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GntR transcription factor of Streptococcus suis serotype 2 (SS2) is a potential substrate protein of STK, but the regulation mechanisms of GntR phosphorylation are still unclear. This study confirmed that STK phosphorylated GntR in vivo , and in vitro phosphorylation experiments showed that STK phosphorylated GntR at Ser-41. The phosphomimetic strain (GntR-S41E) had significantly reduced lethality in mice and reduced bacterial load in the blood, lung, liver, spleen, and brain of infected mice compared to wild-type (WT) SS2. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) experiments demonstrated that the promoter of nox was bound by GntR. The phosphomimetic protein GntR-S41E cannot bind to the promoter of nox , and the nox transcription levels were significantly reduced in the GntR-S41E mutant compared to WT SS2. The virulence in mice and the ability to resist oxidative stress of the GntR-S41E strain were restored by complementing transcript levels of nox . NOX is an NADH oxidase that catalyzes the oxidation of NADH to NAD + with the reduction of oxygen to water. We found that NADH is likely accumulated under oxidative stress in the GntR-S41E strain, and higher NADH levels resulted in increased amplified ROS killing. In total, we report GntR phosphorylation could inhibit the transcription of nox , which impaired the ability of SS2 to resist oxidative stress and virulence.

Glaesserella parasuis ( G . parasuis ), the primary pathogen of Glässer’s disease, colonizes the upper respiratory tract and can break through the epithelial barrier of the respiratory tract, leading to lung infection. However, the underlying mechanisms for this adverse effect remain unclear. The G . parasuis serotype 5 SQ strain (HPS5-SQ) infection decreased the integrity of piglets’ lung Occludin and Claudin-1. Autophagy regulates the function of the epithelial barrier and tight junction proteins (TJs) expression. We tested the hypothesis that HPS5-SQ breaking through the porcine respiratory epithelial barrier was linked to autophagy and Claudin-1 degradation. When HPS5-SQ infected swine tracheal epithelial cells (STEC), autophagosomes encapsulated, and autolysosomes degraded oxidatively stressed mitochondria covered with Claudin-1. Furthermore, we found that autophagosomes encapsulating mitochondria resulted in cell membrane Claudin-1 being unable to be replenished after degradation and damaged the respiratory tract epithelial barrier. In conclusion, G . parasuis serotype 5 breaks through the porcine respiratory epithelial barrier by inducing autophagy and interrupting cell membrane Claudin-1 replenishment, clarifying the mechanism of the G . parasuis infection and providing a new potential target for drug design and vaccine development.

Type I interferons (IFNs), mainly IFN-α and IFN-β, play an essential role in defending against viral invasion by inducing the host’s innate antiviral response. Porcine reproductive and respiratory syndrome virus (PRRSV) is known to impair the IFN responses of infected hosts through the antibody-dependent enhancement (ADE) infection pathway, but the precise mechanisms employed are poorly understood. In this study, we showed that PRRSV alone induced a strong secretion of IFN-α and IFN-β in infected porcine alveolar macrophages (PAMs) by activating the retinoic acid-inducible gene I (RIG-I)/melanoma differentiation-associated gene 5 (MDA5) signaling pathway. By contrast, ADE infection of PRRSV significantly down-regulated the production levels of IFN-α and IFN-β in PAMs by negatively regulating the RIG-I/MDA5 signaling pathway and considerably enhancing the replication level of PRRSV in PAMs. Next, small interfering RNA (siRNA) experiments revealed that Fc gamma receptor I (FcγRI) was responsible for the ADE infection of PRRSV in PAMs. In addition, we observed that FcγRI mediated the potent inhibition of IFN-α and IFN-β production through blocking the activation of the RIG-I/MDA5 signaling pathway in PAMs. Further, we found that FcγRI effectively inhibited PRRSV-induced synthesis of IFN-α and IFN-β by negatively regulating PRRSV-induced activation of the RIG-I/MDA5 signaling pathway in PAMs and significantly increased the viral production of PRRSV in PAMs. In conclusion, these results suggest that ADE infection of PRRSV may antagonize the secretion of type I IFNs (IFN-α/β) by interfering with the RIG-I/MDA5 pathway via FcγRI in PAMs, thereby facilitating the proliferation level of PRRSV in PAMs.

Streptococcus suis serotype 2 (SS2) is a major zoonotic pathogen resulting in manifestations as pneumonia and septic shock. The upper respiratory tract is typically thought to be the main colonization and entry site of SS2 in pigs, but the mechanism through which it penetrates the respiratory barrier is still unclear. In this study, a mutant with low invasive potential to swine tracheal epithelial cells (STECs) was screened from the TnYLB-1 transposon insertion mutant library of SS2, and the interrupted gene was identified as autolysin ( atl ). Compared to wild-type (WT) SS2, Δ atl mutant exhibited lower ability to penetrate the tracheal epithelial barrier in a mouse model. Purified Atl also enhanced SS2 translocation across STEC monolayers in Transwell inserts. Furthermore, Atl redistributed the tight junctions (TJs) in STECs through myosin light chain kinase (MLCK) signaling, which led to increased barrier permeability. Using mass spectrometry, co-immunoprecipitation (co-IP), pull-down, bacterial two-hybrid and saturation binding experiments, we showed that Atl binds directly to vimentin. CRISPR/Cas9-targeted deletion of vimentin in STECs (VIM KO STECs) abrogated the capacity of SS2 to translocate across the monolayers, SS2-induced phosphorylation of myosin II regulatory light chain (MLC) and MLCK transcription, indicating that vimentin is indispensable for MLCK activation. Consistently, vimentin null mice were protected from SS2 infection and exhibited reduced tracheal and lung injury. Thus, MLCK-mediated epithelial barrier opening caused by the Atl-vimentin interaction is found to be likely the key mechanism by which SS2 penetrates the tracheal epithelium.

GPR35 is a G protein-coupled receptor with notable involvement in modulating inflammatory responses. Although the precise role of GPR35 in inflammation is not yet fully understood, studies have suggested that it may have both pro- and anti-inflammatory effects depending on the specific cellular environment. Some studies have shown that GPR35 activation can stimulate the production of pro-inflammatory cytokines and facilitate the movement of immune cells towards inflammatory tissues or infected areas. Conversely, other investigations have suggested that GPR35 may possess anti-inflammatory properties in the gastrointestinal tract, liver and certain other tissues by curbing the generation of inflammatory mediators and endorsing the differentiation of regulatory T cells. The intricate role of GPR35 in inflammation underscores the requirement for more in-depth research to thoroughly comprehend its functional mechanisms and its potential significance as a therapeutic target for inflammatory diseases. The purpose of this review is to concurrently investigate the pro-inflammatory and anti-inflammatory roles of GPR35, thus illuminating both facets of this complex issue.

Streptococcus suis serotype 2 (SS2) frequently colonizes the swine upper respiratory tract and can cause Streptococcal disease in swine with clinical manifestations of pneumonia, meningitis, and septicemia. Previously, we have shown that vimentin, a kind of intermediate filament protein, is involved in the penetration of SS2 through the tracheal epithelial barrier. The initiation of invasive disease is closely related to SS2-induced excessive local inflammation; however, the role of vimentin in airway epithelial inflammation remains unclear. Here, we show that vimentin deficient mice exhibit attenuated lung injury, diminished production of proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and the IL-8 homolog, keratinocyte-derived chemokine (KC), and substantially reduced neutrophils in the lungs following intranasal infection with SS2. We also found that swine tracheal epithelial cells (STEC) without vimentin show decreased transcription of IL-6 , TNF- α, and IL-8 . SS2 infection caused reassembly of vimentin in STEC, and pharmacological disruption of vimentin filaments prevented the transcription of those proinflammatory cytokines. Furthermore, deficiency of vimentin failed to increase the transcription of nucleotide oligomerization domain protein 2 (NOD2), which is known to interact with vimentin, and the phosphorylation of NF-κB protein p65. This study provides insights into how vimentin promotes excessive airway inflammation, thereby exacerbating airway injury and SS2-induced systemic infection.

The phagolysosomes of macrophages play a crucial role in eradicating pathogenic microorganisms, but bacteria have evolved sophisticated mechanisms to survive in the acidic environment of phagolysosomes, leading to host infection and subsequent dissemination. However, it is largely unknown how bacteria sense the extracellular stimuli and regulate their acid tolerance capacity to resist the killing by host immune cells. Here, we report the new substrate FadR of the serine/threonine kinase (STK) in Streptococcus suis serotype 2 (SS2) and demonstrate that the phosphorylation site is Thr230. Notably, FadR phosphorylation significantly enhances the acid resistance of SS2, leading to an increase in the lethality of SS2 in mice, and a marked increase in bacterial load in the blood and various organs, and more severe pathological changes in various organs of the mice. Interestingly, this study further indicated that FadR protein can bind to the promoter of arginine deiminase ( adi ), and FadR phosphorylation enhances its binding ability to the adi promoter and increases adi transcription levels. The increase of ADI in SS2 promotes the metabolism of arginine and increases the ammonia content, thus enhancing the acid resistance and intracellular survival capacity of the bacteria in macrophages. Altogether, the research reveals an acid resistance regulatory mechanism that bacteria can utilize the STK-FadR signaling axis to sense changes in the external acidic environment, and then manipulate the ADI system to enhance bacterial resistance to acidic environment or host immunity.

Synthesis of capsular polysaccharide (CPS), an important virulence factor of pathogenic bacteria, is modulated by the CpsBCD phosphoregulatory system in Streptococcus. Serine/threonine kinases (STKs, e.g. Stk1) can also regulate CPS synthesis, but the underlying mechanisms are unclear. Here, we identify a protein (CcpS) that is phosphorylated by Stk1 and modulates the activity of phosphatase CpsB in Streptococcus suis , thus linking Stk1 to CPS synthesis. The crystal structure of CcpS shows an intrinsically disordered region at its N-terminus, including two threonine residues that are phosphorylated by Stk1. The activity of phosphatase CpsB is inhibited when bound to non-phosphorylated CcpS. Thus, CcpS modulates the activity of phosphatase CpsB thereby altering CpsD phosphorylation, which in turn modulates the expression of the Wzx-Wzy pathway and thus CPS production. Serine/threonine kinases (STKs) regulate the synthesis of capsular polysaccharide in bacteria through unclear mechanisms. Here, Tang et al. identify a protein that is phosphorylated by an STK and modulates the activity of a phosphoregulatory system in Streptococcus suis , thus linking STKs to capsular polysaccharide synthesis.

C/SiC composite material is the best choice for important parts such as the hot-end structure of aerospace vehicles. Research and optimization of the cutting force of ultrasonic vibration-assisted grinding are of great significance when it comes to revealing the machining mechanism of C/SiC composites and realizing low-damage and efficient machining. In this paper, the comparative experimental study of ultrasonic vibration-assisted grinding and common grinding of C/SiC composites is carried out; the variation laws of grinding force and grinding force ratio with different machining methods and process parameters are analyzed, and the empirical formulas of ultrasonic-assisted grinding are summarized. The research results show that ultrasonic vibration can soften C/SiC materials and sharpen the cutting to a certain extent through the action of high-frequency impact, greatly reduce the value of the grinding force, and improve the machinability of the material. Thus, ultrasonic-vibration-assisted grinding processing is an effective method to achieve high-efficiency and low-damage processing of C/SiC composites.

Glaesserella parasuis ( G. parasuis ) is a commensal bacterium in the upper respiratory tract of pigs that can also cause the swine Glässer disease, which induces an intensive inflammatory response and results in significant economic losses to the swine industry worldwide. G. parasuis can cause disease through infection of the respiratory tract, resulting in systemic infection, but the mechanism is largely unknown. Recently we showed that Glaesserella parasuis serotype 4 (GPS4) increased swine tracheal epithelial barrier permeability, resulting in easier bacterial translocation. Tight junction proteins (TJ) play a crucial role in maintaining the integrity and impermeability of the epithelial barrier. GPS4 decreased the expression of the TJ ZO-1 and occludin in swine tracheal epithelial cells (STEC). Furthermore, the proinflammatory cytokines IL-6, IL-8 and TNF-α were significantly upregulated in GPS4-infected STEC, and both the MAPK and NF-κB signaling pathways were activated and contributed to the expression of TNF-α. We demonstrate that the production of proinflammatory cytokines, especially TNF-α, during GPS4 infection was involved in barrier dysfunction. Additionally, animal challenge experiments confirmed that GPS4 infection downregulated TJ in the lungs of piglets and induced a severe inflammatory response. In general, G. parasuis infection downregulated the expression of TJ and induced massive secretion of proinflammatory cytokines, resulting in epithelial barrier disruption and favoring bacterial infection. This study allowed us to better understand the mechanism by which G. parasuis crosses the respiratory tract of pigs.