Explore the vast range of titles available.

Staphylococcus aureus persistently colonises the anterior nares of a significant proportion of the healthy population, however the local immune response elicited during S . aureus nasal colonisation remains ill-defined. Local activation of IL-17/IL-22 producing T cells are critical for controlling bacterial clearance from the nasal cavity. However, recurrent and long-term colonisation is commonplace indicating efficient clearance does not invariably occur. Here we identify a central role for the regulatory cytokine IL-10 in facilitating bacterial persistence during S . aureus nasal colonisation in a murine model. IL-10 is produced rapidly within the nasal cavity following S . aureus colonisation, primarily by myeloid cells. Colonised IL-10 -/- mice demonstrate enhanced IL-17+ and IL-22+ T cell responses and more rapidly clear bacteria from the nasal tissues as compared with wild-type mice. S . aureus also induces the regulatory cytokine IL-27 within the nasal tissue, which acts upstream of IL-10 promoting its production. IL-27 blockade reduces IL-10 production within the nasal cavity and improves bacterial clearance. TLR2 signalling was confirmed to be central to controlling the IL-10 response. Our findings conclude that during nasal colonisation S . aureus creates an immunosuppressive microenvironment through the local induction of IL-27 and IL-10, to dampen protective T cell responses and facilitate its persistence.

In apparent contrast to its invasive potential Staphylococcus aureus colonizes the anterior nares of 20-80% of the human population. The relationship between host and microbe appears particularly individualized and colonization status seems somehow predetermined. After decolonization, persistent carriers often become re-colonized with their prior S. aureus strain, whereas non-carriers resist experimental colonization. Efforts to identify factors facilitating colonization have thus far largely focused on the microorganism rather than on the human host. The host responds to S. aureus nasal colonization via local expression of anti-microbial peptides, lipids, and cytokines. Interplay with the co-existing microbiota also influences colonization and immune regulation. Transient or persistent S. aureus colonization induces specific systemic immune responses. Humoral responses are the most studied of these and little is known of cellular responses induced by colonization. Intriguingly, colonized patients who develop bacteremia may have a lower S. aureus-attributable mortality than their non-colonized counterparts. This could imply a staphylococcal-specific immune \"priming\" or immunomodulation occurring as a consequence of colonization and impacting on the outcome of infection. This has yet to be fully explored. An effective vaccine remains elusive. Anti-S. aureus vaccine strategies may need to drive both humoral and cellular immune responses to confer efficient protection. Understanding the influence of colonization on adaptive response is essential to intelligent vaccine design, and may determine the efficacy of vaccine-mediated immunity. Clinical trials should consider colonization status and the resulting impact of this on individual patient responses. We urgently need an increased appreciation of colonization and its modulation of host immunity.

Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans.

Background/Objectives: We aimed to determine safe and immunogenic RSVpreF vaccine dose levels for further clinical development in 2–<18 year olds. Methods: The phase 1, age-descending, open-label Picasso trial evaluated different RSVpreF dose levels in respiratory syncytial virus (RSV)-seropositive 2–<5 year olds and 5–<18 year olds who were either healthy or had chronic medical conditions with increased RSV illness risk. Participants received a single dose of RSVpreF (60 µg or 120 µg dose level). The primary objective was to describe safety and tolerability at each dose level and age group, including frequencies of reactogenicity and adverse events (AEs). The secondary objective was to describe RSV neutralizing antibody responses at each dose level and age group 1 month after vaccination. Results: Overall, 127 participants received RSVpreF 60 µg (2–<5 year olds, n = 20; 5–<18 year olds, n = 35) or 120 µg (n = 24 and n = 48, respectively); 54% were male and 69% were White. Local reactions and systemic events were reported in 17–20% and 33–45% of 2–<5 year olds, respectively, and 49–56% and 52–60% of 5–<18 year olds; most were mild or moderate in severity. AEs were reported in 13–15% of 2–<5 year olds and 8–14% of 5–<18 year olds. No AEs leading to withdrawal or vaccine-related serious AEs were reported. RSV-A and RSV-B neutralizing titer geometric mean fold rises from before to 1 month after vaccination with RSVpreF 60 and 120 µg, which were 17.7–20.6 and 42.8–39.8, respectively, in 2–<5 year olds, and 19.0–23.5 and 20.3–20.3, respectively, in 5–<18 year olds. Conclusions: RSVpreF was safe, well tolerated, and elicited immune responses in RSV-seropositive 2–<18-year-old participants, supporting further clinical development in this pediatric population, including those with chronic conditions.

Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFN[gamma] responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans.

Early life establishment of tolerance to commensal bacteria at barrier surfaces carries enduring implications for immune health but remains poorly understood. Here we show that this process is controlled by microbial interaction with a specialized subset of antigen presenting cells. More particularly, we identify CD301b+ type 2 conventional dendritic cells (DC) as a subset in neonatal skin specifically capable of uptake, presentation and generation of regulatory T cells (Tregs) to commensal antigens. In early life, CD301b+ DC2 are enriched for programs of phagocytosis and maturation, while also expressing tolerogenic markers. In both human and murine skin, these signatures were reinforced by microbial uptake. In contrast to their adult counterparts or other early life DC subsets, neonatal CD301b+ DC2 highly expressed the retinoic acid-producing enzyme, RALDH2, deletion of which limited commensal-specific Tregs. Thus, synergistic interactions between bacteria and a specialized DC subset critically support early life tolerance at the cutaneous interface. Competing Interest Statement T.C.S. is on the Scientific Advisory Board of Concerto Biosciences. Other authors have no competing interests.

Early life microbe-immune interactions at barrier surfaces have lasting impacts on the trajectory towards health versus disease. Monocytes, macrophages and dendritic cells are primary sentinels in barrier tissues, yet the salient contributions of commensal-myeloid crosstalk during tissue development remain poorly understood. Here, we identify that commensal microbes facilitate accumulation of a population of monocytes in neonatal skin. Transient postnatal depletion of these monocytes resulted in heightened IL-17A production by skin T cells, which was particularly sustained among CD4 T cells and sufficient to exacerbate inflammatory skin pathologies. Neonatal skin monocytes were enriched in expression of negative regulators of the IL-1 pathway. Functional in vivo experiments confirmed a key role for excessive IL-1R1 signaling in T cells as contributing to the dysregulated type 17 response in neonatal monocyte-depleted mice. Thus, a commensal-driven wave of monocytes into neonatal skin critically facilitates immune homeostasis in this prominent barrier tissue.

Climate change disrupts ecological systems in many ways. Many documented responses depend on species' life histories, contributing to the view that climate change effects are important but difficult to characterize generally. However, systematic variation in metabolic effects of temperature across trophic levels suggests that warming may lead to predictable shifts in food web structure and productivity. We experimentally tested the effects of warming on food web structure and productivity under two resource supply scenarios. Consistent with predictions based on universal metabolic responses to temperature, we found that warming strengthened consumer control of primary production when resources were augmented. Warming shifted food web structure and reduced total biomass despite increases in primary productivity in a marine food web. In contrast, at lower resource levels, food web production was constrained at all temperatures. These results demonstrate that small temperature changes could dramatically shift food web dynamics and provide a general, species-independent mechanism for ecological response to environmental temperature change.