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Granulocytes are innate immune cells that play a key role in pathogen elimination. Recent studies revealed the diversity of granulocytes in terms of phenotype and function. In particular, a subset of granulocytes identified as low-density granulocytes (LDG) has been described in physiological conditions and with increased frequencies in several pathological contexts. However, the properties of LDG are still controversial as they vary according to the pathophysiological environment. Here we investigated the heterogeneity of granulocyte populations and the potential differences in phenotype and immunomodulatory capacity between LDG and normal density granulocytes (NDG) in people living with HIV-1 (PLWH). To this end, we developed an optimized method to purify LDG and NDG from a single blood sample, and performed in-depth, comparative phenotypic characterization of both granulocyte subtypes. We also assessed the impact of purification steps on the expression of cell surface markers on LDG by immunophenotyping them at different stages of isolation. We identified 9 cell surface markers (CD16, CD32, CD89, CD62L, CD177, CD31, CD10, CXCR4 and CD172α) differentially expressed between LDG and NDG. Noteworthy, markers that distinguish the two subsets include receptors for the Fc part of IgG (CD16, CD32) and IgA (CD89). Importantly, we also highlighted that the purification procedure affects the expression of several cell surface markers (i.e.CD63, CD66b, …) which must be taken into account when characterizing LDG. Our work sheds new light on the properties of LDG in PLWH and provides an extensive characterization of this granulocyte subset in which Fc receptors are key discriminatory markers.

Background The metabolic reprogramming of mesenchymal stem/stromal cells (MSC) favoring glycolysis has recently emerged as a new approach to improve their immunotherapeutic abilities. This strategy is associated with greater lactate release, and interestingly, recent studies have proposed lactate as a functional suppressive molecule, changing the old paradigm of lactate as a waste product. Therefore, we evaluated the role of lactate as an alternative mediator of MSC immunosuppressive properties and its contribution to the enhanced immunoregulatory activity of glycolytic MSCs. Materials and methods Murine CD4 + T cells from C57BL/6 male mice were differentiated into proinflammatory Th1 or Th17 cells and cultured with either L-lactate, MSCs pretreated or not with the glycolytic inductor, oligomycin, and MSCs pretreated or not with a chemical inhibitor of lactate dehydrogenase A (LDHA), galloflavin or LDH siRNA to prevent lactate production. Additionally, we validated our results using human umbilical cord-derived MSCs (UC-MSCs) in a murine model of delayed type 1 hypersensitivity (DTH). Results Our results showed that 50 mM of exogenous L-lactate inhibited the proliferation rate and phenotype of CD4 + T cell-derived Th1 or Th17 by 40% and 60%, respectively. Moreover, the suppressive activity of both glycolytic and basal MSCs was impaired when LDH activity was reduced. Likewise, in the DTH inflammation model, lactate production was required for MSC anti-inflammatory activity. This lactate dependent-immunosuppressive mechanism was confirmed in UC-MSCs through the inhibition of LDH, which significantly decreased their capacity to control proliferation of activated CD4 + and CD8 + human T cells by 30%. Conclusion These findings identify a new MSC immunosuppressive pathway that is independent of the classical suppressive mechanism and demonstrated that the enhanced suppressive and therapeutic abilities of glycolytic MSCs depend at least in part on lactate production.

Unlocking the potential of broadly reactive coronavirus monoclonal antibodies (mAbs) and their derivatives offers a transformative therapeutic avenue against severe COVID-19, especially crucial for safeguarding high-risk populations. Novel mAb-based immunotherapies may help address the reduced efficacy of current vaccines and neutralizing mAbs caused by the emergence of variants of concern (VOCs). Using phage display technology, we discovered a pan-SARS-CoV-2 mAb (C10) that targets a conserved region within the receptor-binding domain (RBD) of the virus. Noteworthy, C10 demonstrates exceptional efficacy in recognizing all assessed VOCs, including recent Omicron variants. While C10 lacks direct neutralization capacity, it efficiently binds to infected lung epithelial cells and induces their lysis via natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Building upon this pan-SARS-CoV-2 mAb, we engineered C10-based, Chimeric Antigen Receptor (CAR)-T cells endowed with efficient killing capacity against SARS-CoV-2-infected lung epithelial cells. Notably, NK and CAR-T-cell mediated killing of lung infected cells effectively reduces viral titers. These findings highlight the potential of non-neutralizing mAbs in providing immune protection against emerging infectious diseases. Our work reveals a pan-SARS-CoV-2 mAb effective in targeting infected cells and demonstrates the proof-of-concept for the potential application of CAR-T cell therapy in combating SARS-CoV-2 infections. Furthermore, it holds promise for the development of innovative antibody-based and cell-based therapeutic strategies against severe COVID-19 by expanding the array of therapeutic options available for high-risk populations. ClinicalTrials.gov identifier: NCT04093596.

The susceptibility of CD4 T cells to human immunodeficiency virus 1 (HIV-1) infection is regulated by glucose and glutamine metabolism, but the relative contributions of these nutrients to infection are not known. Here we show that glutaminolysis is the major pathway fuelling the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in T-cell receptor-stimulated naïve, as well as memory CD4, subsets and is required for optimal HIV-1 infection. Under conditions of attenuated glutaminolysis, the α-ketoglutarate (α-KG) TCA rescues early steps in infection; exogenous α-KG promotes HIV-1 reverse transcription, rendering both naïve and memory cells more sensitive to infection. Blocking the glycolytic flux of pyruvate to lactate results in altered glucose carbon allocation to TCA and pentose phosphate pathway intermediates, an increase in OXPHOS and augmented HIV-1 reverse transcription. Moreover, HIV-1 infection is significantly higher in CD4 T cells selected on the basis of high mitochondrial biomass and OXPHOS activity. Therefore, the OXPHOS/aerobic glycolysis balance is a major regulator of HIV-1 infection in CD4 T lymphocytes. Increased metabolic activity promotes HIV-1 infection in CD4 T lymphocytes, but the contribution of different metabolic pathways is unclear. Here the authors show that carbon entry into the citric acid cycle is required to support the early stages of HIV-1 infection.

The multiple mechanisms of action of antiviral monoclonal antibodies (mAbs) have made these molecules a potential therapeutic alternative for treating severe viral infections. In addition to their direct effect on viral propagation, several studies have shown that mAbs are able to enhance the host’s adaptive immune response and generate long-lasting protective immunity. Such immunomodulatory effects occur in an Fc-dependent manner and rely on Fc-FcγR interactions. It is noteworthy that several FcγR-expressing cells have been shown to play a key role in enhancing humoral and cellular immune responses (so-called “vaccinal effects”) in different experimental settings. This review recalls recent findings concerning the vaccinal effects induced by antiviral mAbs, both in several preclinical animal models and in patients treated with mAbs. It summarizes the main cellular and molecular mechanisms involved in these immunomodulatory properties of antiviral mAbs identified in different pathological contexts. It also describes potential therapeutic interventions to enhance host immune responses that could guide the design of improved mAb-based immunotherapies.

Neutrophils are innate immune cells with key immunomodulatory functions. In a murine retroviral model, we previously showed their essential role in promoting protective immunity during antiviral antibody therapy via Fc–Fcγ receptor (FcγR) interactions. Here, we investigated the immunomodulatory properties of neutrophils in the context of HIV-1 infection and therapy through a comprehensive analysis of their functional activation and the regulation of FcγR expression. Neutrophils from healthy donors (HD) and people living with HIV-1 (PLWH) were stimulated with TLR ligands, free HIV-1, immune complexes (ICs) formed with broadly neutralizing antibodies (bNAbs), or pro-inflammatory cytokines (TNFα, IFNγ). In response, they secreted various cytokines and chemokines that can recruit and activate immune cells in a stimulus-dependent manner. Compared to TLR agonist and cytokine activation, HD neutrophils showed limited cytokine production in response to free HIV-1 or ICs alone as well as a minimal FcγR modulation. However, PLWH neutrophils showed heightened responsiveness to microbial stimuli linked to HIV-1 pathogenesis, secreting higher levels of IFNγ, CXCL1, CCL2, CCL3, and CCL4. They also expressed higher levels of two activating FcγRs (FcγRI and FcγRIIIb), as well as CD11b, CD63, CXCR4, and PD-L1, indicating an altered activation state. These findings highlight the influence of the inflammatory milieu on neutrophil function and FcγR regulation in HIV-1 infection and mAb-based therapies.

Metastasis is largely controlled by Natural Killer (NK) cell-mediated immune surveillance. To colonize new environments, cancer cells undergo epithelial to mesenchymal transition (EMT), which allows them to detach and migrate. EMT is fueled by fatty acid oxidation (FAO), which partially replaces glycolytic-based tumor metabolism. Whether metabolic rewiring affects the targeting of cancer cells by NK cells remains unknown. Here, we show that forcing solid cancer cells to perform FAO by inhibiting pyruvate dehydrogenase kinase 1 with dichloroacetate (DCA) activates extracellular signal-regulated kinase-5 (ERK5), triggering EMT and tumor cell migration and invasion. Concomitantly, FAO induces the expression of ligands that mediate NK cell recognition. Consequently, NK cells better infiltrated DCA-treated 3D tumor spheroids, where they exerted their cytotoxic effects. DCA-treated cells showed increased migration in a zebrafish model, whereas metastasis from mammary cancer cells grafted into immune-deficient mice was enhanced by DCA. These migrating/metastatic cells are preferentially killed by NK cells, which strongly limit their invasive potential. Hence, FAO promotes both metastasis and NK-mediated tumor surveillance, highlighting the Achilles’ heel of metastatic cells, which may offer new therapeutic opportunities. Metastasis recognition and killing by immune cells, such as NK cells, requires a metabolic shift that relies on lipid metabolism.

Neutrophils are innate immune cells that display immunomodulatory properties by secreting cytokines and chemokines. By using a mouse model of retroviral infection, we previously uncovered the key immunomodulatory function of neutrophils in promoting protective immunity during antiviral antibody therapy which occurs in a Fc-dependent manner. Here, we investigated the immunomodulatory properties of neutrophils in the context of HIV-1 infection and therapy. We characterized the functional activation and the modulation of Fcγ receptors (FcγRs) expression on neutrophils isolated from healthy donors (HD) or people living with HIV-1 (PLWH) upon stimulation with virions, free or in the form of immune complexes (ICs) made with broadly neutralizing antibodies (bNAbs). Neutrophils from HD secreted cytokines/chemokines in small amount upon activation by either stimulus. Interestingly, conditioning of neutrophils from HD with pro-inflammatory cytokines enhanced their cytokine/chemokine production upon activation by HIV-1 and ICs, highlighting that the inflammatory environment is key for neutrophils to show a functional response to these stimuli. Noteworthy, under inflammatory conditions, IC-activated neutrophils showed higher secretion of CXCL1 and CCL4 than HIV-1-stimulated neutrophils. Importantly, neutrophils from PLWH on antiretroviral treatment (ART) maintained their cytokine/chemokine secretion abilities when stimulated by TLR agonists, TNFα; or HIV-1/ICs. However, they displayed different phenotypic features as compared with neutrophils isolated from HD, notably higher expression of FcγRs. Our study provides new insights into the immunomodulatory properties of neutrophils during HIV-1 infection and therapy. This might contribute to the improvement of antiviral antibody therapies through the use of therapeutic approaches exploiting the immunomodulatory properties of these cells.Competing Interest StatementThe authors have declared no competing interest.

Blast-related craniofacial and ocular injuries have traditionally been associated with battlefields. In civilian populations, these injuries were infrequent, primarily arising from accidental explosions or terrorism incidents. Explosions can inflict severe damage to the neurological, ocular, and auditory systems through blast waves, high-velocity foreign bodies, and thermal radiation. The pathophysiology of blast-related craniofacial injuries is specific and complex, with severe cases often involving both penetrating and blunt trauma, leading to high mortality and morbidity rates. These injuries necessitate multidisciplinary management and can be defined as intracranial polytrauma. Recently, Niger has seen a surge in blast injuries, predominantly due to the increase in clandestine artisanal gold mining. Managing these injuries in resource-limited settings poses significant challenge. Comprehensive national data on these injuries are sparse due to high pre-hospital mortality rates and their infrequent occurrence, resulting in limited experience among our local physicians in their management. We present a rare case involving an artisanal gold miner with a history of smoking and previous concussions from explosion exposures. The patient was transferred to our hospital following severe craniofacial and ocular injuries caused by an accidental dynamite explosion at a mining site. On admission, the patient presented altered consciousness, agitation, unstable vital signs, multiple craniofacial wounds, including a large frontal wound with brain substance extrusion, diffuse facial burns, left globe rupture, and rhinorrhagia. After resuscitation and stabilization, brain imaging revealed multiple complex craniofacial fractures with foreign bodies. The patient underwent multidisciplinary surgical management. However, the postoperative course was complicated by post-concussive syndrome, and infection of the surgical wounds, necessitating surgical revision. Following the second surgery, the postoperative course was uneventful, although the patient experienced reduced visual acuity. This case highlights the management challenges in Niger and underscores the urgent need for clinical studies and training for gold miners to enhance safety practices in their activities.