Biology subjects

Nunez, N.

Publications and source records attributed to Nunez, N..

6 recordsLinked to original sources

bioRxiv2025

Disease progression is associated with differential neutrophil maturation in Mycobacterium tuberculosis-infected macaques

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is associated with clinical diversity and outcomes ranging from latent TB to active TB with distinct pathophysiologies. However, our understanding of the innate immune mechanisms related to the protection or progression of TB is limited. Among innate immune cells, the role of neutrophils is not fully elucidated, as they have been shown to exhibit both protective and harmful capacities in TB. This duality suggests possible differences in the nature and type of neutrophils present during the infection, generating different effects. We hypothesized that Mtb infection induces changes in neutrophil phenotype and function, influencing the infection outcomes. In order to decipher the link between neutrophils and disease progression, we used a cynomolgus macaque model of human TB. Based on clinical, bacteriological, and positron emission tomography with X-ray computed tomography (PET/CT) scan parameters, animals were stratified into two categories: animals that rapidly progressed to an active form of TB, designated as "fast progressors", and "slow progressors", which include low symptomatic or asymptomatic animals. In this study, we identified transcriptomic signatures of type I interferons and neutrophil degranulation in macaques with fast progression to active TB, which were not observed in animals with slow TB progression. Unsuppervised mass cytometry analysis showed the emergence of blood immature neutrophils (CD101+ CD10-) in fast progressing animals. In addition, circulating neutrophils from infected animals displayed capacities to modulate TNF- production and cytotoxic function of CD8 T cells in a contact-dependent mechanism. In the lungs, neutrophils infiltration in granuloma was higher in fast progressors and specifically located in the lymphocyte-rich region in lesions. These data suggest that specific neutrophil subpopulations are associated with disease progression. Furthermore, these data suggest that neutrophils may modulate CD8 T cells functions, which in turn contribute to the loss of Mtb control and fuel inflammation. AUTHORS SUMMARYMycobacterium tuberculosis (Mtb) infection in humans is associated with a wide range of disease progression, ranging from latent tuberculosis (TB) to active TB. Understanding immune factors leading to the control of the infection or disease progression is essential to identify new biomarkers and targets for host-directed therapies. Innate immunity plays an important role in inflammatory imbalance observed in active TB, among which neutrophils have both beneficial and detrimental roles. Using a macaque model developing a broad range of clinical forms of TB, we seek to understand the links between neutrophils and disease progression. We found that rapid progression to active TB leads to type I interferon signalling and neutrophil activation. In the blood, immature neutrophils were enriched when the disease progressed. In case of severe TB, Neutrophils also infiltrate a specific region of lung TB lesions rich in T lymphocytes, whereas they could modulate CD8 T cells. Our study provides new insights into the role of neutrophils in TB progression.

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↗

bioRxiv2024

Regulatory T cells control type 1-driven immunopathology restraining GM-CSF-producing helper T cells

Regulatory T (Treg) cells are critical for maintaining peripheral tolerance and preventing autoimmunity. Treg cell depletion or dysfunction rapidly results in fatal multiorgan inflammation linked to unrestrained effector T cell expansion, but the cytokine network underlying immunopathology, and its direct cellular mediators, remain elusive. Here, we combined gene targeting, fate-mapping tools, and high-dimensional cytometry to identify the T helper (TH) cell-derived cytokines and responding cells that execute inflammatory tissue damage upon global loss of peripheral tolerance in mice. We found that TH cell-derived GM-CSF, but not IL-17A, directed the ensuing immunopathology and thereby mortality through recruitment of tissue-invading phagocytes and granulocytes, and enhancement of their reactive oxygen species production and phagocytic proficiency. Our study highlights the critical role of Treg cells in controlling GM-CSF- producing TH cells and type 1-responses to restrain phagocyte-mediated tissue destruction and provides a framework for the use of anti-GM-CSF therapies in patients with chronic inflammatory disorders.

immunology↗

bioRxiv2023

Seminal plasma inhibits Chlamydia trachomatis infection in vitro, and may have consequences on mucosal immunity

Seminal plasma (SP) is the main vector of C. trachomatis (CT) during heterosexual transmission from male to female. It has immunomodulatory properties and impacts the susceptibility to HIV-1 infection, but its role has not been explored during CT infection. In the female reproductive tract (FRT), CT infection induces cytokine production and neutrophil recruitment. The role of neutrophils during CT infection is partially described, they could be at the origin of the pathology observed during CT infection. During this study, we developed an experimental in vitro model to characterize the impact of CT infection and SP on endocervical epithelial cell immune response in the FRT. We also studied the impact of the epithelial cell response on neutrophil phenotype and functions. We showed that the production by epithelial cells of pro-inflammatory cytokines increased during CT infection. Moreover, the pool of SP as well as individuals SP inhibited CT infection in a dose-dependent manner. The pool of SP inhibited cytokine production in a dose-dependent manner. The pool of SP altered gene expression profiles of infected cells. The culture supernatants of cells infected or not with CT, in presence or not of the pool of SP, had an impact on neutrophil phenotype and functions: they affected markers of neutrophil maturation, activation and adhesion capacity, as well as the survival, ROS production and phagocytosis ability. This study proposes a novel approach to study the impact of the environment on the phenotype and functions of neutrophils in the FRT. It highlights the impact of the factors of the FRT environment, in particular SP and CT infection, on the mucosal inflammation and the need to take into account the SP component while studying sexually transmitted infections during heterosexual transmission from male to female.

immunology↗

bioRxiv2021

The unforeseen intracellular lifestyle of Enterococcus faecalis in hepatocytes

Enterococcus faecalis is a bacterial species present at a sub-dominant level in the human gut microbiota. This commensal turns into an opportunistic pathogen under specific conditions involving dysbiosis and host immune deficiency. E. faecalis is also the only intestinal pathobiont identified to date as contributing to liver damage in alcoholic liver disease. We have previously observed that E. faecalis is internalized in hepatocytes. Here, the survival and fate of E. faecalis was examined in hepatocytes, the main epithelial cell type in the liver. Although referred to as an extracellular pathogen, we demonstrate that E. faecalis is able to survive and divide in hepatocytes, and form intracellular clusters in two distinct hepatocyte cell lines, in primary mouse hepatocytes, as well as in vivo. This novel process extends to kidney cells. Unravelling the intracellular lifestyle of E. faecalis, our findings contribute to the understanding of pathobiont-driven diseases.

microbiology↗

bioRxiv2020

CD39+PD-1+CD8+ T cells mediate metastatic dormancy in breast cancer

Some breast tumors metastasize aggressively whereas others remain in a state of metastatic dormancy for months or even years. The mechanism governing such metastatic dormancy remains largely unknown. Through high-parametric single-cell mapping in mice, we identified a discrete population of CD39+PD-1+CD8+ T cells present both in primary tumors and in dormant metastasis, which was hardly found in aggressively metastasizing tumors. Using blocking antibodies, we found that dormancy depended on TNF and IFN{gamma}. Of note, immunotherapy reduced the number of dormant cancer cells in the lungs. Adoptive transfer of purified CD39+PD-1+CD8+ T cells prevented metastatic outgrowth. In human breast cancer, the frequency of CD39+PD-1+CD8+ but not of total CD8+ T cells correlated with delayed metastatic relapse after resection (disease-free survival), thus underlining the biological relevance of CD39+PD-1+CD8+ T cells for controlling experimental and human breast cancer. Furthermore, density of CD39+PD-1+CD8+ T cells may serve as a novel biomarker and may serve as a potential immunotherapy target. Thus, we discovered that a primary breast tumor primes a systemic, CD39+PD-1+CD8+ T cell response that is essential for metastatic dormancy in the lungs.

cancer biology↗