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Pneumonia caused by Streptococcus pneumoniae is a leading cause of death worldwide. A growing body of evidence indicates that the successful treatment of bacterial infections results from synergy between antibiotic-mediated direct antibacterial activity and the host's immune defenses. However, the mechanisms underlying the protective immune responses induced by amoxicillin, a β-lactam antibiotic used as the first-line treatment of S. pneumoniae infections, have not been characterized. A better understanding of amoxicillin's effects on host-pathogen interactions might facilitate the development of other treatment options. Given the crucial role of neutrophils in the control of S. pneumoniae infections, we decided to investigate amoxicillin's impact on neutrophil development in a mouse model of pneumococcal superinfection. A single therapeutic dose of amoxicillin almost completely eradicated the bacteria and prevented local and systemic inflammatory responses. Interestingly, in this context, amoxicillin treatment did not impair the emergency granulopoiesis triggered in the bone marrow by S. pneumoniae. Importantly, treatment of pneumonia with amoxicillin was associated with a greater mature neutrophil count in the bone marrow; these neutrophils had specific transcriptomic and proteomic profiles. Furthermore, amoxicillin-conditioned, mature neutrophils in the bone marrow had a less activated phenotype and might be rapidly mobilized in peripheral tissues in response to systemic inflammation. Thus, by revealing a novel effect of amoxicillin on the development and functions of bone marrow neutrophils during S. pneumoniae pneumonia, our findings provide new insights into the impact of amoxicillin treatment on host immune responses. [ABSTRACT FROM AUTHOR]

Neutrophil subsets endowed with regulatory/suppressive properties are widely regarded as deleterious immune cells that can jeopardize antitumoral response and/or antimicrobial resistance. Here, we describe a sizeable fraction of neutrophils characterized by the expression of programmed death-ligand 1 (PD-L1) in biological fluids of humans and mice with severe viral respiratory infections (VRI). Biological and transcriptomic approaches indicated that VRI-driven PD-L1+ neutrophils are endowed with potent regulatory functions and reduced classical antimicrobial properties, as compared to their PD-L1-counterpart. VRI-induced regulatory PD-L1+ neutrophils were generated remotely in the bone marrow in an IFN dependent manner and were quickly mobilized into the inflamed lungs where they fulfilled their maturation. Neutrophil depletion and PD-L1 blockade during experimental VRI resulted in higher mortality, increased local inflammation, and reduced expression of resolving factors. These findings suggest that PD-L1+ neutrophils are important players in disease tolerance by mitigating local inflammation during severe VRI and that they may constitute relevant targets for future immune interventions. [ABSTRACT FROM AUTHOR]

Novel therapeutic strategies are urgently needed to combat pneumonia caused by Streptococcus pneumoniae strains resistant to standard-of-care antibiotics. Previous studies have shown that targeted stimulation of lung innate immune defenses through intranasal administration of the Toll-like receptor 5 agonist flagellin improves the treatment of pneumonia when combined with antibiotics. To promote translation to the clinic application, this study assessed the direct delivery of flagellin to the airways through nebulization using a vibrating mesh nebulizer in mice. Intranasal delivery achieved approximately 40% lung deposition of the administered flagellin dose, whereas nebulization yielded less than 1%. Despite these differences, nebulized flagellin induced transient activation of lung innate immunity characterized by cytokine/chemokine production and neutrophil infiltration into airways analogous to intranasal administration. Furthermore, inhalation by nebulization resulted in an accelerated resolution of systemic pro-inflammatory responses. Lastly, adjunct therapy combining nebulized flagellin and amoxicillin proved effective against antibiotic-resistant pneumococcal pneumonia in mice. We posit that flagellin aerosol therapy represents a safe and promising approach to address bacterial pneumonia within the context of antimicrobial resistance., Competing Interests: J.-C.S., C. Carnoy, and N.H.-V. are inventors of the patents WO2009156405, WO2011161491, WO2015011254, and WO2016102536 that describe the use of flagellin as biologic against infectious diseases and the patent WO2023275292 on the formulation of FLMAOD. N.H.-V. is a cofounder of Cynbiose Respiratory and does not hold stock options. In the last few years, she has been paid as a scientific advisor (Novartis, European Commission, Immune Biosolution, ANR, Alvea/Telis Bioscience). Her group has financial relationships with private-sector entities (Nemera, Aptar Pharma, Affilogic, 4P-Pharma, EuroAPI) outside the scope of the present work and Aerogen within the scope of this study. R.M. is named inventor on several vibrating mesh nebulizer patents. Authors declare no other competing interests.

Active co-delivery of tumor antigens (Ag) and α-galactosylceramide (α-GalCer), a potent agonist for invariant Natural Killer T ( i NKT) cells, to cross-priming CD8α + dendritic cells (DCs) was previously shown to promote strong anti-tumor responses in mice. Here, we designed a nanoparticle-based vaccine able to target human CD141 + (BDCA3 + ) DCs - the equivalent of murine CD8α + DCs - and deliver both tumor Ag (Melan A) and α-GalCer. This nanovaccine was inoculated into humanized mice that mimic the human immune system (HIS) and possess functional i NKT cells and CD8 + T cells, called HIS-CD8/NKT mice. We found that multiple immunizations of HIS-CD8/NKT mice with the nanovaccine resulted in the activation and/or expansion of human CD141 + DCs and i NKT cells and ultimately elicited a potent Melan-A-specific CD8 + T cell response, as determined by tetramer staining and ELISpot assay. Single-cell proteomics further detailed the highly polyfunctional CD8 + T cells induced by the nanovaccine and revealed their predictive potential for vaccine potency. This finding demonstrates for the first time the unique ability of human i NKT cells to license cross-priming DCs in vivo and adds a new dimension to the current strategy of cancer vaccine development., (Copyright © 2020 Huang, Zhou, Ghinnagow, Seki, Iketani, Soulard, Paczkowski, Tsuji, MacKay, Cruz, Trottein and Tsuji.)