Conserved moonlighting protein pyruvate dehydrogenase induces robust protection against Staphylococcus aureus infection.

Developing an effective Staphylococcus aureus (S. aureus) vaccine has been a challenging endeavor, as demonstrated by numerous failed clinical trials over the years. In this study, we formulated a vaccine containing a highly conserved moonlighting protein, the pyruvate dehydrogenase complex E2 subunit (PDHC), and showed that it induced strong protective immunity against epidemiologically relevant staphylococcal strains in various murine disease models. While antibody responses contributed to bacterial control, they were not essential for protective immunity in the bloodstream infection model. Conversely, vaccine-induced systemic immunity relied on γδ T cells. It has been suggested that prior S. aureus exposure may contribute to the reduction of vaccine efficacy. However, PDHC-induced protective immunity still facilitated bacterial clearance in mice previously exposed to S. aureus. Collectively, our findings indicate that PDHC is a promising serotype-independent vaccine candidate effective against both methicillin-sensitive and methicillin-resistant S. aureus isolates.

Quantifying the mitigating effect of organic matter on heavy metal availability in soils with different manure applications: A geochemical modelling study.

Manure is one of the main sources of heavy metal (HM) pollution on farmlands. It has become the focus of global ecological research because of its potential threat to human health and the sustainability of food systems. Soil pH and organic matter are improved by manure and play pivotal roles in determining soil HM behavior. Geochemical modeling has been widely used to assess and predict the behavior of soil HMs; however, there remains a research gap in manure applications. In this study, a geochemical model (LeachXS) coupled with a pH-dependent leaching test with continuously simulations over a broad pH range was used to determine the effects and pollution risks of pig or cattle manure separate application on soil HMs distribution. Both pig and cattle manure applications led to soil pH reduction in alkaline soils and increased organic matter content. Pig manure application resulted in a potential 90.5-156.0 % increase in soil HM content. Cattle manure did not cause significant HM contamination. The leaching trend of soil HMs across treatments exhibited a V-shaped change, with the lowest concentration at pH = 7, gradually increasing toward strong acids and bases. The dissolved organic matter-bound HM content directly increased the HM availability, especially for Cu (up to 8.4 %) after pig manure application. However, more HMs (Cr, Cu, Zn, Ni) were in the particulate organic matter-bound state than in other solid phases (e.g., Fe-Al(hydr) oxides, clay minerals), which inhibited the HMs leaching by more than 19.3 % after cattle manure application. Despite these variations, high HM concentrations introduced by pig manure raised the soil contamination risk, potentially exceeding 40 times at pH ±1. When manure is returned to the field, reducing its HM content and mitigating possible pollution is necessary to realize the healthy and sustainable development of circular agriculture.

Field performance of sweet sorghum in salt-affected soils in China: A quantitative synthesis.

Sweet sorghum is a high-yield crop with strong resistance, which has the potential to support the development of the forage farming industry in China where vast salt-affected lands are potentially arable. Nutrient management is imperative for sweet sorghum growing on salt-affected lands. Although nitrogen (N) synthetic fertilizers have long been recognized as a key factor for increasing crop yields, their effects on sweet sorghum cultivation are under debate. Consequently, this study integrated the current available observations of yield (n = 255) and partial factor productivity of nitrogen (NPFP, n = 242) of sweet sorghum in salt-affected lands, which included both inland (n = 189) and coastal (n = 66) areas. We quantitatively analyzed the effects of climatic, soil properties and management measures on biomass yield and NPFP of sweet sorghum, comparing the differences between inland and coastal salt-affected lands. We found that average biomass yield and NPFP of sweet sorghum in coastal areas were 19,082.48 ± 8262.75 kg/ha and 107.29 ± 51.44 kg/kg respectively, both significantly lower than that in inland areas (p < 0.05). The N application rate did not have significant promoting effect on the biomass yield of sweet sorghum in inland salt-affected areas (p > 0.05), whereas in coastal salt-affected areas, N application significantly increased the biomass yield of sweet sorghum. Increasing soil organic matter content could promote NPFP in inland areas. The recommended N application rate for inland salt-affected and coastal salt-affected areas were 100 kg/ha and 150 kg/ha respectively. The results indicate that it is crucial to apply nutrient management measures based on the local climatic and soil conditions, since the causes of salinity differ in coastal and inland salt-affected lands. More systematic field studies are required in the future to optimize the management of water and nutrients for sweet sorghum planting in salt-affected lands.

Soil inorganic carbon stocks increase non-synergistically with soil organic carbon after ecological restoration practices in drylands.

Ecological restoration practices have been widely adopted to increase soil carbon stocks by improving soil organic carbon (SOC). However, the effects of these practices on the other important soil carbon component, soil inorganic carbon (SIC), remain unclear. To address this, a meta-analysis based on 45 publications and 37 sites was conducted to quantitatively assess the dynamic changes in SIC stocks due to typical restoration practices, including conversion of cropland to forest (C-F), cropland to grassland (C-G), desert to cropland (D-C), conservation agriculture (CA), and desert to forest (D-F). Results showed that, among the restoration practices increasing the SOC stocks, the SIC stocks decreased after the C-F (-34.7%) and C-G (-15.8%) conversions and CA (-6.8%), but increased after the conversion of D-C (2.6%) and D-F (46.9%). Additionally, in terms of recovery duration, the negative effect of C-G on SIC stocks may vanish with increased recovery duration, whereas SIC stocks showed a prominent increase initially after CA and then decreased over time; the response to D-F conversion of SIC stocks remained consistently positive over time. Furthermore, the non-synergistic changes with SIC and SOC could be due to variations in edaphic factors, while the effects edaphic factors on SIC stocks were different under various ecological restoration practices. Among all the impact factors, mean annual temperature, initial SIC stocks, and types of ecological restoration practice, were the most crucial factors explaining the variation in SIC stocks with ecological restoration. Collectively, the results highlight that the change in SIC stocks is asynchronous with the increase in SOC stocks in space and time after ecological restoration, further indicating that changes in SIC stocks should be paid more attention when assessing and predicting carbon sequestration following various ecological restoration practices.

Sodium salicylate enhances neural excitation via reducing GABAergic transmission in the dentate gyrus area of rat hippocampus in vivo.

Sodium salicylate, one of the non-steroidal anti-inflammatory drugs, is widely prescribed in the clinic, but a high dose of usage can cause hyperactivity in the central nervous system, including the hippocampus. At present, the neural mechanism underlying the induced hyperactivity is not fully understood, in particular, in the hippocampus under an in vivo condition. In this study, we found that systemic administration of sodium salicylate increased the field excitatory postsynaptic potential slope and the population spike amplitude in a dose-dependent manner in the hippocampal dentate gyrus area of rats with in vivo field potential extracellular recordings, which indicates that sodium salicylate enhances basal synaptic transmission and neural excitation. In the presence of picrotoxin, a GABA-A receptor antagonist, sodium salicylate failed to increase the initial slope of the field excitatory postsynaptic potential and the amplitude of the population spike in vivo. To further explore how sodium salicylate enhances the neural excitation, we made whole-cell patch-clamp recordings from hippocampal slices. We found that perfusion of the slice with sodium salicylate decreased electrically evoked GABA receptor-mediated currents, increased paired-pulse ratio, and lowered frequency and amplitude of miniature inhibitory postsynaptic currents. Together, these results demonstrate that sodium salicylate enhances the neural excitation through suppressing GABAergic synaptic transmission in presynaptic and postsynaptic mechanisms in the hippocampal dentate gyrus area. Our findings may help understand the side effects caused by sodium salicylate in the central nervous system.

Optimization of coupling crop and livestock production system's eco-efficiency in northern China based on a life cycle assessment and data envelopment analysis method.

Under the twin pressures of global food security and dual­carbon strategies, improving farm eco-efficiency is critical for achieving China's goal of a 50 Pg increase in grain production, meeting the ambitious climate mitigation targets set by the Paris Agreement, and meeting seven of the seventeen Sustainable Development Goals (SDGs) set by the United Nations. However, there is limited research on eco-efficiency measures supported by localised fine-scale data and coupling mechanisms for the structure, production process, efficiency improvement, and carbon reduction synergies of integrated farming systems in China. This study used the Life Cycle Assessment (LCA) and Data Envelopment Analysis (DEA) methods to assess eco-efficiency at the farm level in northern China, included in the National Coupling Crop and Livestock Production Pilot Programs, to improve the eco-efficiency of farms to achieve increased production and emission reductions. The results showed that the overall eco-efficiency of farms was in the lower-middle range, with only 20.18 % of the farms having a technical efficiency exceeding 1. Problems included a backward level of pure technical efficiency and a return to scale. Non-integrated farms have the lowest profitability (41.33 %) and the highest carbon emission intensity of 3.03 kg CO2eq/USD. The global warming potential impact of non-integrated farms optimization could be reduced by 25 Pg CO2eq. Implementing the integrated farming mode has a significant advantage in reducing carbon emissions and improving productivity. Overall, farm fodder optimization can be increased by up to 42.41 %. Simultaneously, farms with sufficient farmland are more likely to realise a highly integrated business mode for crop cultivation and livestock breeding. Therefore, constructing a new type of green integrated farming system will help farms achieve increased production and emission reductions, promote the development of sustainable agriculture, and provide a Chinese model for the realisation of global SDGs.

Breaking Latent Infection: How ORF37/38-Deletion Mutants Offer New Hope against EHV-1 Neuropathogenicity.

Equid alphaherpesvirus 1 (EHV-1) has been linked to the emergence of neurological disorders, with the horse racing industry experiencing significant impacts from outbreaks of equine herpesvirus myeloencephalopathy (EHM). Building robust immune memory before pathogen exposure enables rapid recognition and elimination, preventing infection. This is crucial for effectively managing EHV-1. Removing neuropathogenic factors and immune evasion genes to develop live attenuated vaccines appears to be a successful strategy for EHV-1 vaccines. We created mutant viruses without ORF38 and ORF37/38 and validated their neuropathogenicity and immunogenicity in hamsters. The ∆ORF38 strain caused brain tissue damage at high doses, whereas the ∆ORF37/38 strain did not. Dexamethasone was used to confirm latent herpesvirus infection and reactivation. Dexamethasone injection increased viral DNA load in the brains of hamsters infected with the parental and ∆ORF38 strains, but not in those infected with the ∆ORF37/38 strain. Immunizing hamsters intranasally with the ∆ORF37/38 strain as a live vaccine produced a stronger immune response compared to the ∆ORF38 strain at the same dose. The hamsters demonstrated effective protection against a lethal challenge with the parental strain. This suggests that the deletion of ORF37/38 may effectively inhibit latent viral infection, reduce the neuropathogenicity of EHV-1, and induce a protective immune response.

Lineage-specific pathogenicity, immune evasion, and virological features of SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3.

SARS-CoV-2 JN.1 with an additional L455S mutation on spike when compared with its parental variant BA.2.86 has outcompeted all earlier variants to become the dominant circulating variant. Recent studies investigated the immune resistance of SARS-CoV-2 JN.1 but additional factors are speculated to contribute to its global dominance, which remain elusive until today. Here, we find that SARS-CoV-2 JN.1 has a higher infectivity than BA.2.86 in differentiated primary human nasal epithelial cells (hNECs). Mechanistically, we demonstrate that the gained infectivity of SARS-CoV-2 JN.1 over BA.2.86 associates with increased entry efficiency conferred by L455S and better spike cleavage in hNECs. Structurally, S455 altered the mode of binding of JN.1 spike protein to ACE2 when compared to BA.2.86 spike at ACE2H34, and modified the internal structure of JN.1 spike protein by increasing the number of hydrogen bonds with neighboring residues. These findings indicate that a single mutation (L455S) enhances virus entry in hNECs and increases immune evasiveness, which contribute to the robust transmissibility of SARS-CoV-2 JN.1. We further evaluate the in vitro and in vivo virological characteristics between SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3, and identify key lineage-specific features of the two Omicron sublineages that contribute to our understanding on Omicron antigenicity, transmissibility, and pathogenicity.

Irrigation Optimization via Crop Water Use in Saline Coastal Areas-A Field Data Analysis in China's Yellow River Delta.

Freshwater resources are becoming increasingly scarce in coastal areas, limiting crop productivity in coastal farmlands. Although the characteristic of crop water use is an important factor for water conservation in coastal farmlands, it has not been studied extensively. This study aimed to depict the water use process of soil-plant systems under saline stress in coastal ecosystems and optimize water management. An intensive observation experiment was performed within China's Yellow River Delta to identify the water use processes and crop coefficients (KC) and also quantify the impacts of salt stress on crop water use. The results show that shallow groundwater did not contribute to soil water in the whole rotation; KC values for wheat-maize, wheat-sorghum, and wheat-soybean rotation systems were 45.0, 58.4, and 57% less, respectively, than the FAO values. The water use efficiency of the maize (8.70) and sorghum (9.00) in coastal farmlands was higher than that of the soybean (4.37). By identifying the critical periods of water and salt stress, this paper provides suggestions for water-saving and salinity control in coastal farmlands. Our findings can inform the sustainable development of coastal farmlands and provide new insights to cope with aspects of the global food crisis.

Vaccine-induced protection against SARS-CoV-2 requires IFN-γ-driven cellular immune response.

The overall success of worldwide mass vaccination in limiting the negative effect of the COVID-19 pandemics is inevitable, however, recent SARS-CoV-2 variants of concern, especially Omicron and its sub-lineages, efficiently evade humoral immunity mounted upon vaccination or previous infection. Thus, it is an important question whether these variants, or vaccines against them, induce anti-viral cellular immunity. Here we show that the mRNA vaccine BNT162b2 induces robust protective immunity in K18-hACE2 transgenic B-cell deficient (µMT) mice. We further demonstrate that the protection is attributed to cellular immunity depending on robust IFN-γ production. Viral challenge with SARS-CoV-2 Omicron BA.1 and BA.5.2 sub-variants induce boosted cellular responses in vaccinated µMT mice, which highlights the significance of cellular immunity against the ever-emerging SARS-CoV-2 variants evading antibody-mediated immunity. Our work, by providing evidence that BNT162b2 can induce significant protective immunity in mice that are unable to produce antibodies, thus highlights the importance of cellular immunity in the protection against SARS-CoV-2.

Rational design of a booster vaccine against COVID-19 based on antigenic distance.

Current COVID-19 vaccines are highly effective against symptomatic disease, but repeated booster doses using vaccines based on the ancestral strain offer limited additional protection against SARS-CoV-2 variants of concern (VOCs). To address this, we used antigenic distance to in silico select optimized booster vaccine seed strains effective against both current and future VOCs. Our model suggests that a SARS-CoV-1-based booster vaccine has the potential to cover a broader range of VOCs. Candidate vaccines including the spike protein from ancestral SARS-CoV-2, Delta, Omicron (BA.1), SARS-CoV-1, or MERS-CoV were experimentally evaluated in mice following two doses of the BNT162b2 vaccine. The SARS-CoV-1-based booster vaccine outperformed other candidates in terms of neutralizing antibody breadth and duration, as well as protective activity against Omicron (BA.2) challenge. This study suggests a unique strategy for selecting booster vaccines based on antigenic distance, which may be useful in designing future booster vaccines as new SARS-CoV-2 variants emerge.

Wireless, battery-free, multifunctional integrated bioelectronics for respiratory pathogens monitoring and severity evaluation.

The rapid diagnosis of respiratory virus infection through breath and blow remains challenging. Here we develop a wireless, battery-free, multifunctional pathogenic infection diagnosis system (PIDS) for diagnosing SARS-CoV-2 infection and symptom severity by blow and breath within 110 s and 350 s, respectively. The accuracies reach to 100% and 92% for evaluating the infection and symptom severity of 42 participants, respectively. PIDS realizes simultaneous gaseous sample collection, biomarker identification, abnormal physical signs recording and machine learning analysis. We transform PIDS into other miniaturized wearable or portable electronic platforms that may widen the diagnostic modes at home, outdoors and public places. Collectively, we demonstrate a general-purpose technology for rapidly diagnosing respiratory pathogenic infection by breath and blow, alleviating the technical bottleneck of saliva and nasopharyngeal secretions. PIDS may serve as a complementary diagnostic tool for other point-of-care techniques and guide the symptomatic treatment of viral infections.

Non-Neutralizing Epitopes Shade Neutralizing Epitopes against Omicron in a Multiple Epitope-Based Vaccine.

The ongoing coronavirus disease 2019 pandemic has raised concerns about the risk of re-infection. Non-neutralizing epitopes are one of the major reasons for antibody-dependent enhancement. Past studies on the ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have revealed an infectivity-enhancing site on the ancestral SARS-CoV-2 spike protein. However, infection enhancement associated with the SARS-CoV-2 Omicron strain remains elusive. In this study, we examined the antibodies induced by a multiple epitope-based vaccine, which showed infection enhancement for the Omicron strain but not for the ancestral SARS-CoV-2 or Delta strain. By examining the antibodies induced by single epitope-based vaccines, we identified a conserved epitope, IDf (450-469), with neutralizing activity against ancestral SARS-CoV-2, Delta, and Omicron. Although neutralizing epitopes are present in the multiple epitope-based vaccine, other immunodominant non-neutralizing epitopes such as IDg (480-499) can shade their neutralizing activity, leading to infection enhancement of Omicron. Our study provides up-to-date epitope information on SARS-CoV-2 variants to help design better vaccines or antibody-based therapeutics against future variants.

Intradermal delivery of mRNA using cryomicroneedles.

Microneedles can realize the intradermal and transdermal delivery of drugs. However, most conventional microneedles made of metal, polymer and ceramics are unsuitable for the delivery of mRNA drugs that are fragile and temperature-sensitive. This study explores the usage of cryomicroneedles (CryoMNs) for the intradermal delivery of mRNA molecules. Taking luciferase mRNA as an example, we first optimize the formulation of CryoMNs to maximize mRNA stability. Later, in the mouse model, we compare the delivery efficiency with the conventional subcutaneous injection for both the luciferase mRNA and COVID-19 Comirnaty mRNA vaccines, where CryoMNs delivered mRNA vaccines successfully induce specific B-cell antibody, neutralizing activity and T-cell responses. STATEMENT OF SIGNIFICANCE: mRNA vaccines are fragile and temperature-sensitive, so they are mainly delivered by intramuscular injection that often causes pain and requires clinical expertise to immunize patients. Microneedles permit convenient, fast and safe vaccination. However, existing microneedle platforms are ineffective to protect the integrity of mRNA vaccines in fabrication, storage, and administration. This work utilizes cryomicroneedles (CryoMNs) technology to intradermally deliver mRNA. In the mouse model, CryoMNs are compared with the subcutaneous injection for the delivery efficiency of both the luciferase mRNA and COVID-19 Comirnaty mRNA vaccines, where CryoMNs delivered mRNA vaccines successfully produce specific B-cell antibodies, T-cell responses, and neutralizing activity. This work is expected to provide a new delivery strategy for the emerging mRNA therapeutics.

Computation of Antigenicity Predicts SARS-CoV-2 Vaccine Breakthrough Variants.

It has been reported that multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) including Alpha, Beta, Gamma, and Delta can reduce neutralization by antibodies, resulting in vaccine breakthrough infections. Virus-antiserum neutralization assays are typically performed to monitor potential vaccine breakthrough strains. However, experiment-based methods took several weeks whether newly emerging variants can break through current vaccines or therapeutic antibodies. To address this, we sought to establish a computational model to predict the antigenicity of SARS-CoV-2 variants by sequence alone. In this study, we firstly identified the relationship between the antigenic difference transformed from the amino acid sequence and the antigenic distance from the neutralization titers. Based on this correlation, we obtained a computational model for the receptor-binding domain (RBD) of the spike protein to predict the fold decrease in virus-antiserum neutralization titers with high accuracy (~0.79). Our predicted results were comparable to experimental neutralization titers of variants, including Alpha, Beta, Delta, Gamma, Epsilon, Iota, Kappa, and Lambda, as well as SARS-CoV. Here, we predicted the fold of decrease of Omicron as 17.4-fold less susceptible to neutralization. We visualized all 1,521 SARS-CoV-2 lineages to indicate variants including Mu, B.1.630, B.1.633, B.1.649, and C.1.2, which can induce vaccine breakthrough infections in addition to reported VOCs Beta, Gamma, Delta, and Omicron. Our study offers a quick approach to predict the antigenicity of SARS-CoV-2 variants as soon as they emerge. Furthermore, this approach can facilitate future vaccine updates to cover all major variants. An online version can be accessed at http://jdlab.online.

Bacillus Calmette-Guérin-induced trained immunity protects against SARS-CoV-2 challenge in K18-hACE2 mice.

SARS-CoV-2 has been confirmed in over 450 million confirmed cases since 2019. Although several vaccines have been certified by the WHO and people are being vaccinated on a global scale, it has been reported that multiple SARS-CoV-2 variants can escape neutralization by antibodies, resulting in vaccine breakthrough infections. Bacillus Calmette-Guérin (BCG) is known to induce heterologous protection based on trained immune responses. Here, we investigated whether BCG-induced trained immunity protected against SARS-CoV-2 in the K18-hACE2 mouse model. Our data demonstrate that i.v. BCG (BCG-i.v.) vaccination induces robust trained innate immune responses and provides protection against WT SARS-CoV-2, as well as the B.1.617.1 and B.1.617.2 variants. Further studies suggest that myeloid cell differentiation and activation of the glycolysis pathway are associated with BCG-induced training immunity in K18-hACE2 mice. Overall, our study provides the experimental evidence that establishes a causal relationship between BCG-i.v. vaccination and protection against SARS-CoV-2 challenge.

Induction of Humoral and Cellular Immunity by Intradermal Delivery of SARS-CoV-2 Nucleocapsid Protein Using Dissolvable Microneedles.

The nucleocapsid protein (NP) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains immunogenic epitopes that can induce cytotoxic T lymphocyte (CTL) against viral infection. This makes the nucleocapsid protein a suitable candidate for developing a vaccine against SARS-CoV-2 infection. This article reports the intradermal delivery of NP antigen using dissolvable microneedle skin patches that could induce both significant B cell and T cell responses.

Intradermal delivery of receptor-binding domain of SARS-CoV-2 spike protein with dissolvable microneedles to induce humoral and cellular responses in mice.

The S1 subunit of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein contains an immunogenic receptor-binding domain (RBD), which is a promising candidate for the development of a potential vaccine. This study demonstrated that intradermal delivery of an S-RBD vaccine using a dissolvable microneedle skin patch can induce both significant B-cell and significant T-cell responses against S-RBD. Importantly, the outcomes were comparable to that of conventional bolus injection.

IFN-γ-dependent NK cell activation is essential to metastasis suppression by engineered Salmonella.

Metastasis accounts for 90% of cancer-related deaths and, currently, there are no effective clinical therapies to block the metastatic cascade. A need to develop novel therapies specifically targeting fundamental metastasis processes remains urgent. Here, we demonstrate that Salmonella YB1, an engineered oxygen-sensitive strain, potently inhibits metastasis of a broad range of cancers. This process requires both IFN-γ and NK cells, as the absence of IFN-γ greatly reduces, whilst depletion of NK cells in vivo completely abolishes, the anti-metastatic ability of Salmonella. Mechanistically, we find that IFN-γ is mainly produced by NK cells during early Salmonella infection, and in turn, IFN-γ promotes the accumulation, activation, and cytotoxicity of NK cells, which kill the metastatic cancer cells thus achieving an anti-metastatic effect. Our findings highlight the significance of a self-regulatory feedback loop of NK cells in inhibiting metastasis, pointing a possible approach to develop anti-metastatic therapies by harnessing the power of NK cells.

Adenosine synthase A contributes to recurrent Staphylococcus aureus infection by dampening protective immunity.

BACKGROUND: Staphylococcus aureus is a common human pathogen capable of causing diverse illnesses with possible recurrent infections. Although recent studies have highlighted the role of cellular immunity in recurrent infections, the mechanism by which S. aureus evades host responses remains largely unexplored. METHODS: This study utilizes in vitro and in vivo infection experiments to investigate difference of pro-inflammatory responses and subsequent adaptive immune responses between adsA mutant and WT S. aureus strain infection. FINDINGS: We demonstrated that adenosine synthase A (AdsA), a potent S. aureus virulence factor, can alter Th17 responses by interfering with NLRP3 inflammasome-mediated IL-1ß production. Specifically, S. aureus virulence factor AdsA dampens Th1/Th17 immunity by limiting the release of IL-1ß and other Th polarizing cytokines. In particular, AdsA obstructs the release of IL-1ß via the adenosine/A2aR/NLRP3 axis. Using a murine infection model, pharmacological inhibition of A2a receptor enhanced S. aureus-specific Th17 responses, whereas inhibition of NLRP3 and caspase-1 downregulated these responses. Our results showed that AdsA contributes to recurrent S. aureus infection by restraining protective Th1/Th17 responses. INTERPRETATION: Our study provides important mechanistic insights for therapeutic and vaccination strategies against S. aureus infections. FUNDING: This work was supported by grants from Shenzhen Peacock project (KQTD2015033-117210153), and Guangdong Science and Technology Department (2020B1212030004) to J.H. and China Postdoctoral Science Foundation (2019M663167) to BZZ. We also thank the L & T Charitable Foundation, the Guangdong Science and Technology Department (2020B1212030004), and the Program for Guangdong Introducing Innovative and Entrepreneurial Teams (2019BT02Y198) for their support.