Synergistic developmental effects of zebrafish exposed to combined perfluorooctanoic acid and atrazine.

Perfluorooctanoic acid (PFOA) and atrazine are two endocrine disruptors that are widely found in waters. Negative effects of PFOA and atrazine have been studied individually, but few data have focused on their combined effects. Here, zebrafish embryos were used as model to investigate the combined toxicity of PFOA and atrazine. The acute toxicity of atrazine (11.9 mg/L) to zebrafish embryos was much higher than that of perfluorooctanoic acid (224.6 mg/L) as shown by the 120h-LC50 value. Developmental effects, including delayed yolk sac absorption, spinal curvature, and liver abnormalities, were observed in both one- and two-component exposures. Notably, the rate of embryonic malformations in the co-exposure group was more than twice as high as that of single component exposure in the concentration range of 1/8-1/2 EC50, which indicated a synergistic effect of the binary mixture. The synergistic effect of PFOA-atrazine was further validated by combinatorial index (CI) modeling. In addition, changes of amino acid metabolites, reactive oxygen species and superoxide dismutase indicated that oxidative stress might be the main pathway for enhanced toxicity under co-exposure condition. Overall, co-exposure of PFOA and atrazine resulted in stronger developmental effects and more complicated amino acid metabolic response toward zebrafish, compared with single component exposure.

Immunization with Multiple Virulence Factors Provides Maternal and Neonatal Protection against Group B Streptococcus Serotypes.

Group B streptococcus (GBS) commonly colonizes the vaginal tract and is a leading cause of life-threatening neonatal infections and adverse pregnancy outcomes. No effective vaccine is clinically available. Conserved bacterial virulence factors, including those of GBS, have been employed as vaccine components. We investigated serotype-independent protection against GBS by intranasal immunization with six conserved GBS virulence factors (GBSV6). GBSV6 induced systemic and vaginal antibodies and T cell responses in mice. The immunity reduced mouse mortality and vaginal colonization by various GBS serotypes and protected newborn mice of immunized dams against GBS challenge. Intranasal GBSV6 immunization also provided long-lasting protective immunity and had advantages over intramuscular GBSV6 immunization regarding restricting vaginal GBS colonization. Our findings indicate that intranasal immunization targeting multiple conserved GBS virulence factors induces serotype-independent immunity, which protects against GBS infection systemically and vaginally in dams and prevents newborn death. The study presents valuable strategies for GBS vaccine development.

Coevolution of furA-Regulated Hyper-Inflammation and Mycobacterial Resistance to Oxidative Killing through Adaptation to Hydrogen Peroxide.

Mycobacterium tuberculosis (Mtb) is highly resistant to host oxidative killing. We hypothesized that the evolutionary adaptation of M. smegmatis to hydrogen peroxide (H2O2) would endow the nonpathogenic Mycobacterium persistent in a host. In the study, we screened a highly H2O2-resistant strain (mc2114) via evolutionary H2O2 adaptation in vitro. The MIC of mc2114 to H2O2 is 320 times that of wild-type mc2155. Mouse infection experiments showed that mc2114, similar to Mtb, was persistent in the lungs and caused high lethality in mice with restricted responses of NOX2, ROS, IFN-γ, decreased macrophage apoptosis, and overexpressed inflammatory cytokines in the lungs. Whole-genome sequencing analysis revealed that mc2114 harbored 29 single nucleotide polymorphisms in multiple genes; one of them was on the furA gene that caused FurA deficiency-mediated overexpression of KatG, a catalase-peroxidase to detoxify ROS. Complementation of mc2114 with a wild-type furA gene reversed lethality and hyper-inflammatory response in mice with rescued overexpression of KatG and inflammatory cytokines, whereas NOX2, ROS, IFN-γ, and macrophage apoptosis remained reduced. The results indicate that although FurA regulates KatG expression, it does not contribute significantly to the restriction of ROS response. Instead, FurA deficiency is responsible for the detrimental pulmonary inflammation that contributes to the severity of the infection, a previously nonrecognized function of FurA in mycobacterial pathogenesis. The study also indicates that mycobacterial resistance to oxidative burst results from complex mechanisms involving adaptive genetic changes in multiple genes. IMPORTANCE Mycobacterium tuberculosis (Mtb) causes human tuberculosis (TB), which has killed more people in human history than any other microorganism. However, the mechanisms underlying Mtb pathogenesis and related genes have not yet been fully elucidated, which impedes the development of effective strategies for containing and eradicating TB. In the study, we generated a mutant of M. smegmatis (mc2114) with multiple mutations by an adaptive evolutionary screen with H2O2. One of the mutations in furA caused a deficiency of FurA, which mediated severe inflammatory lung injury and higher lethality in mice by overexpression of inflammatory cytokines. Our results indicate that FurA-regulated pulmonary inflammation plays a critical role in mycobacterial pathogenesis in addition to the known downregulation of NOX2, ROS, IFN-γ responses, and macrophage apoptosis. Further analysis of the mutations in mc2114 would identify more genes related to the increased pathogenicity and help in devising new strategies for containing and eradicating TB.

Intranasal streptococcal infection exacerbates psoriasis-like dermatitis via the induction of skin tissue-resident memory T cells.

Recurrent streptococcal tonsillitis exacerbates psoriasis. Studies have indicated that T cells responding to streptococcal antigens in the skin are involved in the pathogenesis of the disease. However, a direct link between streptococcal tonsillitis and psoriasis has not been evidenced. In the present study, the impact of intranasal (i.n.) streptococcal infection on psoriasis was investigated using the imiquimod (IMQ) psoriasis mouse model. The results showed that repeated i.n. infection with group A Streptococcus (GAS) induced a robust and persistent Th17 response in the nasal-associated lymphoid tissue (NALT) and exacerbated IMQ-mediated psoriatic skin lesions. ELISpot and flow cytometry analyses revealed that GAS-reactive tissue-resident memory T cells (TRM) were present in the skin of GAS-infected mice and produced IL-17/IL-23 axis cytokines in response to IMQ, compared to mice uninfected with GAS. In addition, i.n. infection with Streptococcus pneumoniae (Sp), a pathogen not associated with the development of psoriasis, also induced a persistent Th17 response in NALT but did not exacerbate IMQ-induced psoriatic inflammation nor elicited Sp-specific T cells in the skin. The results provide in vivo evidence that GAS-associated psoriasis is dependent on the skin GAS-specific TRM cells induced by GAS nasopharyngeal infection and can be later activated by environmental triggers, leading to psoriatic inflammation. Reducing the reservoir of Th17 cells, which are source of skin TRM cells, may constitute a promising treatment for psoriasis.

CWcollab: Presenting multimedia with web-based context-aware collaboration.

Remote collaboration tools for conferencing and presentation are gaining significant popularity during the COVID-19 pandemic period. Most prior work has drawbacks, such as a) limited support for media types, b) lack of interactivity, for example, an efficient replay mechanism, c) large bandwidth consumption for screen sharing tools. In this paper, we propose a general-purpose multimedia collaboration platform-CWcollab. It supports collaboration on general multimedia by using simple messages to represent media controls with an object-prioritized synchronization approach. Thus, CWcollab can not only support fine-grained accurate collaboration, but also rich functionalities such as replay of these collaboration events. The evaluation shows hundreds of kilobytes can be enough to store the events in a collaboration session for accurate replays, compared with hundreds of megabytes of Google Meet.

Differential Effects of Toll-Like Receptor Signaling on the Activation of Immune Responses in the Upper Respiratory Tract.

Vaccination through the upper respiratory tract (URT) is highly effective for the prevention of respiratory infectious diseases. Toll-like receptor (TLR)-based adjuvants are immunostimulatory and considered potential adjuvant candidates. However, the patterns of immune response to different TLRs at the URT have not been revealed. In this study, SPF mice were preexposed to TLR agonists intranasally to simulate the status of humans. Inflammatory response to TLR agonists and TLR signal-mediated adaptive immune responses were analyzed. The results revealed that similar to human tonsils, inflammatory response to stimulation with TLR4 or TLR2 agonist was attenuated in agonist-exposed mice but not in mice without this exposure. In contrast, TLR9 or TLR3 agonist preexposure did not affect the inflammatory response to restimulation by matching agonists. For the adaptive immune response, after agonist preexposure the antibody response to antigens adjuvanted with TLR4 or TLR2 agonist was substantially restricted, whereas, both antibody and T cell responses to antigens adjuvanted with TLR9 or TLR3 agonist were activated as robustly as in mice without agonist exposure. Moreover, we demonstrate that the mechanisms underlying the differential activation of TLRs are regulated at the level of TLR expression in innate and adaptive immune cells. These results indicate that TLRs on the cell surface (TLR4 and 2) and in the endolysosomal compartments (TLR9 and 3) display distinct immune response patterns. The findings provide important information for the use of TLR agonists as mucosal adjuvants and enhance our understanding of immune responses to bacterial and viral infections in the respiratory mucosa. IMPORTANCE Agonists of TLRs are potential adjuvant candidates for mucosal vaccination. We demonstrated that the TLR-mediated inflammatory and antibody responses in the URT of SPF mice exposed to extracellular TLR agonists were substantially restricted. In contrast, inflammatory and adaptive immune responses, including B and T cell activation, were not desensitized in mice exposed to intracellular TLR agonists. The distinct responsive patterns of extra and intracellular TLRs regulated at TLR expression in immune cells. The results indicated that TLRs differentially impact the innate and adaptive immune response in the URT, which contributes to the selection of TLR-based mucosal adjuvants and helps understand the difference between the immune response in bacterial and viral infections.

Immunity to Sda1 Protects against Infection by Sda1+ and Sda1- Serotypes of Group A Streptococcus.

Group A Streptococcus (GAS) causes a variety of diseases globally. The DNases in GAS promote GAS evasion of neutrophil killing by degrading neutrophil extracellular traps (NETs). Sda1 is a prophage-encoded DNase associated with virulent GAS strains. However, protective immunity against Sda1 has not been determined. In this study, we explored the potential of Sda1 as a vaccine candidate. Sda1 was used as a vaccine to immunize mice intranasally. The effect of anti-Sda1 IgG in neutralizing degradation of NETs was determined and the protective role of Sda1 was investigated with intranasal and systemic challenge models. Antigen-specific antibodies were induced in the sera and pharyngeal mucosal site after Sda1 immunization. The anti-Sda1 IgG efficiently prevented degradation of NETs by supernatant samples from different GAS serotypes with or without Sda1. Sda1 immunization promoted clearance of GAS from the nasopharynx independent of GAS serotypes but did not reduce lethality after systemic GAS challenge. Anti-Sda1 antibody can neutralize degradation of NETs by Sda1 and other phage-encoded DNases and decrease GAS colonization at the nasopharynx across serotypes. These results indicate that Sda1 can be a potential vaccine candidate for reduction in GAS reservoir and GAS tonsillitis-associated diseases.

Diversification of Sinorhizobium populations associated with Medicago polymorpha and Medicago lupulina in purple soil of China.

The double selection of environment adaptation and host specificity forced the diversification of rhizobia in nature. In the tropical region of China, Medicago polymorpha and Medicago lupulina are widely distributed, particularly in purple soil. However, the local distribution and diversity of rhizobia associated with these legumes has not been systematically investigated. To this end, root nodules of M. polymorpha and M. lupulina grown in purple soil at seven locations in Yunnan Province of China were collected for rhizobial isolation. The obtained rhizobia were characterized by RFLP of 16S-23S rRNA intergenic spacer, BOXAIR fingerprinting, and phylogeny of housekeeping and symbiosis genes. As result, a total of 91 rhizobial strains were classified into species Sinorhizobium medicae and S. meliloti, while three nodC gene types were identified among them. S. medicae containing nodC of type I was dominant in farmlands associated with M. polymorpha; while S. meliloti harboring nodC of type III was dominant in wild land nodulated by M. lupulina. For both rhizobial species, greater genetic diversity was detected in the populations isolated from their preferred host plant. A high level of genetic differentiation was observed between the two Sinorhizobium species, and gene flow was evident within the populations of the same species derived from different soil types, indicating that rhizobial evolution is likely associated with the soil features. To examine the effects of environmental features on rhizobial distribution, soil physicochemical traits and rhizobial genotypes were applied for constrained analysis of principle coordinates, which demonstrated that soil features like pH, nitrogen and sodium were the principle factors governing the rhizobial geographical distribution. Altogether, both S. medicae and S. meliloti strains could naturally nodulate with M. polymorpha and M. lupulina, but the rhizobium-legume symbiosis compatibility determined by both the host species and soil factors was also highlighted.

Induction of cyclophilin A by influenza A virus infection facilitates group A Streptococcus coinfection.

During influenza A epidemics, bacterial coinfection is a major cause of increased morbidity and mortality. However, the roles of host factors in regulating influenza A virus (IAV)-triggered bacterial coinfection remain elusive. Cyclophilin A (CypA) is an important regulator of infection and immunity. Here, we show that IAV-induced CypA expression facilitates group A Streptococcus (GAS) coinfection both in vitro and in vivo. Upon IAV infection, CypA interacts with focal adhesion kinase (FAK) and inhibited E3 ligase cCbl-mediated, K48-linked ubiquitination of FAK, which positively regulates integrin α5 expression and actin rearrangement via the FAK/Akt signaling pathway to facilitate GAS colonization and invasion. Notably, CypA deficiency or inhibition by cyclosporine A significantly inhibits IAV-triggered GAS coinfection in mice. Collectively, these findings reveal that CypA is critical for GAS infection, and induction of CypA expression is another way for IAV to promote bacterial coinfection, suggesting that CypA is a promising therapeutic target for the secondary bacterial infection.

IFN-γ-/- Mice Resist Actinobacillus pleuropneumoniae Infection by Promoting Early Lung IL-18 Release and PMN-I Accumulation.

Porcine pleuropneumonia is a common infectious disease of pigs caused by Actinobacillus pleuropneumoniae Interferon gamma (IFN-γ) expression increases in the lung of pigs after A. pleuropneumoniae infection, but the role of IFN-γ during the infection is still obscure. In this study, an IFN-γ-/- mouse infection model was established, and bacterial load, levels of inflammatory cytokines, and types of neutrophils in the lungs were studied at different times post-A. pleuropneumoniae infection. We found that wild-type (WT) mice were more susceptible to A. pleuropneumoniae than IFN-γ-/- mice. At 6 h postinfection (hpi), the expression of interleukin 18 (IL-18) and IL-1ß in the lungs of IFN-γ-/- mice was significantly increased compared to WT mice. The bacterial load and levels of inflammatory cytokines (IL-1ß and IL-6) of IFN-γ-/- mice were significantly reduced at 12 hpi compared to WT mice. After an initial loss, the numbers of lung polymorphonuclear (PMN)-I cells dramatically increased in the lungs of IFN-γ-/- but not WT mice, whereas PMN-II cells continually decreased. Finally, in vivo administration of IL-18 significantly reduced clinical scores and bacterial load in the lungs of A. pleuropneumoniae-infected mice. This study identifies IFN-γ as a target for regulating the inflammatory response in the lung and provides a basis for understanding the course of clinical bacterial pneumonia and for the formulation of treatment protocols.

Intrapulmonary Vaccination Induces Long-lasting and Effective Pulmonary Immunity Against Staphylococcus aureus Pneumonia.

BACKGROUND: Staphylococcus aureus causes community- and hospital-acquired pneumonia linked to a high mortality rate. The emergence and rapid transmission of multidrug-resistant S. aureus strains has become a serious health concern, highlighting the challenges associated with the development of a vaccine to combat S. aureus pneumonia. METHODS: This study evaluated the effects of intrapulmonary immunization on the immune response and protection against S. aureus lung infection in a respiratory mouse model using a subunit vaccine. RESULTS: Compared with the intranasal immunized mice, the intrapulmonarily immunized mice had lower levels of pulmonary bacterial colonization and lethality, accompanied by alleviated lung inflammation with reduced proinflammatory cytokines and increased levels of interleukin-10 and antimicrobial peptide following intrapulmonary challenge. Optimal protection was associated with increased pulmonary antibodies and resident memory T cells. Moreover, intrapulmonary immunization provided long-lasting pulmonary protection for at least 6 months, with persistent cellular and humoral immunity in the lungs. CONCLUSIONS: Vaccine reaching the deep lung by intrapulmonary immunization plays a significant role in the induction of efficacious and long-lasting immunity against S. aureus in the lung parenchyma. Hence, intrapulmonary immunization can be a strategy for the development of a vaccine against S. aureus pneumonia.Immunization through the intrapulmonary route with a subunit of S. aureus vaccine elicited tissue resident memory T cells and antigen-specific antibodies in the lungs, and provided optimal and long-term protection against S. aureus pneumonia.

Flu Virus Attenuates Memory Clearance of Pneumococcus via IFN-γ-Dependent Th17 and Independent Antibody Mechanisms.

Bacterial coinfection is a major cause of influenza-associated mortality. Most people have experienced infections with bacterial pathogens commonly associated with influenza A virus (IAV) coinfection before IAV exposure; however, bacterial clearance through the immunological memory response (IMR) in coinfected patients is inefficient, suggesting that the IMR to bacteria is impaired during IAV infection. Adoptive transfer of CD4+ T cells from mice that had experienced bacterial infection into IAV-infected mice revealed that memory protection against bacteria was weakened in the latter. Additionally, memory Th17 cell responses were impaired due to an IFN-γ-dependent reduction in Th17 cell proliferation and delayed migration of CD4+ T cells into the lungs. A bacterium-specific antibody-mediated memory response was also substantially reduced in coinfected mice, independently of IFN-γ. These findings provide additional perspectives on the pathogenesis of coinfection and suggest additional strategies for the treatment of defective antibacterial immunity and the design of bacterial vaccines against coinfection.

Infection of Mycobacterium tuberculosis Promotes Both M1/M2 Polarization and MMP Production in Cigarette Smoke-Exposed Macrophages.

Pulmonary tuberculosis (PTB) is a risk factor for COPD. Our previous study revealed more severe emphysema in COPD patients (mostly smokers) with prior tuberculosis. However, the mechanisms of interactions between cigarette smoke (CS) and Mycobacterium tuberculosis (Mtb) are unknown. In this study, we found that the frequencies of both M1 and M2 macrophages, and levels of MMP9 and MMP12 in bronchoalveolar lavage were increased in PTB patients with smoking. Between-group analysis showed that the frequency of M1 macrophages was higher in non-smoker PTB patients while more M2 macrophages were found in smokers without PTB, as compared to the non-smoker healthy controls. Bacille Calmette-Guérin (BCG) infection in CS extract (CSE)-incubated MH-S cells further enhanced secretion of M1-related (iNOS, IFN-γ and TNF-α) and M2-related (TGF-ß and IL-10) cytokines, reactive oxygen species (ROS) production and cellular apoptosis, concomitantly with up-regulation of MMP9 and MMP12, but not TIMP1. Moreover, BCG infection in acutely CS-exposed mice promoted macrophage polarization toward both M1 and M2 phenotypes, along with increased lung inflammatory infiltration. MMP9 and MMP12, but not TIMP1, were further up-regulated in lung tissues and BAL fluid after BCG infection in this model. Taken together, Mtb Infection promoted CS-exposed macrophages to polarize toward both M1 and M2 phenotypes, along with enhanced production of MMP9 and MMP12. These findings provide insights into the mechanistic interplay between CS exposure and tuberculosis in the pathogenesis of COPD.

Distinct Quality Changes of Garlic Bulb during Growth by Metabolomics Analysis.

Garlic-specialized metabolites contribute to both spicy flavor and healthy function of garlic. Their accumulation pattern and regulatory mechanism vary greatly at different environments and maturities. Herein, metabolomics models were built to evaluate and predict the quality and chemical composition variances of four garlic varieties in two regions at six growth stages. A total of 91 metabolites were identified, and their accumulation pattern during growth in three varieties of garlic in Shandong was similar but obviously distinct from that planted in Heilongjiang. Active metabolism for organosulfur compounds and amino acids was observed, and most metabolites with the "γ-glutamyl-" group were the storage compounds of nitrogen and sulfur in garlic because they increased remarkably during growth. The levels of functional components in garlic varied among different stages, and reliable prediction models for these compounds were provided, which may give a new idea for the estimation of garlic quality and confirmation of the best harvest time.

Long-lasting protective immunity against H7N9 infection is induced by intramuscular or CpG-adjuvanted intranasal immunization with the split H7N9 vaccine.

There is an urgent need for efficient vaccines against the highly pathogenic avian influenza A viral strain H7N9. The duration and intensity of the immune response to H7N9 critically impacts the epidemiology of influenza viral infection at the population level. However, the insufficient immunogenicity of H7N9 raises concerns about vaccine efficacy. In this study, we evaluated the impact of immunization routes and the adjuvant CpG on the immune response to a split H7N9 vaccine in mice. Determination of humoral and cellular responses to the vaccine revealed that after four vaccine doses, high titers of H7N9-specific serum IgG, determined by the influenza hemagglutination inhibition (HI) assay, were induced through the intramuscular (i.m.) route and lasted for at least 40 weeks. CpG-adjuvanted immunization increased the levels of long-lived IFN-γ+ T cells and raised the Th1-biased IgG2a/IgG1 response ratio. In addition, aside from mucosal IgA, CpG-adjuvanted intranasal (i.n.) immunization elicited serum IgG and cellular responses of a similar duration and intensity to CpG-adjuvanted i.m. immunization. Mouse challenge assays demonstrated that 24 weeks following i.m. immunization without CpG or CpG-adjuvanted immunization through the i.m. or i.n. routes, both offered a high level of protection against H7N9 infection. These results indicate that efficient long-term protection against H7N9 can be achieved via the optimization of vaccination strategies, such as immunization doses, routes, and adjuvants.

A Multicomponent Vaccine Provides Immunity against Local and Systemic Infections by Group A Streptococcus across Serotypes.

Group A streptococcus (GAS) species are responsible for a broad spectrum of human diseases, ranging from superficial to invasive infections, and are associated with autoimmune disorders. There is no commercial vaccine against GAS. The clinical manifestations of GAS infection may be attributable to the large repertoire of virulence factors used selectively in different types of GAS disease. Here, we selected five molecules, highly conserved among GAS serotypes, and involved in different pathogenic mechanisms, as a multicomponent vaccine, 5CP. Intranasal (i.n.) immunization with 5CP protected mice against both mucosal and systemic GAS infection across serotypes; the protection lasted at least 6 months. Immunization of mice with 5CP constrained skin lesion development and accelerated lesion recovery. Flow cytometry and enzyme-linked immunosorbent assay analyses revealed that 5CP induced Th17 and antibody responses locally and systemically; however, the Th17 response induced by 5CP resolved more quickly than that to GAS when challenge bacteria were cleared, suggesting that 5CP is less likely to cause autoimmune responses. These findings support that immunization through the i.n. route targeting multiple nonredundant virulence factors can induce immunity against different types of GAS disease and represents an alternative strategy for GAS vaccine development, with favorable efficacy, coverage, duration, and safety.IMPORTANCE GAS is among the most common human pathogens and causes a wide variety of diseases, likely more than any other microorganism. The diverse clinical manifestations of GAS may be attributable to its large repertoire of virulence factors that are selectively and synergistically involved in streptococcal pathogenesis. To date, GAS vaccines have not been successful due to multiple serotypes and postinfection sequelae associated with autoimmunity. In this study, five conserved virulence factors that are involved in GAS pathogenesis were used as a combined vaccine. Intranasal immunization with this vaccine induced humoral and cellular immune responses across GAS serotypes and protected against mucosal, systemic, and skin infections. The significance of this work is to demonstrate that the efficacy of GAS vaccines can be achieved by including multiple nonredundant critical virulence factors and inducing local and systemic immunity. The strategy also provides valuable insights for vaccine development against other pathogens.

Intracellular Invasion by Streptococcus pyogenes: Invasins, Host Receptors, and Relevance to Human Disease.

The human oral-nasal mucosa is the primary reservoir for Streptococcus pyogenes infections. Although the most common infection of consequence in temperate climates is pharyngitis, the past 25 years have witnessed a dramatic increase in invasive disease in many regions of the world. Historically, S. pyogenes has been associated with sepsis and fulminate systemic infections, but the mechanism by which these streptococci traverse mucosal or epidermal barriers is not understood. The discovery that S. pyogenes can be internalized by mammalian epithelial cells at high frequencies (1-3) and/or open tight junctions to pass between cells (4) provides potential explanations for changes in epidemiology and the ability of this species to breach such barriers. In this article, the invasins and pathways that S. pyogenes uses to reach the intracellular state are reviewed, and the relationship between intracellular invasion and human disease is discussed.

Intranasal Vaccination With Multiple Virulence Factors Promotes Mucosal Clearance of Streptococcus suis Across Serotypes and Protects Against Meningitis in Mice.

BACKGROUND: Streptococcus suis is an emerging zoonotic agent. Its natural habitat is the tonsils, which are the main portals of S. suis entry into the bloodstream of pigs. The remarkable variability of the bacteria and complex pathogenic mechanisms make the development of a vaccine a difficult task. METHOD: Five conserved virulence factors involved in critical events of S. suis pathogenesis were combined and used as an intranasal vaccine (V5). The effect of V5 was investigated with intranasal and systemic challenge models. RESULTS: V5 induced antibody and T-cell responses at the mucosal site and systemically. The immunity promoted clearance of S. suis from the nasopharynx independent of S. suis serotypes and reduced lethality after systemic challenge with S. suis serotype 2. Moreover, mice that survived sepsis from intravenous infection developed meningitis, whereas none of these mice showed neuropathological symptoms after V5 receipt. CONCLUSION: Intranasal immunization with multiple conserved virulence factors decreases S. suis colonization at the nasopharynx across serotypes and inhibits the dissemination of the bacteria in the host. The protective mucosal immunity effects would potentially reduce the S. suis reservoir and prevent S. suis disease in pigs.

Protective immune mechanisms of Yifei Tongluo, a Chinese herb formulation, in the treatment of mycobacterial infection.

Yifei Tongluo (YFTL) is a traditional Chinese medicine (TCM) formulation which has been shown clinical efficacy in treatment of patients with multidrug-resistant tuberculosis in China. However, the underlying mechanisms of the effects of YFTL are lacking. This study investigated the effects of YFTL on immune regulation with a mouse lung infection model with Bacille Calmette-Guérin (BCG). We found that compared with untreated mice, the lung mycobacterial load in YFTL-treated mice was significantly reduced, accompanied by alleviated pulmonary inflammation with reduction of pro-inflammatory cytokines and increase of prostaglandin E2 (PGE2). Flow cytometry analyses showed that Th1 cells were significantly higher in the lungs of YFTL-treated mice at early infection time. The results suggest that YFTL-treatment down-regulates pulmonary inflammation, which facilitates a rapid infiltration of Th1 cells into the lungs. Moreover, the Th1 cells in the lungs were resolved faster at later time concomitant with increased the regulatory T cells (Tregs). The reduction of mycobacterial burden associated with improved tissue pathology, faster Th1 cell trafficking, and accelerated resolution of Th1 cells in the lungs of YFTL-treated mice indicates that YFTL improves mycobacterial clearance by maintaining lung homeostasis and dynamically regulating T cells in the lung parenchyma, and suggests that YFTL can be used as host-directed therapies that target immune responses to mycobacterial infection.

Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth.

Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function1. Among the genes coding for the MYST family of KATs (KAT5-KAT8) are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF)2,3. KAT6A has essential roles in normal haematopoietic stem cells4-6 and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia7,8. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers8. KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus9,10, a function that requires its KAT activity10. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days11. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.