Biology subjects

Dereuddre-Bosquet, N.

Publications and source records attributed to Dereuddre-Bosquet, N..

10 recordsLinked to original sources

bioRxiv2026

Modeling how memory CD8 T cells can elicit post-treatment control of HIV infection

While most people living with HIV suffer progressive disease following cessation of antiretroviral therapy, a small fraction elicits lasting post-treatment control. Understanding the mechanisms underlying this control is key to devising effective HIV remission strategies. Although recent studies implicate memory CD8 T cells, how these cells establish lasting viremic control remains unknown. Here, we combine mathematical modeling and analysis of data from SIV-infected non-human primates to elucidate the underlying mechanisms. We recognized that sustained antigenic stimulation leads to heritable epigenetic remodeling of the CD8 T cell pool, impairing memory cell survivability. Antiretroviral therapy rapidly suppresses viremia, thereby arresting antigenic stimulation and preserving memory potential. The greater this preservation is, the better would be the memory recall response following viral rebound post-treatment. Our mathematical model based on this hypothesis predicts that post-treatment control is an alternative steady state to progressive infection, realized by strong memory-driven recall responses. Our model fits longitudinal virological data spanning the pre-, during-, and post-antiretroviral treatment phases of infection, and recapitulates the outcomes of progressive disease and long-term remission realized, the latter predominantly with early treatment initiation. It shows, consistently with data, that memory CD8 T cells could drive post-treatment control independently of the size of the latent reservoir, explaining how such control may be realized more widely than estimated with prevalent hypotheses. Our model further explains the existence of a window of treatment initiation times that maximizes the chances of post-treatment control. Finally, model predictions inform interventions targeting memory CD8 T cells for HIV remission.

immunology↗

bioRxiv2026

Joint mechanistic modeling of viral and antibody responses to vaccines in non-human primates to quantify SARS-CoV-2 mechanistic correlates of protection

In a global SARS-CoV-2 landscape of hybrid immunity resulting from a vaccinated worldwide population and the emergence of new variants able to escape immunity, the identification and quantification of correlates of protection (CoPs) is crucial for the adaptation of next-generation SARS-CoV-2 vaccines. Antibodies and their neutralizing capacity have been identified as reliable mechanistic CoPs. Here, we proposed an original mechanistic model jointly describing viral and antibody dynamics, and their mutual interactions, observed after SARS-CoV-2 infection in non-human primates (NHPs) with distinct immunological backgrounds. From the model, the concentration of neutralizing antibodies being protective against viral infection spreading was derived using the reproduction number. Counterfactual simulations were also performed to better understand and validate immune mechanisms driving immune control. The model was estimated on viral, binding (bAb), and neutralizing (nAb) antibody dynamics, with data collected in 34 naive and convalescent NHPs. Animals were involved in a preclinical study evaluating two next-generation protein-based vaccines targeting the RBD of the Spike protein to CD40-expressing cells, and the original BNT162b2 mRNA vaccine against Delta SARS-CoV-2 infection. Our model validated the functionality of nAb to neutralize viruses as the primary mechanism of protection. An inhibitory antibody concentration against Delta variant of 20 AU/mL was deemed protective against Delta infection in naive animals. Moreover, we showed the strong benefit of hybrid immunity to induce faster and more protective antibody responses pointing out the crucial role of the memory B-cell immune response in viral control. Finally, an additional effect of natural immunity beyond antibodies and enhancing the elimination of infected cells was identified, suggesting the potential role of the T-cell response in viral control. Our model showed the benefit of combining information from both viral and antibody responses to better qualitatively and quantitatively inform on their protective capacity against Delta SARS-CoV-2 infection.

immunology↗

bioRxiv2025

The vaginal microbiota composition influences cervicovaginal and systemic inflammation induced by Chlamydia trachomatis infection.

BackgroundChlamydiosis, a sexually transmitted infection (STI) induced by Chlamydia trachomatis (CT), increases local inflammation (cytokine production, recruitment of immune cells such as neutrophils). Few is known on the impact of CT infection on the phenotype of cervicovaginal neutrophils. Vaginal microbiota (VM) is a key factor in the regulation of local immune responses and STI acquisition where Lactobacillus spp are associated with protection. In this study, the VM of cynomolgus macaques was enriched with Lactobacillus crispatus after local metronidazole treatment followed by repeated intravaginal inoculations of CT. VM composition, CT infection and local and systemic inflammation were monitored. ResultsFirst, we observed that metronidazole treatment induced drastic modifications of the VM by reducing the abundance of several anaerobes and increasing the number of natural Lactobacillus spp (Lactobacillus johnsonii and its prophage mainly) as well as opportunistic bacteria (Streptococcus spp and Staphylococcus spp). After CT exposure of L. crispatus treated or not animals, a non-persisting CT infection and no association between L. crispatus enrichment and a lower susceptibility to CT infection were detected. However, the production of serum specific anti-CT IgG was higher in L. crispatus treated animals. Moreover, the production of anti-CT IgG was associated with various bacterial species. An increased production of peripheral blood cytokines after CT infection was observed in untreated animals, whereas L. crispatus treated animals exhibited an increased production of cervicovaginal cytokines. Peripheral blood neutrophils were more mature and activated after CT infection/inoculation in both groups. Very few alterations of the cervicovaginal neutrophil phenotype were noticed after CT infection. Markers expressed on neutrophils were associated with bacterial species and differences were detected according to groups. ConclusionThese results suggest a better local immune response as well as a better control on systemic inflammation upon CT infection in L. crispatus treated animals compared to untreated animals. Indeed, it highlight an impact of VM composition on the local and systemic immune responses induced by CT infection. This study confirmed that VM composition can be a powerful tool to modulate local inflammation and STI susceptibility.

immunology↗

bioRxiv2023

Multi-target mode of action of Sulfodyne(R), a stabilized Sulforaphane, against pathogenic effects of SARS-CoV-2 infection

The coronavirus disease 2019 (COVID-19) due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown that, except vaccination, few therapeutics options for its treatment or prevention are available. Among the pathways that can be targeted for COVID-19 treatment, the Keap1/Nrf2 pathway seems of high interest as it regulates redox homeostasis and inflammation that are altered during SARS-CoV-2 infection. Here, we use three potent activators of the Keap1/Nrf2 pathway and showed that Sulfodyne(R), a stabilized natural Sulforaphane preparation with optimal bioavailability, had the highest antiviral activity in pulmonary or colonic epithelial cell lines even when added late after SARS-CoV-2 infection. This antiviral activity was not dependent on NRF2 activity but associated with action on ER stress and mTOR signaling that are activated during SARS-CoV-2 infection. Sulfodyne(R) also decreased the inflammatory response of epithelial cell lines infected by SARS-CoV-2 independently of SARS-CoV-2 replication and reduced the activation of human monocytes that are recruited after infection of epithelial cells by SARS-CoV-2. Administration of Sulfodyne(R) had little effects on SARS-CoV-2 replication in mice and hamsters infected with SARS-CoV-2 but significantly reduced weight loss and disease severity. Altogether, these results pinpoint the natural compound Sulfodyne(R) as a potent therapeutic agent of COVID-19 symptomatology. Author SummaryAccumulating evidence shows that oxidative stress coupled with the systemic inflammation contribute to COVID-19 pathogenesis. As the Keap1/Nrf2 pathway is the major regulator of redox homeostasis and promotes resolution of inflammation and as lung biopsies from COVID-19 patients showed a decreased NRF2 target gene signature, pharmacological agents that are known to activate NRF2 are good candidates for COVID-19 treatment. We show herein that Sulfodyne(R), an NRF2 activator that consists in a stabilized Sulforaphane preparation with optimal bioavailability, impairs SARS-CoV-2 replication in colonic or pulmonary epithelial cells. We show that this antiviral activity of Sulfodyne(R) is not dependent of NRF2 activation, characterize the pathways associated with the Sulfodyne(R) antiviral activity and show that Sulfodyne(R) displays multiple actions that result in a decrease of the inflammation associated with SARS-CoV-2 infection. Finally, we show that Sulfodyne(R) decreases the pathogenesis of mice or hamster infected with SARS-CoV-2. Overall, this study provides mechanistic explanations of the action of Sulfodyne(R) during SARS-CoV-2 infection and suggests that Sulfodyne(R) is a potential therapeutic agent of COVID-19 pathogenesis.

cell biology↗

bioRxiv2023

Antiviral capacity of the early CD8 T-cell response is predictive of natural control of SIV infection

While most individuals suffer progressive disease following HIV infection, a small fraction spontaneously controls the infection. Although CD8 T-cells have been implicated in this natural control, their mechanistic roles are yet to be established. Here, we combined mathematical modeling and analysis of data from 16 SIV-infected macaques, of which 12 were natural controllers, to elucidate the role of CD8 T-cells in natural control. For each macaque, we considered, in addition to the canonical in vivo plasma viral load and SIV DNA data, longitudinal ex vivo measurements of the virus suppressive capacity of CD8 T-cells. Available mathematical models do not allow analysis of such combined in vivo-ex vivo datasets. By explicitly modeling the ex vivo assay and integrating it with in vivo dynamics, we developed a new framework that enabled the analysis. Our model fit the data well and estimated that the recruitment rate and/or maximal killing rate of CD8 T-cells was up to 2-fold higher in controllers than non-controllers (p=0.013). Importantly, the cumulative suppressive capacity of CD8 T-cells over the first 4-6 weeks of infection was associated with virus control (Spearmans {rho}=- 0.51; p=0.05). Thus, our analysis identified the early cumulative suppressive capacity of CD8 T-cells as a predictor of natural control. Furthermore, simulating a large virtual population, our model quantified the minimum capacity of this early CD8 T-cell response necessary for long-term control. Our study presents new, quantitative insights into the role of CD8 T-cells in the natural control of HIV infection and has implications for remission strategies.

microbiology↗

bioRxiv2021

SARS-CoV-2 mechanistic correlates of protection: insight from modelling response to vaccines

The definition of correlates of protection is critical for the development of next generation SARS-CoV-2 vaccine platforms. Here, we propose a new framework for identifying mechanistic correlates of protection based on mathematical modelling of viral dynamics and data mining of immunological markers. The application to three different studies in non-human primates evaluating SARS-CoV-2 vaccines based on CD40-targeting, two-component spike nanoparticle and mRNA 1273 identifies and quantifies two main mechanisms that are a decrease of rate of cell infection and an increase in clearance of infected cells. Inhibition of RBD binding to ACE2 appears to be a robust mechanistic correlate of protection across the three vaccine platforms although not capturing the whole biological vaccine effect. The model shows that RBD/ACE2 binding inhibition represents a strong mechanism of protection which required significant reduction in blocking potency to effectively compromise the control of viral replication. One Sentence SummaryA framework for modelling the immune control of viral dynamics is applied to quantify the effect of several SARS-CoV-2 vaccine platforms and to define mechanistic correlates of protection.

immunology↗

bioRxiv2021

The route of vaccine administration determines whether blood neutrophils undergo long-term phenotypic modifications

Innate immunity modulates adaptive immunity and defines the magnitude, quality, and longevity of antigen-specific T- and B- cell immune memory. Various vaccine and administration factors influence the immune response to vaccination, including the route of vaccine delivery. We studied the dynamics of innate cell responses in blood using a preclinical model of non-human primates immunized with a live attenuated vaccinia virus, Modified vaccinia virus Ankara (MVA), and mass cytometry. We previously showed that MVA induces a strong, early, and transient innate response, but also late phenotypic modifications of blood myeloid cells after two months when injected subcutaneously. Here, we show that the early innate effector cell responses and plasma inflammatory cytokine profiles differ between subcutaneous and intradermal vaccine injection. Additionally, we show that the intradermal administration fails to induce more highly activated/mature neutrophils long after immunization, in contrast to subcutaneous administration. Different batches of antibodies, staining protocols and generations of mass cytometers were used to generate the two datasets that were compared. Mass cytometry data were analyzed in parallel using the same analytical pipeline based on three successive clustering steps, including SPADE, and categorical heatmaps were compared using the Manhattan distance to measure the similarity between cell cluster phenotypes. Overall, we show that the vaccine per se is not sufficient for the late phenotypic modifications of innate myeloid cells, which are evocative of innate immune training. Its route of administration is also crucial, likely by influencing the early innate response, and systemic inflammation, and the vaccine biodistribution.

immunology↗

bioRxiv2021

Artemisinin-independent inhibitory activity of Artemisia sp. infusions against different Plasmodium stages including relapse-causing hypnozoites

Artemisinin-based combination therapies (ACT) are the frontline treatments against malaria worldwide. Recently the use of traditional infusions from Artemisia annua (from which artemisinin is obtained) or A. afra (lacking artemisinin) has been controversially advocated. Such unregulated plant-based remedies are strongly discouraged as they might constitute sub-optimal therapies and promote drug resistance. Here, we conducted the first comparative study of the anti-malarial effects of both plant infusions in vitro against the asexual erythrocytic stages of P. falciparum and the pre-erythrocytic (i. e., liver) stages of various Plasmodium species. Low concentrations of either infusion accounted for significant inhibitory activities across every parasite species and stage studied. We show that these antiplasmodial effects were essentially artemisinin-independent and were additionally monitored by observations of the parasite apicoplast and mitochondrion. In particular, the infusions significantly incapacitated sporozoites, and for P. vivax and P. cynomolgi, disrupted the hypnozoites. This provides the first indication that compounds other than 8-aminoquinolines could be effective antimalarials against relapsing parasites. These observations advocate for further screening to uncover urgently needed novel antimalarial lead compounds.

microbiology↗

bioRxiv2020

Two-component spike nanoparticle vaccine protects macaques from SARS-CoV-2 infection

The SARS-CoV-2 pandemic is continuing to disrupt personal lives, global healthcare systems and economies. Hence, there is an urgent need for a vaccine that prevents viral infection, transmission and disease. Here, we present a two-component protein-based nanoparticle vaccine that displays multiple copies of the SARS-CoV-2 spike protein. Immunization studies show that this vaccine induces potent neutralizing antibody responses in mice, rabbits and cynomolgus macaques. The vaccine-induced immunity protected macaques against a high dose challenge, resulting in strongly reduced viral infection and replication in upper and lower airways. These nanoparticles are a promising vaccine candidate to curtail the SARS-CoV-2 pandemic.

immunology↗

bioRxiv2020

Modeling SIV kinetics supports that cytotoxic response drives natural control and unravels heterogeneous populations of infected cells

SIVmac251-infected Mauritius cynomolgus macaques presenting a M6 MHC haplotype or challenged with a low inoculum dose by mucosal route are models for natural HIV control. Here we characterized by modeling the dynamics of plasma SIV-RNA and of SIV-DNA in blood cells of 16 macaques of the ANRS SIC study. SIV-RNA kinetics was best fitted using a model where the cytotoxic immune response progressively mounted up and reduced actively infected cells half-life (t1/2) from 5.5 days early on to about 0.3 days. The model predicted that the control was achieved in animals able to mount an effective immune response within three months, and this was corroborated by the longitudinal analysis of the CD8+ T-cell antiviral activity measured ex vivo. The control of SIV-RNA was accompanied in parallel by a slow and biphasic decline of SIV-DNA. This unravels the presence of at least two compartments of non-actively infected cells that are not rapidly eliminated by the immune system, one with a rapid turnover rate (t1/2=5.1 days) and predominant as long as SIV-RNA levels are still large, and one with a slow turnover (t1/2=118 days) consistent with the half-life of memory T-cells, and only visible when control is achieved. In summary, our analysis suggests that the establishment of an efficient CD8+ T-cell response in the first three months of the infection, and that progressively increases overtime is key to achieve SIV-RNA control in this model. Frequent SIV-DNA quantifications allowed identifying that most cells infected after viral peak have a short t1/2 but do not contribute significantly to viral production. One sentence summaryModeling viral dynamics in SIV natural controller macaques predicts that viral control is primarily driven by the capability to establish an efficient cytotoxic response and the viral decline during control unravels distinct compartments of infected cells.

microbiology↗