Biology subjects

Ciucci, T.

Publications and source records attributed to Ciucci, T..

6 recordsLinked to original sources

bioRxiv2022

Specific targeting of inflammatory osteoclastogenesis by the probiotic yeast S. boulardii CNCM I-745 reduces bone loss in osteoporosis

Bone destruction is a hallmark of chronic inflammation, and bone-resorbing osteoclasts arising under such a condition differ from steady-state ones. However, osteoclast diversity remains poorly explored. Here, we combined transcriptomic profiling, differentiation assays and in vivo analysis in mouse to decipher specific traits for inflammatory and steady state osteoclasts. We identified and validated the pattern-recognition receptors (PRR) TLR2, Dectin-1 and Mincle, all involved in yeast recognition as major regulators of inflammatory osteoclasts. We showed that administration of the yeast probiotic Saccharomyces boulardi CNCM I-745 (Sb) in vivo reduced bone loss in OVX but not sham mice by reducing inflammatory osteoclasts. This beneficial impact of Sb is mediated by the regulation of the inflammatory environment required for the generation of inflammatory osteoclasts. We also showed that Sb derivatives as well as agonists of TLR2, Dectin-1 and Mincle specifically inhibited directly the differentiation of inflammatory but not steady state osteoclasts in vitro. These findings demonstrate a preferential use of the PRR-associated costimulatory differentiation pathway by inflammatory osteoclasts, thus enabling their specific inhibition, which opens new therapeutic perspectives for inflammatory bone loss.

physiology↗

bioRxiv2021

A single-cell reference atlas delineates CD4+ T cell subtype-specific adaptation during acute and chronic viral infections

CD4+ T cells are critical orchestrators of immune responses against a large variety of pathogens, including viruses. The multifaceted roles of CD4+ T cells, including their help to innate cells, CD8+ T and B cells and their support for long-lived immunity rely on a profound functional heterogeneity. While multiple CD4+ T cell subtypes and their key transcriptional regulators have been identified, there is a lack of consistent definition for CD4+ T cell transcriptional states. In addition, the progressive changes affecting CD4+ T cell subtypes during and after immune responses remain poorly defined. Taking advantage of single-cell transcriptomics, efficient computational methods, and robust animal models, we characterize the transcriptional landscape of CD4+ T cells responding to self-resolving and chronic viral infections. We build a comprehensive atlas of virus-specific CD4+ T cells and their evolution over time, and identify six major distinct cell states that are consistently observed in acute and chronic infections. During the course of acute infection, T cell composition progressively changes from effector to memory states, with subtype-specific gene modules and kinetics. Conversely, T cells in persistent infections fail to transition from effector to memory states, and acquire distinct, chronicity-associated transcriptional programs. By single-cell T cell receptor (TCR) sequencing analysis, we characterize the clonal structure of virus-specific CD4+ T cells across individuals and T cell subtypes. We find that virus-specific CD4+ T cell responses are mainly private across individuals and that most T cells differentiate into all subtypes independently of their TCR, in both acute and chronic infections. Finally, we show that our CD4+ T cell atlas can be used as a reference to accurately interpret cell states in external single-cell datasets. Overall, this study describes a previously unappreciated level of adaptation of the transcriptional states of CD4+ T cells responding to viruses and provides a new computational resource for CD4+ T cell analysis, available online at https://spica.unil.ch.

immunology↗

bioRxiv2021

SARS coronavirus vaccines protect against different coronaviruses

Although SARS-CoV-2 vaccines have shown efficacy against SARS-CoV-2, it is unclear if they can also protect against other coronaviruses that may infect humans in the future. Here, we show that SARS-CoV-2 vaccination in humans elicits cross-reactive antibodies against other coronaviruses. Our studies in mice demonstrate that SARS-CoV-2 vaccination protects against a common cold coronavirus, and that SARS-CoV-1 vaccination protects against SARS-CoV-2. Similarly, infection with a common cold coronavirus also conferred enhanced protection from subsequent infections with other coronaviruses. Mechanistically, both T cells and antibodies mediated cross-protection. This is the first direct demonstration that coronavirus-specific immunity can confer heterologous protection in vivo, providing a rationale for universal coronavirus vaccines. HighlightsO_LISARS-CoV-2 vaccination elicits cross-reactive antibody against other coronaviruses in humans. C_LIO_LICOVID-19 patients generate cross-reactive antibody against other coronaviruses. C_LIO_LIA SARS-CoV-1 vaccine protects against SARS-CoV-2. C_LIO_LIPrior coronavirus infections improve immune protection following heterologous coronavirus challenges. C_LI

immunology↗

bioRxiv2021

Limiting the priming dose of a SARS CoV-2 vaccine improves virus-specific immunity

Since late 2019, SARS-CoV-2 has caused a global pandemic that has infected 128 million people worldwide. Although several vaccine candidates have received emergency use authorization (EUA), there are still a limited number of vaccine doses available. To increase the number of vaccinated individuals, there are ongoing discussions about administering partial vaccine doses, but there is still a paucity of data on how vaccine fractionation affects vaccine-elicited immunity. We performed studies in mice to understand how the priming dose of a SARS CoV-2 vaccine affects long-term immunity to SARS CoV-2. We first primed C57BL/6 mice with an adenovirus-based vaccine encoding SARS CoV-2 spike protein (Ad5-SARS-2 spike), similar to that used in the CanSino and Sputnik V vaccines. This prime was administered either at a low dose (LD) of 106 PFU or at a standard dose (SD) of 109 PFU, followed by a SD boost in all mice four weeks later. As expected, the LD prime induced lower immune responses relative to the SD prime. However, the LD prime elicited immune responses that were qualitatively superior, and upon boosting, mice that were initially primed with a LD exhibited significantly more potent immune responses. Overall, these data demonstrate that limiting the priming dose of a SARS CoV-2 vaccine may confer unexpected benefits. These findings may be useful for improving vaccine availability and for rational vaccine design.

immunology↗

bioRxiv2020

Osteoclasts contribute to early development of chronic inflammation by promoting dysregulated hematopoiesis and myeloid skewing

Increased myelopoiesis is a hallmark of many chronic inflammatory diseases. However, the mechanisms involved in the myeloid skewing of hematopoiesis upon inflammation are still incompletely understood. Here, we identify an unexpected role of bone-resorbing osteoclasts in promoting hematopoietic stem cell (HSC) proliferation and differentiation towards myeloipoiesis in the early phases of chronic colitis. RNAseq analysis revealed that osteoclasts in colitis differ from control ones and overexpress genes involved in the remodeling of HSC niches. We showed that colitic osteoclasts modulate the interaction of HSCs with their niche and promote myeloid differentiation. Increased osteoclast activity was correlated with an augmentation of myelopoiesis in patients with chronic colitis. Therapeutic blockade of osteoclasts reduced HSC proliferation and myeloid skewing and resulted in a decreased inflammation and severity of colitis. Together, these data identify osteoclasts as potent regulators of HSCs and promising target in chronic colitis.

immunology↗

bioRxiv2019

Single-cell profiling of tumor-reactive CD4+ T-cells reveals unexpected transcriptomic diversity

Most current tumor immunotherapy strategies leverage cytotoxic CD8+ T cells. Despite evidence for clinical potential of CD4+ tumor-infiltrating lymphocytes (TILs), their functional diversity has limited our ability to harness their activity. To address this issue, we have used single-cell mRNA sequencing to analyze the response of CD4+ T cells specific for a defined recombinant tumor antigen, both in the tumor microenvironment and draining lymph nodes (dLN). Designing new computational approaches to characterize subpopulations, we identify TIL transcriptomic patterns strikingly distinct from those elicited by responses to infection, and dominated by diversity among T-bet-expressing T helper type 1 (Th1)-like cells. In contrast, the dLN response includes follicular helper (Tfh)-like cells but lacks Th1 cells. We identify a type I interferon-driven signature in Th1-like TILs, and show that it is found in human liver cancer and melanoma, in which it is negatively associated with response to checkpoint therapy. Our study unveils unsuspected differences between tumor and virus CD4+ T cell responses, and provides a proof-of-concept methodology to characterize tumor specific CD4+ T cell effector programs. Targeting these programs should help improve immunotherapy strategies. One Sentence SummarySingle-cell RNA sequencing reveals novel and highly diverse transcriptomic patterns characteristic of CD4+ T cell responses to tumors.

immunology↗