IL-7 as a mucosal adjuvant in pulmonary immunization protocols

International audienceObjective: Mucosae are the gateway for many pathogens. However, few vaccines have been developed to specifically target mucosal immunity. Recent studies in the laboratory evidenced local expression of IL-7 in the acutely SIV-infected intestinal mucosa and IAV-infected lung in macaques or mice, respectively. This overexpression led to chemokine production and infiltration of immune cells into these mucosae. In addition, systemic injection of IL-7 to macaques rapidly stimulates both the production of chemokines and immune cells homing into the mucosa. These results prompted us to study if IL-7 could be used as a mucosal vaccine adjuvant.Methods: Mice were intratracheally treated with IL-7 or PBS, then immunized by the same route against diphtheria toxoid (DT) or inactivated influenza virus (IAVi) two days later. DT immunized-mice were sacrificed at day 14 while those immunized with IAVi were infected with virulent IAV at day 14 and sacrificed at day 29. We measured antigen-specific antibody responses (anti-DT & anti-IAV) in both bronchoalveolar lavages (BAL) and sera, as well as chemokine expressions in lung tissue, by ELISA. The immune cell infiltration into the pulmonary mucosa was evaluated by immunochemistry on lung sections. The effectiveness of IL-7-adjuvanted vaccine in providing protection against IAV pathology was assessed by daily monitoring of animal body weight.Results: Intratracheal administration of IL-7 stimulated the production of pro-inflammatory chemokines in the lung parenchyma, leading to massive infiltration of immune cells found to be mainly organized in lymphoid aggregates. Moreover, intratracheal administration of IL-7 before primo-immunization allowed antigens-specific IgAs and IgGs production in the pulmonary mucosa. These effects were not observed in control mice vaccinated without IL-7 administration. In addition, only IL-7-treated immunized mice were protected against influenza pathology. This protection seems to be related to a high level of IAV-specific antibodies in BAL and lymphoid aggregate appearance in the pulmonary mucosa.Conclusion: By attracting immune cells into mucosae, local IL-7 administration prepares the mucosal immune system, gathering conditions that result in enhanced antigen-specific pulmonary immune responses upon antigenic stimulation. Hence, IL-7 appears as a mucosal adjuvant able to increase mucosal antibody responses, an important immune arm implicated in the protection against most mucosal infections

Antimalarial potential of xestoquinone, a protein kinase inhibitor isolated from a Vanuatu marine sponge Xestospongia sp.

As part of our search for new antimalarial drugs, we have screened for inhibitors of Pfnek-1, a protein kinase of Plasmodium falciparum, in south Pacific marine sponges. On the basis of a preliminary screening, the ethanolic crude extract of a new species of Xestospongia collected in Vanuatu was selected for its promising activity. A bioassay-guided fractionation led us to isolate xestoquinone which inhibits Pfnek-1 with an IC50 around 1 mu M. Among a small panel of plasmodial protein kinases, xestoquinone showed modest protein kinase inhibitory activity toward PfPK5 and no activity toward PfPK7 and PfGSK-3. Xestoquinone showed in vitro antiplasmodial activity against a FCB1 P. falciparum strain with an IC50 of 3 mu M and a weak selectivity index (SI 7). Xestoquinone exhibited a weak in vivo activity at 5 mg/kg in Plasmodium berghei NK65 infected mice and was toxic at higher doses. (c) 2006 Elsevier Ltd. All rights reserved

The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation

Centrioles are microtubule-based, barrel-shaped structures that initiate the assembly of centrosomes and cilia. How centriole length is precisely set remains elusive. The microcephaly protein CPAP (also known as MCPH6) promotes procentriole growth, whereas the oral-facial-digital (OFD) syndrome protein OFD1 represses centriole elongation. Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene. Concordant with the clinical overlap, C2CD3 colocalizes with OFD1 at the distal end of centrioles, and C2CD3 physically associates with OFD1. However, whereas OFD1 deletion leads to centriole hyperelongation, loss of C2CD3 results in short centrioles without subdistal and distal appendages. Because C2CD3 overexpression triggers centriole hyperelongation and OFD1 antagonizes this activity, we propose that C2CD3 directly promotes centriole elongation and that OFD1 acts as a negative regulator of C2CD3. Our results identify regulation of centriole length as an emerging pathogenic mechanism in ciliopathies

Dolutegravir-based dual maintenance regimens combined with lamivudine/emtricitabine or rilpivirine: risk of virological failure in a real-life setting

International audienceBackground Maintenance ART with dolutegravir-based dual regimens have proved their efficacy among HIV-1-infected subjects in randomized trials. However, real-life data are scarce, with limited populations and follow-up. Objectives We assessed virological failure (VF) and resistance-associated mutations (RAMs) on dolutegravir maintenance regimens in combination with rilpivirine or with lamivudine or emtricitabine (xTC) and analysed the factors associated with VF. Methods Between 2014 and 2018, all HIV-1-infected adults included in the Dat’AIDS cohort and starting dolutegravir/rilpivirine or dolutegravir/xTC as a maintenance dolutegravir-based dual regimen were selected. VF was defined as two consecutive HIV RNA values >50 copies/mL or a single value >400 copies/mL. We compared cumulative genotypes before initiation of a maintenance dolutegravir-based dual regimen with genotype at VF. Results We analysed 1374 subjects (799 on dolutegravir/rilpivirine and 575 on dolutegravir/xTC) with a median follow-up of 20 months (IQR = 11–31) and 19 months (IQR = 11–31), respectively. VF occurred in 3.8% (n = 30) of dolutegravir/rilpivirine subjects and 2.6% (n = 15) of dolutegravir/xTC subjects. Among subjects receiving dolutegravir/rilpivirine, two genotypes harboured emerging RAMs at VF: E138K on NNRTI (n = 1); and E138K+K101E on NNRTI and N155H on INSTI (n = 1). Among subjects receiving dolutegravir/xTC, no new RAM was detected. The only predictive factor of VF on dolutegravir/rilpivirine was the history of failure on an NNRTI-based regimen (adjusted HR = 2.97, 95% CI = 1.28–6.93). No factor was associated with VF on dolutegravir/xTC. Conclusions In this large real-life cohort, dolutegravir/rilpivirine and dolutegravir/xTC sustained virological suppression and were associated with a low rate of VF and RAM emergence. Careful virological screening is essential before switching to dolutegravir/rilpivirine in virologically suppressed patients with a history of NNRTI therapy