Inflammasome-triggered IL-18 controls skin inflammation in the progression of Buruli ulcer.

Buruli ulcer is an emerging chronic infectious skin disease caused by Mycobacterium ulcerans. Mycolactone, an exotoxin produced by the bacterium, is the only identified virulence factor so far, but the functions of this toxin and the mechanisms of disease progression remain unclear. By interfering Sec61 translocon, mycolactone inhibits the Sec61-dependent co-translational translocation of newly synthesized proteins, such as induced cytokines and immune cell receptors, into the endoplasmic reticulum. However, in regard to IL-1ß, which is secreted by a Sec61-independent mechanism, mycolactone has been shown to induce IL-1ß secretion via activation of inflammasomes. In this study, we clarified that cytokine induction, including that of IL-1ß, in infected macrophages was suppressed by mycolactone produced by M. ulcerans subsp. shinshuense, despite the activation of caspase-1 through the inflammasome activation triggered in a manner independent of mycolactone. Intriguingly, mycolactone suppressed the expression of proIL-1ß as well as TNF-α at the transcriptional level, suggesting that mycolactone of M. ulcerans subsp. shinshuense may exert additional inhibitory effect on proIL-1ß expression. Remarkably, constitutively produced IL-18 was cleaved and mature IL-18 was actually released from macrophages infected with the causative mycobacterium. IL-18-deficient mice infected subcutaneously with M. ulcerans exhibited exacerbated skin inflammation during the course of disease progression. On the other hand, IL-1ß controls bacterial multiplication in skin tissues. These results provide information regarding the mechanisms and functions of the induced cytokines in the pathology of Buruli ulcer.

A unique bacterial tactic to circumvent the cell death crosstalk induced by blockade of caspase-8.

Upon invasive bacterial infection of colonic epithelium, host cells induce several types of cell death to eliminate pathogens. For instance, necroptosis is a RIPK-dependent lytic cell death that serves as a backup system to fully eliminate intracellular pathogens when apoptosis is inhibited; this phenomenon has been termed "cell death crosstalk". To maintain their replicative niche and multiply within cells, some enteric pathogens prevent epithelial cell death by delivering effectors via the type III secretion system. In this study, we found that Shigella hijacks host cell death crosstalk via a dual mechanism: inhibition of apoptosis by the OspC1 effector and inhibition of necroptosis by the OspD3 effector. Upon infection by Shigella, host cells recognize blockade of caspase-8 apoptosis signaling by OspC1 effector as a key danger signal and trigger necroptosis as a backup form of host defense. To counteract this backup defense, Shigella delivers the OspD3 effector, a protease, to degrade RIPK1 and RIPK3, preventing necroptosis. We believe that blockade of host cell death crosstalk by Shigella is a unique intracellular survival tactic for prolonging the bacterium's replicative niche.

Fusobacterium nucleatum infection activates the noncanonical inflammasome and exacerbates inflammatory response in DSS-induced colitis.

Caspase activation results in pyroptosis, an inflammatory cell death that contributes to several inflammatory diseases by releasing inflammatory cytokines and cellular contents. Fusobacterium nucleatum is a periodontal pathogen frequently detected in human cancer and inflammatory bowel diseases. Studies have reported that F. nucleatum infection leads to NLRP3 activation and pyroptosis, but the precise activation process and disease association remain poorly understood. This study demonstrated that F. nucleatum infection exacerbates acute colitis in mice and activates pyroptosis through caspase-11-mediated gasdermin D cleavage in macrophages. Furthermore, F. nucleatum infection in colitis mice induces the enhancement of IL-1⍺ secretion from the colon, affecting weight loss and severe disease activities. Neutralization of IL-1⍺ protects F. nucleatum infected mice from severe colitis. Therefore, F. nucleatum infection facilitates inflammation in acute colitis with IL-1⍺ from colon tissue by activating noncanonical inflammasome through gasdermin D cleavage.

Influence of scene aspect ratio and depth cues on verticality perception bias.

Perceiving verticality is crucial for accurate spatial orientation. Previous research has revealed that tilted scenes can bias verticality perception. Verticality perception bias can be represented as the sum of multiple periodic functions that play a role in the perception of visual orientation, where the specific factors affecting each periodicity remain uncertain. This study investigated the influence of the width and depth of an indoor scene on each periodic component of the bias. The participants were presented with an indoor scene showing a rectangular checkerboard room (Experiment 1), a rectangular aperture on the wall (Experiment 2), or a rectangular dotted room (Experiment 3), with various aspect ratios. The stimuli were presented with roll orientations ranging from 90° clockwise to 90° counterclockwise. The participants were asked to report their subjective visual vertical (SVV) perceptions. The contributions of 45°, 90°, and 180° periodicities to the SVV error were assessed by the weighted vector sum model. In Experiment 1, the periodic components of the SVV error increased with the aspect ratio. In Experiments 2 and 3, only the 90° component increased with the aspect ratio. These findings suggest that extended transverse surfaces may modulate the periodic components of verticality perception.

Postural adjustment as a function of scene orientation.

Visual orientation plays an important role in postural control, but the specific characteristics of postural response to orientation remain unknown. In this study, we investigated the relationship between postural response and the subjective visual vertical (SVV) as a function of scene orientation. We presented a virtual room including everyday objects through a head-mounted display and measured head tilt around the naso-occipital axis. The room orientation varied from 165° counterclockwise to 180° clockwise around the center of display in 15° increments. In a separate session, we also conducted a rod adjustment task to record the participant's SVV in the tilted room. We applied a weighted vector sum model to head tilt and SVV error and obtained the weight of three visual cues to orientation: frame, horizon, and polarity. We found significant contributions for all visual cues to head tilt and SVV error. For SVV error, frame cues made the largest contribution, whereas polarity contribution made the smallest. For head tilt, there was no clear difference across visual cue types, although the order of contribution was similar to the SVV. These findings suggest that multiple visual cues to orientation are involved in postural control and imply different representations of vertical orientation across postural control and perception.

Effect of low oxygen concentration on activation of inflammation by Helicobacter pylori.

The gastrointestinal tract of the human body is characterized by a highly unique oxygenation profile, where the oxygen concentration decreases toward the lower tract, not found in other organs. The epithelial cells lining the mucosa where Helicobacter pylori resides exist in a relatively low oxygen environment with a partial pressure of oxygen (pO2) below 58 mm Hg. However, the contribution of hypoxia to H. pylori-induced host immune responses remains elusive. In this study, we investigated the inflammasome activation induced by H. pylori under hypoxic, compared with normoxic, conditions. Our results indicated that the activation of caspase-1 and the subsequent secretion of IL-1ß were significantly enhanced in infected macrophages under 1% oxygen, compared with those under a normal 20% oxygen concentration. The proliferation of H. pylori under aerobic conditions was 3-fold higher than under microaerophilic conditions, and the bacterial growth was more dependent on CO2 than on oxygen. Also, we observed that hypoxia-induced cytokine production as well as HIF-1α accumulation were both decreased when murine macrophages were treated with an HIF-1α inhibitor, KC7F2. Furthermore, hypoxia enhanced the phagocytosis of H. pylori in an HIF-1α-dependent manner. IL-1ß production was also affected by the HIF-1α inhibitor in a mouse infection model, suggesting the important role of HIF-1α in the host defense system during infection with H. pylori. Our findings provide new insights into the intersection of low oxygen, H. pylori, and inflammation and disclosed how H. pylori under low oxygen tension can aggravate IL-1ß secretion.

Shigella effector IpaH4.5 targets 19S regulatory particle subunit RPN13 in the 26S proteasome to dampen cytotoxic T lymphocyte activation.

Subversion of antigen-specific immune responses by intracellular pathogens is pivotal for successful colonisation. Bacterial pathogens, including Shigella, deliver effectors into host cells via the type III secretion system (T3SS) in order to manipulate host innate and adaptive immune responses, thereby promoting infection. However, the strategy for subverting antigen-specific immunity is not well understood. Here, we show that Shigella flexneri invasion plasmid antigen H (IpaH) 4.5, a member of the E3 ubiquitin ligase effector family, targets the proteasome regulatory particle non-ATPase 13 (RPN13) and induces its degradation via the ubiquitin-proteasome system (UPS). IpaH4.5-mediated RPN13 degradation causes dysfunction of the 19S regulatory particle (RP) in the 26S proteasome, inhibiting guidance of ubiquitinated proteins to the proteolytically active 20S core particle (CP) of 26S proteasome and thereby suppressing proteasome-catalysed peptide splicing. This, in turn, reduces antigen cross-presentation to CD8+ T cells via major histocompatibility complex (MHC) class I in vitro. In RPN13 knockout mouse embryonic fibroblasts (MEFs), loss of RPN13 suppressed CD8+ T cell priming during Shigella infection. Our results uncover the unique tactics employed by Shigella to dampen the antigen-specific cytotoxic T lymphocyte (CTL) response.

Porphyromonas gingivalis triggers NLRP3-mediated inflammasome activation in macrophages in a bacterial gingipains-independent manner.

Porphyromonas gingivalis is a Gram-negative anaerobic bacterium that has been considered to be one of the bacteria associated with progression of human periodontitis. Subgingival biofilms formed by bacteria, including P. gingivalis, induce chronic inflammation, and activation of inflammasome in the gingival tissue. However, the mechanisms of P. gingivalis-triggering inflammasome activation and the role of bacteria-host interactions are controversial. In this study, we investigated the potential of P. gingivalis for triggering inflammasome activation in human cells and mouse models. We demonstrated that secreted or released factors from bacteria are involved in triggering NLR family, pyrin-domain containing 3 protein (NLRP3) inflammasome in a gingipain-independent manner. Our data indicated that released active caspase-1 and mature IL-1ß are eliminated by proteolytic activity of secreted gingipains. These results elucidate the molecular bases for the mechanisms underlying P. gingivalis-triggered inflammasome activation.

Ozone ultrafine bubble water induces the cellular signaling involved in oxidative stress responses in human periodontal ligament fibroblasts.

Periodontitis is a chronic inflammatory disease caused by oral microorganisms in the subgingival biofilm. Stable aqueous ozone ultrafine bubble water (OUFBW) has recently begun to be used as an antiseptic in the treatment of periodontitis. The effectiveness of OUFBW is thought to depend on the bactericidal actions of dissolved ozone exerted via its oxidizing effect. On the other hand, the effects of ozone on the periodontal tissues are largely unknown. In this paper we examined the cellular responses after OUFBW treatment. Human primary periodontal ligament fibroblasts (hPDLFs) or Ca9-22 human gingival epithelial cells were treated with OUFBW or UV-inactivated OUFBW. The production of reactive oxygen species (ROS), the activation of mitogen-activated protein kinase (MAPK) and the nuclear factor-kappa B (NF-κB) activation were analyzed. The transcript profiles of hPDLFs after OUFBW treatment were also analyzed by RNA sequencing (RNA-seq). Our results showed that OUFBW induces oxidative stress by generating ROS, which, in turn, activated the MAPK pathway. OUFBW triggered activation of c-Fos, a major component of the transcription factor activator protein 1 (AP-1), and also nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), which possessed a high sensitivity to oxidative stress. The results of RNA-seq analysis revealed that the numerous genes involved in oxidative stress responses or MAPK signaling pathway were up-regulated after OUFBW treatment. Investigation of the signaling pathways activated by OUFBW highlights another aspect of the biological roles of OUFBW, in addition to its bactericidal activity, in the treatment of periodontitis.

Shigella hacks host immune responses by reprogramming the host epigenome.

Bacterial pathogens alter host transcriptional programs to promote infection. Shigella OspF is an essential virulence protein with a unique phosphothreonine lyase activity. A new study in The EMBO Journal (Harouz et al, 2014) reveals a novel function of OspF: targeting of heterochromatin protein 1γ (HP1γ) and downregulation of a subset of immune genes. These results illustrate how bacterial pathogens exploit epigenetic modifications to counteract host immune responses.

Executive control and faithfulness: only long-term romantic relationships require prefrontal control.

Individuals in the early stages of a romantic relationship generally express intense passionate love toward their partners. This observation allows us to hypothesize that the regulation of interest in extra-pair relationships by executive control, which is supported by the function of the prefrontal cortex, is less required in individuals in the early stages of a relationship than it is in those who are in a long-term relationship. To test this hypothesis, we asked male participants in romantic relationships to perform a go/no-go task during functional magnetic resonance imaging (fMRI), which is a well-validated task that can measure right ventrolateral prefrontal cortex (VLPFC) activity implicated in executive control. Subsequently, the participants engaged in a date-rating task in which they rated how much they wanted to date unfamiliar females. We found that individuals with higher right VLPFC activity better regulated their interest in dates with unfamiliar females. Importantly, this relationship was found only in individuals with long-term partners, but not in those with short-term partners, indicating that the active regulation of interest in extra-pair relationships is required only in individuals in a long-term relationship. Our findings extend previous findings on executive control in the maintenance of monogamous relationships by highlighting the role of the VLPFC, which varies according to the stage of the romantic relationship.

The Shigella flexneri effector OspI deamidates UBC13 to dampen the inflammatory response.

Many bacterial pathogens can enter various host cells and then survive intracellularly, transiently evade humoral immunity, and further disseminate to other cells and tissues. When bacteria enter host cells and replicate intracellularly, the host cells sense the invading bacteria as damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) by way of various pattern recognition receptors. As a result, the host cells induce alarm signals that activate the innate immune system. Therefore, bacteria must modulate host inflammatory signalling and dampen these alarm signals. How pathogens do this after invading epithelial cells remains unclear, however. Here we show that OspI, a Shigella flexneri effector encoded by ORF169b on the large plasmid and delivered by the type ΙΙΙ secretion system, dampens acute inflammatory responses during bacterial invasion by suppressing the tumour-necrosis factor (TNF)-receptor-associated factor 6 (TRAF6)-mediated signalling pathway. OspI is a glutamine deamidase that selectively deamidates the glutamine residue at position 100 in UBC13 to a glutamic acid residue. Consequently, the E2 ubiquitin-conjugating activity required for TRAF6 activation is inhibited, allowing S. flexneri OspI to modulate the diacylglycerol-CBM (CARD-BCL10-MALT1) complex-TRAF6-nuclear-factor-κB signalling pathway. We determined the 2.0 Å crystal structure of OspI, which contains a putative cysteine-histidine-aspartic acid catalytic triad. A mutational analysis showed this catalytic triad to be essential for the deamidation of UBC13. Our results suggest that S. flexneri inhibits acute inflammatory responses in the initial stage of infection by targeting the UBC13-TRAF6 complex.

Front-Presented Looming Sound Selectively Alters the Perceived Size of a Visual Looming Object.

In spite of accumulating evidence for the spatial rule governing cross-modal interaction according to the spatial consistency of stimuli, it is still unclear whether 3D spatial consistency (i.e., front/rear of the body) of stimuli also regulates audiovisual interaction. We investigated how sounds with increasing/decreasing intensity (looming/receding sound) presented from the front and rear space of the body impact the size perception of a dynamic visual object. Participants performed a size-matching task (Experiments 1 and 2) and a size adjustment task (Experiment 3) of visual stimuli with increasing/decreasing diameter, while being exposed to a front- or rear-presented sound with increasing/decreasing intensity. Throughout these experiments, we demonstrated that only the front-presented looming sound caused overestimation of the spatially consistent looming visual stimulus in size, but not of the spatially inconsistent and the receding visual stimulus. The receding sound had no significant effect on vision. Our results revealed that looming sound alters dynamic visual size perception depending on the consistency in the approaching quality and the front-rear spatial location of audiovisual stimuli, suggesting that the human brain differently processes audiovisual inputs based on their 3D spatial consistency. This selective interaction between looming signals should contribute to faster detection of approaching threats. Our findings extend the spatial rule governing audiovisual interaction into 3D space.

Evidence of spawning by hermaphroditic skipjack tuna Katsuwonus pelamis.

Hermaphroditic gonads were collected from three skipjack tuna Katsuwonus pelamis in the western and central Pacific Ocean. Both ovarian and testicular tissues were found in the same gonad lobe for each of the three fish. Histological sections of the hermaphroditic gonad from one K. pelamis showed postovulatory follicles, which is evidence of spawning.

Implicit attitudes and executive control interact to regulate interest in extra-pair relationships.

Do we actively maintain monogamous relationships by force of will, or does monogamy flow automatically? During functional magnetic resonance imaging (fMRI), male participants in a romantic relationship performed the Implicit Association Test (IAT) to evaluate implicit attitudes toward adultery and a go/no-go task to measure prefrontal activity implicated in explicit executive control. Subsequently, they were engaged in a date-rating task in which they rated how much they wanted to date unfamiliar females. We found that the individuals with higher prefrontal activity during go/no-go task could regulate the interest for dates with unattractive females; moreover, the individuals with both a stronger negative attitude toward adultery and higher prefrontal activity could regulate their interest for dates with attractive females, and such individuals tended to maintain longer romantic relationships with a particular partner. These results indicate that regulation of amorous temptation via monogamous relationship is affected by the combination of automatic and reflective processes.

Shigella IpaH7.8 E3 ubiquitin ligase targets glomulin and activates inflammasomes to demolish macrophages.

When nucleotide-binding oligomerization domain-like receptors (NLRs) sense cytosolic-invading bacteria, they induce the formation of inflammasomes and initiate an innate immune response. In quiescent cells, inflammasome activity is tightly regulated to prevent excess inflammation and cell death. Many bacterial pathogens provoke inflammasome activity and induce inflammatory responses, including cell death, by delivering type III secreted effectors, the rod component flagellin, and toxins. Recent studies indicated that Shigella deploy multiple mechanisms to stimulate NLR inflammasomes through type III secretion during infection. Here, we show that Shigella induces rapid macrophage cell death by delivering the invasion plasmid antigen H7.8 (IpaH7.8) enzyme 3 (E3) ubiquitin ligase effector via the type III secretion system, thereby activating the NLR family pyrin domain-containing 3 (NLRP3) and NLR family CARD domain-containing 4 (NLRC4) inflammasomes and caspase-1 and leading to macrophage cell death in an IpaH7.8 E3 ligase-dependent manner. Mice infected with Shigella possessing IpaH7.8, but not with Shigella possessing an IpaH7.8 E3 ligase-null mutant, exhibited enhanced bacterial multiplication. We defined glomulin/flagellar-associated protein 68 (GLMN) as an IpaH7.8 target involved in IpaH7.8 E3 ligase-dependent inflammasome activation. This protein originally was identified through its association with glomuvenous malformations and more recently was described as a member of a Cullin ring ligase inhibitor. Modifying GLMN levels through overexpression or knockdown led to reduced or augmented inflammasome activation, respectively. Macrophages stimulated with lipopolysaccharide/ATP induced GLMN puncta that localized with the active form of caspase-1. Macrophages from GLMN(+/-) mice were more responsive to inflammasome activation than those from GLMN(+/+) mice. Together, these results highlight a unique bacterial adaptation that hijacks inflammasome activation via interactions between IpaH7.8 and GLMN.

Attentional cueing induces false memory.

The fluency of stimulus processing significantly contributes to recognition memory judgments. We investigated the effect of processing fluency induced by attentional cueing on recognition judgments. Participants performed a Remember/Know recognition test, while their spatial attention was manipulated in the test session. Stimulus location was either predicted (congruent condition) or unpredicted (incongruent condition) using an arrow cue. The results revealed that familiarity-based false recognition increased in the incongruent condition wherein the participants may have attributed part of the perceived disfluency to the attentional cue, and they may have overestimated the fluency for the stimulus, leading to increased false recognition. However, in the congruent condition, the participants may have attributed some parts of the perceived fluency to the attentional cue and underestimated the fluency for the stimulus, leading to decreased false recognition. In sum, stimulus-irrelevant attentional cueing induces unintentional processing about the source of fluency and biases recognition memory.

Shigella IpaH0722 E3 ubiquitin ligase effector targets TRAF2 to inhibit PKC-NF-κB activity in invaded epithelial cells.

NF-κB plays a central role in modulating innate immune responses to bacterial infections. Therefore, many bacterial pathogens deploy multiple mechanisms to counteract NF-κB activation. The invasion of and subsequent replication of Shigella within epithelial cells is recognized by various pathogen recognition receptors as pathogen-associated molecular patterns. These receptors trigger innate defense mechanisms via the activation of the NF-κB signaling pathway. Here, we show the inhibition of the NF-κB activation by the delivery of the IpaH E3 ubiquitin ligase family member IpaH0722 using Shigella's type III secretion system. IpaH0722 dampens the acute inflammatory response by preferentially inhibiting the PKC-mediated activation of NF-κB by ubiquitinating TRAF2, a molecule downstream of PKC, and by promoting its proteasome-dependent degradation.

Manipulation of the host cell death pathway by Shigella.

Host cells deploy multiple defences against microbial infection. One prominent host defence mechanism, the death of infected cells, plays a pivotal role in clearing damaged cells, eliminating pathogens, removing replicative niches, exposing intracellular bacterial pathogens to extracellular immune surveillance and presenting bacteria-derived antigens to the adaptive immune system. Although cell death can occur under either physiological or pathophysiological conditions, it acts as an innate defence mechanism against bacterial pathogens by limiting their persistent colonization. However, many bacterial pathogens, including Shigella, have evolved mechanisms that manipulate host cell death for their own benefit.