL-4, and IL-7 responses, as well as TCR-mediated activation and proliferation, of CD4+ T cells. PLA2G1B also decreased CD4+ T cell survival in vitro, likely playing a role in CD4 lymphopenia in conjunction with its induced IL-7 receptor defects. The effects on CD4+ T cell anergy could be blocked by a PLA2G1B-specific neutralizing mAb in vitro and in vivo. The PLA2G1B/gp41 pair constitutes what we believe is a new mechanism of immune dysfunction and a compelling target for boosting immune responses in HIV-infected patients.
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http://dx.doi.org/10.1172/JCI131842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301387PMC
June 2020

Surfactant-secreted phospholipase A interplay and respiratory outcome in preterm neonates.

Am J Physiol Lung Cell Mol Physiol 2020 07 13;319(1):L95-L104. Epub 2020 May 13.

Cystic fibrosis and Bronchial diseases team-INSERM U938, Institut Pasteur, Paris, France.

Secreted phospholipase A hydrolyzes surfactant phospholipids and is crucial for the inflammatory cascade; preterm neonates are treated with exogenous surfactant, but the interaction between surfactant and phospholipase is unknown. We hypothesize that this interplay is complex and the enzyme plays a relevant role in neonates needing surfactant replacement. We aimed to: ) identify phospholipases A isoforms expressed in preterm lung; ) study the enzyme role on surfactant retreatment and function and the effect of exogenous surfactant on the enzyme system; and ) verify whether phospholipase A is linked to respiratory outcomes. In bronchoalveolar lavages of preterm neonates, we measured enzyme activity (alone or with inhibitors), enzyme subtypes, surfactant protein-A, and inflammatory mediators. Surfactant function and phospholipid profile were also tested. Urea ratio was used to obtain epithelial lining fluid concentrations. Follow-up data were prospectively collected. Subtype-IIA is the main phospholipase isoform in preterm lung, although subtype-IB may be significantly expressed. Neonates needing surfactant retreatment have higher enzyme activity ( = 0.021) and inflammatory mediators ( always ≤ 0.001) and lower amounts of phospholipids ( always < 0.05). Enzyme activity was inversely correlated to surfactant adsorption (ρ = -0.6; = 0.008; adjusted = 0.009), total phospholipids (ρ = -0.475; = 0.05), and phosphatidylcholine (ρ = -0.622; = 0.017). Exogenous surfactant significantly reduced global phospholipase activity ( < 0.001) and subtype-IIA ( = 0.005) and increased dioleoylphosphatidylglycerol ( < 0.001) and surfactant adsorption ( < 0.001). Enzyme activity correlated with duration of ventilation (ρ = 0.679, = 0.005; adjusted = 0.04) and respiratory morbidity score at 12 mo postnatal age (τ = 0.349, = 0.037; adjusted = 0.043) but was not associated with mortality, bronchopulmonary dysplasia, or other long-term respiratory outcomes.
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http://dx.doi.org/10.1152/ajplung.00462.2019DOI Listing
July 2020

Antimalarial Activity of Human Group IIA Secreted Phospholipase A in Relation to Enzymatic Hydrolysis of Oxidized Lipoproteins.

Infect Immun 2019 11 18;87(11). Epub 2019 Oct 18.

Université Côte d'Azur, CNRS, IPMC, Valbonne Sophia Antipolis, France

The level of human group IIA secreted phospholipase A (hGIIA sPLA) is increased in the plasma of malaria patients, but its role is unknown. In parasite culture with normal plasma, hGIIA is inactive against , contrasting with hGIIF, hGV, and hGX sPLAs, which readily hydrolyze plasma lipoproteins, release nonesterified fatty acids (NEFAs), and inhibit parasite growth. Here, we revisited the anti- activity of hGIIA under conditions closer to those of malaria physiopathology where lipoproteins are oxidized. In parasite culture containing oxidized lipoproteins, hGIIA sPLA was inhibitory, with a 50% inhibitory concentration value of 150.0 ± 40.8 nM, in accordance with its capacity to release NEFAs from oxidized particles. With oxidized lipoproteins, hGIIF, hGV, and hGX sPLAs were also more potent, by 4.6-, 2.1-, and 1.9-fold, respectively. Using specific immunoassays, we found that hGIIA sPLA is increased in plasma from 41 patients with malaria over levels for healthy donors (median [interquartile range], 1.6 [0.7 to 3.4] nM versus 0.0 [0.0 to 0.1] nM, respectively; < 0.0001). Other sPLAs were not detected. Malaria plasma, but not normal plasma, contains oxidized lipoproteins and was inhibitory to when spiked with hGIIA sPLA Injection of recombinant hGIIA into mice infected with reduced the peak of parasitemia, and this was effective only when the level of plasma peroxidation was increased during infection. In conclusion, we propose that malaria-induced oxidation of lipoproteins converts these into a preferential substrate for hGIIA sPLA, promoting its parasite-killing effect. This mechanism may contribute to host defense against in malaria where high levels of hGIIA are observed.
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http://dx.doi.org/10.1128/IAI.00556-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803347PMC
November 2019

Enzymatic activity of mouse group X-sPLA2 improves in vitro production of preimplantation bovine embryos.

Theriogenology 2019 Jun 1;131:113-122. Epub 2019 Apr 1.

Université Grenoble Alpes, Grenoble, F-38000, France; Institute for Advanced Biosciences INSERM U1209, CNRS UMR5309, Grenoble, F-38000, France. Electronic address:

Assisted reproductive technologies (ART) are widely used for both humans and domestic animals. In bovine species, in vitro embryo production is increasingly used and significant efforts are being made to optimize media and culture conditions. Phospholipase A2 (PLA2) are lipolytic enzymes that hydrolyze glycerophospholipids to produce free fatty acids and lysophospholipids that have been found to be critical for many biological processes. Mouse group X secreted PLA (mGX) is abundant in the male reproductive tract and its use during sperm capacitation has been shown to improve in vitro production of viable embryos in a mouse model. Here, we examined its effect in the bovine species, testing the impact of mGX on the three steps involved in vitro production of preimplantation embryos: oocyte maturation, fertilization and preimplantation development. We found that incubating cumulus oocyte complexes (COC) or gametes with mGX resulted in increased blastocyst hatching and blastocyst production, respectively. The increases of embryo production induced by the phospholipase mGX were not observed for the catalytically inactive mutant H48Q-mGX, suggesting that these effects require the enzymatic activity of mGX. We also tested bGIB, a bovine homolog of mGX. bGIB failed to improve blastocyst production, underlining the high specificity of mGX. In conclusion, the results presented show that the effects of mGX are not restricted to the mouse model and that it is potent in the bovine species as well. This result strengthens the potential of mGX as a "pro-fertility drug" for mammalian reproduction.
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http://dx.doi.org/10.1016/j.theriogenology.2019.03.030DOI Listing
June 2019

Secreted Phospholipases A2 Are Intestinal Stem Cell Niche Factors with Distinct Roles in Homeostasis, Inflammation, and Cancer.

Cell Stem Cell 2016 07 9;19(1):38-51. Epub 2016 Jun 9.

Department of Pathology, Erasmus MC Cancer Institute, Rotterdam 3000CA, The Netherlands. Electronic address:

The intestinal stem cell niche provides cues that actively maintain gut homeostasis. Dysregulation of these cues may compromise intestinal regeneration upon tissue insult and/or promote tumor growth. Here, we identify secreted phospholipases A2 (sPLA2s) as stem cell niche factors with context-dependent functions in the digestive tract. We show that group IIA sPLA2, a known genetic modifier of mouse intestinal tumorigenesis, is expressed by Paneth cells in the small intestine, while group X sPLA2 is expressed by Paneth/goblet-like cells in the colon. During homeostasis, group IIA/X sPLA2s inhibit Wnt signaling through intracellular activation of Yap1. However, upon inflammation they are secreted into the intestinal lumen, where they promote prostaglandin synthesis and Wnt signaling. Genetic ablation of both sPLA2s improves recovery from inflammation but increases colon cancer susceptibility due to release of their homeostatic Wnt-inhibitory role. This "trade-off" effect suggests sPLA2s have important functions as genetic modifiers of inflammation and colon cancer.
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http://dx.doi.org/10.1016/j.stem.2016.05.023DOI Listing
July 2016

Cross-reactivity of anti-PLA2R1 autoantibodies to rabbit and mouse PLA2R1 antigens and development of two novel ELISAs with different diagnostic performances in idiopathic membranous nephropathy.

Biochimie 2015 Nov 19;118:104-15. Epub 2015 Aug 19.

Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS and Université de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France. Electronic address:

About 70% of patients with idiopathic membranous nephropathy (iMN) have autoantibodies to the phospholipase A2 receptor PLA2R1. We screened sera from iMN patients for their cross-reactivity to human (h), rabbit (rb) and mouse (m) PLA2R1 by western blot (WB) and antigen-specific ELISAs. All iMN patients recognized hPLA2R1 and rbPLA2R1 by WB, and a rbPLA2R1 ELISA was as sensitive as the standardized hPLA2R1 ELISA to monitor anti-PLA2R1 in patients with active disease or in drug-induced remission. In contrast, only 51% of patients were reactive to mPLA2R1 by WB, and a maximum of 78% were weakly to highly positive in the mPLA2R1 ELISA, suggesting that iMN patients exhibit different subsets of anti-PLA2R1 autoantibodies against epitopes that are shared or not among PLA2R1 orthologs. In a cohort of 41 patients with a mean follow-up of 42 months from anti-PLA2R1 assay, the detection of anti-mPLA2R1 autoantibodies was an independent predictor of clinical outcome in multivariate analysis (p = 0.009), and a ROC curve analysis identified a threshold of 605 RU/mL above which 100% of patients (12 patients) had a poor renal outcome (p < 0.001). A similar threshold could not be defined in hPLA2R1 and rbPLA2R1 ELISAs. We conclude that rbPLA2R1 is an alternative antigen to hPLA2R1 to measure anti-PLA2R1 in active disease while mPLA2R1 is a unique antigen that can detect a subset of anti-PLA2R1 autoantibodies present at high levels (>605 RU/mL) only in iMN patients at risk of poor prognosis, and is thus useful to predict iMN outcome.
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http://dx.doi.org/10.1016/j.biochi.2015.08.007DOI Listing
November 2015

In vitro anti-Plasmodium falciparum properties of the full set of human secreted phospholipases A2.

Infect Immun 2015 Jun 30;83(6):2453-65. Epub 2015 Mar 30.

Muséum National d'Histoire Naturelle, UMR 7245 CNRS/MNHN, MCAM équipe BAMEE, Paris, France

We have previously shown that secreted phospholipases A2 (sPLA2s) from animal venoms inhibit the in vitro development of Plasmodium falciparum, the agent of malaria. In addition, the inflammatory-type human group IIA (hGIIA) sPLA2 circulates at high levels in the serum of malaria patients. However, the role of the different human sPLA2s in host defense against P. falciparum has not been investigated. We show here that 4 out of 10 human sPLA2s, namely, hGX, hGIIF, hGIII, and hGV, exhibit potent in vitro anti-Plasmodium properties with half-maximal inhibitory concentrations (IC50s) of 2.9 ± 2.4, 10.7 ± 2.1, 16.5 ± 9.7, and 94.2 ± 41.9 nM, respectively. Other human sPLA2s, including hGIIA, are inactive. The inhibition is dependent on sPLA2 catalytic activity and primarily due to hydrolysis of plasma lipoproteins from the parasite culture. Accordingly, purified lipoproteins that have been prehydrolyzed by hGX, hGIIF, hGIII, and hGV are more toxic to P. falciparum than native lipoproteins. However, the total enzymatic activities of human sPLA2s on purified lipoproteins or plasma did not reflect their inhibitory activities on P. falciparum. For instance, hGIIF is 9-fold more toxic than hGV but releases a lower quantity of nonesterified fatty acids (NEFAs). Lipidomic analyses of released NEFAs from lipoproteins demonstrate that sPLA2s with anti-Plasmodium properties are those that release polyunsaturated fatty acids (PUFAs), with hGIIF being the most selective enzyme. NEFAs purified from lipoproteins hydrolyzed by hGIIF were more potent at inhibiting P. falciparum than those from hGV, and PUFA-enriched liposomes hydrolyzed by sPLA2s were highly toxic, demonstrating the critical role of PUFAs. The selectivity of sPLA2s toward low- and high-density (LDL and HDL, respectively) lipoproteins and their ability to directly attack parasitized erythrocytes further explain their anti-Plasmodium activity. Together, our findings indicate that 4 human sPLA2s are active against P. falciparum in vitro and pave the way to future investigations on their in vivo contribution in malaria pathophysiology.
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http://dx.doi.org/10.1128/IAI.02474-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432757PMC
June 2015

Pseudomonas aeruginosa eradicates Staphylococcus aureus by manipulating the host immunity.

Nat Commun 2014 Oct 7;5:5105. Epub 2014 Oct 7.

1] Unité de défense innée et inflammation, Institut Pasteur, 75015 Paris, France [2] INSERM U874, 75015 Paris, France.

Young cystic fibrosis (CF) patients' airways are mainly colonized by Staphylococcus aureus, while Pseudomonas aeruginosa predominates in adults. However, the mechanisms behind this infection switch are unclear. Here, we show that levels of type-IIA-secreted phospholipase A2 (sPLA2-IIA, a host enzyme with bactericidal activity) increase in expectorations of CF patients in an age-dependent manner. These levels are sufficient to kill S. aureus, with marginal effects on P. aeruginosa strains. P. aeruginosa laboratory strains and isolates from CF patients induce sPLA2-IIA expression in bronchial epithelial cells from CF patients (these cells are a major source of the enzyme). In an animal model of lung infection, P. aeruginosa induces sPLA2-IIA production that favours S. aureus killing. We suggest that sPLA2-IIA induction by P. aeruginosa contributes to S. aureus eradication in CF airways. Our results indicate that a bacterium can eradicate another bacterium by manipulating the host immunity.
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http://dx.doi.org/10.1038/ncomms6105DOI Listing
October 2014

The effect of group X secreted phospholipase A2 on fertilization outcome is specific and not mimicked by other secreted phospholipases A2 or progesterone.

Biochimie 2014 Apr 25;99:88-95. Epub 2013 Nov 25.

Université Joseph Fourier, Grenoble F-38000, France; Laboratoire AGIM, Equipe AGC, CNRS FRE3405, La Tronche F-38700, France. Electronic address:

Mouse group X sPLA2 (mGX) is an acrosomal protein playing an important role in fertilization and controlling acrosome reaction (AR) occurring during capacitation. We demonstrated previously that sperm from mGX knock-out mice had a severely impaired fertilization potential in vitro. We also showed that treatment of wild-type sperm with recombinant mGX during capacitation improved fertilization outcome. This interesting property suggests that sPLA2s could be used to improve fertilization in assisted reproductive technologies (ART). However the molecular mechanism explaining the mGX-dependent enhancing effect on fertilization outcome remains unclear so far. Interestingly, like progesterone (P4), mGX is a very potent activator of AR and the role of mGX-induced AR in fertilization outcome was not evaluated so far. To assess the role of sPLA2-induced AR in IVF, we first tested the potency of 9 mouse and 2 human sPLA2s and P4 to trigger AR of mouse sperm. We then tested the ability of 6 of these molecules (mouse Group IIA, mouse Group IID, mouse Group X, human Group V, human Group X and P4) to improve the yield of 2-cell embryos obtained by IVF in mouse. We showed that in the mouse neither P4 nor any of the other sPLA2s tested were able to mimic the IVF improvement produced by mGX-treatment. These results demonstrate that sPLA2s are not commutable in the context of mouse sperm fertility, indicating that their utilisation in other species, is subjected to the identification of probably unique species-specific active sPLA2.
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http://dx.doi.org/10.1016/j.biochi.2013.11.012DOI Listing
April 2014