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Herrmann, B.

Publications and source records attributed to Herrmann, B..

At least 19 recordsLinked to original sources

The Listening Effort Profile of Eye Movements: Easy, Difficult, and Impossible Speech Comprehension

Speech comprehension in noisy environments often requires cognitive effort, but listeners may disengage when comprehension becomes impossible. Eye movements have recently emerged as a promising new measure of listening effort, but it remains unclear whether eye movements are sensitive to the full effort profile across easy, difficult, and impossible speech comprehension. Across four experiments, participants listened to sentences at easy, difficult, and impossible levels of multi-talker background babble while pupil size and eye movements were recorded. Pupil size generally followed the expected inverted u-shaped effort profile: low for easy speech, maximal for difficult but still intelligible speech and lower again for impossible speech, although this pattern partly reflected sustained, condition-specific differences and not only sentence-evoked responses. Gaze dispersion - measuring the spread of eye movements - decreased with high temporal selectivity during difficult relative to easy and impossible speech, indicating reduced eye movements during active, effortful listening. However, gaze dispersion was also lower, but less temporally selective, during impossible compared to easy listening, especially in non-baseline-corrected analyses, suggesting that reduced eye movements do not index listening effort uniquely. Instead, eye movements appear to reflect both attentional engagement during difficult listening and disengagement or inward attention when meaningful listening is no longer possible. These findings indicate that pupil size and eye movements provide complementary indices of listening-related cognition, and highlight the integration of listening, cognition, and motor systems.

neuroscience↗

Altered Tonsillar Microbiome in Children with Down Syndrome and Obstructive Sleep Apnea

Background and ObjectivesChildren with Down syndrome (DS) have a high prevalence of obstructive sleep apnea (OSA) due to anatomic, neuromuscular, immunological and metabolic factors, yet the contribution of the tonsillar microbiome to airway obstruction in this population remains unexplored. We hypothesized that DS-associated OSA would be associated with a distinct tonsillar microbiome compared to non-DS OSA. MethodsTonsillar tissue from 22 DS and 18 NDS participants were analyzed by 16S rRNA sequencing. Alpha and beta diversity were assessed using Faiths phylogenetic diversity and UniFrac distances, respectively, and significantly different taxa were identified with ANCOM-BC and Mann-Whitney testing. ResultsAlthough overall microbial richness and community structure were similar between groups, overweight DS participants demonstrated increased phylogenetic diversity compared to normal-weight DS peers. Taxonomic profiling of the entire patient cohort revealed that in DS tonsils there were selective alterations in key genera with selective depletion of Haemophilus and enrichment of Staphylococcus, Rothia, and Lactobacillales. Haemophilus abundance correlated positively with tonsil weight in both cohorts. ConclusionsThese findings suggest that while global diversity is preserved, specific microbial shifts distinguish the DS tonsillar niche, potentially reflecting altered immune and metabolic environments associated with trisomy 21. Understanding these microbial differences may reveal mechanisms underlying the higher incidence and persistence of OSA in DS and inform targeted therapeutic strategies.

microbiology↗

Attentional disengagement during external and internal distractions reduces neural speech tracking in background noise

Within-situation disengagement - the mental withdrawal during conversations in acoustically challenging environments - is a common experience of older people with hearing difficulties. Yet, most research on the neural mechanisms of attentional disengagement from speech listening has focused on the distraction by one competing speaker, whereas within-situation disengagement is often characterized by distraction towards external visual stimuli or internal thoughts and occurs in situations with ambient, multi-talker background masking. Across three electroencephalography (EEG) experiments in human participants of either sex, the current study examined how disengagement due to external and internal distractions affect the neural tracking of speech masked by different levels of multi-talker babble (speech in quiet, +6 dB, and -3 dB SNR). We observed enhanced early neural responses (<0.2 s) to the speech envelope for speech masked by background babble compared to speech in quiet (Experiments 1-3), suggesting stochastic facilitation. Importantly, neural tracking of the speech envelope was reduced when individuals were distracted by a visual-stimulus stream (Experiment 2) and by internal thought and imagination (Experiment 3). There were some indices suggesting the greatest disengagement-related decline in neural speech tracking occurs for the most difficult speech-masking condition, but this was not consistent across all measures. The current data show that disengagement due to external and internal distractions yield decreases in neural speech tracking, potentially suggesting converging neural pathways through which gain is downregulated in auditory cortex. These results indicate that disengagement from listening can be identified through non-invasive neural measures. SignificanceMany older adults with hearing difficulties mentally "tune out" during conversations in noisy environments, yet the neural mechanisms underlying this within-situation disengagement remain poorly understood. Across three electroencephalography experiments, we examined how external (visual) and internal (thought-based) distractions influence neural tracking of speech masked by multi-talker babble. We observed that attentional disengagement - whether induced by external stimuli or internal thoughts - reduced the brains tracking of the speech envelope. These findings demonstrate that listening disengagement can be objectively identified through neural measures and suggest a convergence in neural pathways through which both external and internal distractions down-regulate auditory gain, providing new insight into attentional control in challenging listening conditions.

neuroscience↗

Mobile Eye-Tracking Glasses Capture Ocular and Head Markers of Listening Effort

To extend the assessment of listening effort beyond a sound booth, we validated mobile eye-tracking glasses (Pupil Labs Neon) by comparing them to a stationary system (Eyelink DUO) in a controlled environment. We recorded eye movements, pupil size, and head movements from 26 young adults during a speech-in-noise task. When listening conditions became challenging, we observed reduced gaze dispersion and increased pupil sizes of similar magnitude from both devices, in addition to reduced head movements recorded solely by the mobile device. These findings suggest that mobile eye-trackers reliably capture listening effort, paving the path towards assessments in daily settings.

neuroscience↗

Neural signatures of engagement and event segmentation during story listening in background noise

Speech in everyday life is often masked by background noise, making comprehension effortful. Characterizing brain activity patterns when individuals listen to masked speech can help clarify the mechanisms underlying such effort. However, most previous research has focused on neural activity related to short, disconnected sentences that little resemble the more continuous, story-like spoken speech individuals typically encounter. In the current study, we used functional magnetic resonance imaging (fMRI) in humans (both sexes) to investigate how neural signatures of story listening change in the presence of masking by 12-talker babble noise. We show that, as speech masking increases, spatial and temporal activation patterns in auditory regions become more idiosyncratic to each listener. In contrast, spatial (and to some extent temporal) activity patterns in brain networks linked to effort (e.g. cinguloopercular network involving the anterior insula and anterior cingulate) are more similar across listeners when speech is highly masked and less intelligible, suggesting shared neural processes. Moreover, at times during stories when one meaningful event ended and another began, neural activation increased over extensive regions in frontal, parietal, and medial cortices. This event-boundary response appeared little affected by background noise, suggesting that listeners process meaningful units and, in turn, the gist in naturalistic, continuous speech even when it is masked somewhat by background noise. Overall, the current data may indicate that people stay engaged and cognitive processes associated with naturalistic speech processing remain intact under moderate levels of background noise, whereas auditory processing becomes more idiosyncratic to each listener. Significance statementThis functional imaging study investigates how neural signatures of story listening change in the presence of masking multi-talker babble noise. We show that, as speech masking increases, auditory activity patterns become more idiosyncratic to each listener. Spatial activation patterns in effort-related regions (anterior insula, cingulate) become more similar across listeners when speech is strongly masked, indicating shared neural representations. Neural activation also increased at times when one meaningful story event ended and another began. This event-boundary response appeared little affected by moderate levels of background noise, suggesting that listeners process meaningful units in continuous speech even as background babble reduces speech intelligibility. The data indicate that many cognitive processes associated with listening to spoken stories remain intact under background noise.

neuroscience↗

Targeted sex ratio distortion in the mouse

In animal breeding, female or male progeny is preferred depending on the use of the animals. Especially in livestock, offspring with undesired sex is of low economic value and often culled. Here we achieve targeted sex ratio distortion in the mouse, leveraging components of a selfish supergene, the t-haplotype. Utilizing its central element, the t-responder, we generate a highly "selfless" genetic element disabling transgenic sperm. When integrated on the X or Y chromosome it results in a high prevalence of non-transgenic offspring of the desired sex. Our strategy overcomes key limitations of existing strategies, including compromised animal health, reduced fertility, and fully transgenic breeding stocks, which might foster acceptance of its application to livestock. The efficacy of our approach marks a groundbreaking advancement in animal breeding. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=130 HEIGHT=200 SRC="FIGDIR/small/660540v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1b11374org.highwire.dtl.DTLVardef@742ec5org.highwire.dtl.DTLVardef@1aaafc0org.highwire.dtl.DTLVardef@f87dac_HPS_FORMAT_FIGEXP M_FIG C_FIG Transgene integration on X or Y chromosome affects the motility of transgenic sperm resulting in a strong sex-bias towards non-transgenic/wildtype offspring. Application to livestock can reduce unwanted progeny and transform farm animal breeding.

genetics↗

Eye movements of younger and older adults decrease during story listening in background noise

Assessments of listening effort are increasingly relevant to understanding the speech-comprehension difficulties experienced by older adults. Pupillometry is the most common tool to assess listening effort but has limitations. Recent research has shown that eye movements decrease when listening is effortful and proposed indicators of eye movements as alternative measures. However, much of the work was conducted in younger adults in trial-based sentence-listening paradigm, during concurrent visual stimulation. The extent to which eye movements index listening effort during con tinuous speech listening, independently of visual stimuli, and in older adults, is unknown. In the current study, younger and older adults listened to continuous stories with varying degrees of background noise under free and moving-dot viewing conditions. Eye movements decreased (as indexed by fixation duration, gaze dispersion, and saccade rate) with increasing speech masking. The reduction in eye movements did not depend on age group or viewing conditions, indicating that eye movements can be used to assess effects of speech masking in different visual situations and in people of different ages. The pupil area was only sensitive to speech masking early in the experiment. In sum, the current study suggests that eye movements are a potential tool to assess listening effort during continuous speech listening.

neuroscience↗

Intracochlear pressure measurements quantify overall noise exposure to the inner ear during mastoidectomy

IntroductionThe acoustic trauma patients are exposed to during otologic surgery is unclear, as previous studies have not captured the effects of vibrational noise on the inner ear. To fill this knowledge gap, we examined inner ear noise directly via intracochlear pressure changes during a mastoidectomy and cochleostomy. MethodsInner ear stimulation was measured using fiber optic pressure sensors inserted into the cochlea of cadaveric heads using a trans-canal approach. A tympanomeatal flap was elevated, cochleostomies were made into scala vestibuli and tympani, and sensors placed and secured to the cochlear promontory, and the flap resecured. Intracochlear pressures were measured with different drill bits, speeds, and during mastoidectomy and cochleostomy. The equivalent sound pressure level in the ear canal (LEq) was calculated using the middle ear transfer function. Microphones were also placed in the surgeons ear, cadaver ear, and approximately three feet away. ResultsResults show sound pressure levels that could exceed 120 dBA (A-weighted dB SPL LEq), with the highest levels observed during cochleostomy. Results showed broad band exposure, with a distinct peak at 1.33 kHz during the 80k RPM drill speed. Importantly, SPLs in the surgeons ear did not always predict patient noise exposure. ConclusionSurgically induced cochlear noise revealed levels high enough to potentially induce acoustic trauma, and sometimes at frequencies that may cause hearing loss not captured by a traditional audiogram (i.e. 1.33 kHz). This data characterizes surgical noise exposures, and will lead to permissible noise exposure guidelines and durations for both patients and surgeons.

bioengineering↗

Reduced neural sensitivity to musical tempo despite enhanced neural tracking of musical features in older adults

A substantial body of prior research has focused on how aging affects the neural processing of speech, whereas less is known about how older adults encode naturalistic music. Here, we investigated whether the neural tracking of different features in naturalistic music differs between age groups. Younger and older adults (both sexes) listened to excerpts of naturalistic music with different tempi (1-4 Hz) while electroencephalography (EEG) was recorded. The results show an age-related enhancement of neural responses to sound onsets, suggesting a loss of inhibition in the aged auditory cortex that is thought to arise from peripheral decline. This hyperresponsiveness generalized to the neural tracking of multiple features (amplitude envelope, onsets, beat, and spectral flux) in naturalistic music. Crucially, older adults showed reduced sensitivity of early brain responses (0-130 ms) to tempo: Unlike younger adults, whose neural tracking decreased systematically with increasing tempo, older listeners maintained uniformly enhanced tracking across tempi. Spectral flux best predicted tempo- related changes in EEG activity, but this was reduced in older compared to younger adults. In sum, the current study demonstrates that cortical hyperactivity in aging enhances the tracking of different features during naturalistic music listening but impairs the sensitivity to musical tempo. This dissociation highlights the complex changes and functional consequences of auditory aging related to the processing of naturalistic music. SIGNIFICANCE STATEMENTHow aging affects the encoding of ecologically-valid, naturalistic music is not well understood, although music is an important part of older peoples lives. Here, we used electroencephalography and temporal response function approaches to investigate how younger and older adults encode different features of naturalistic music at different tempi (1 to 4 Hz). The results reveal a fundamental trade-off in the aging auditory system: enhanced neural tracking of acoustic features coexists with declined sensitivity to musical tempo. This dissociation between hyperactivity for feature encoding and impaired temporal sensitivity highlights complex changes in the aged auditory system that can have implications for music perception in older adulthood.

neuroscience↗

Acquisition of ampliconic sequences marks a selfish mouse t-haplotype

Mendelian genetics posits equal transmission of alleles, but selfish alleles can bias the transmission of large genomic regions or entire chromosomes1-4. One long-standing question is how transmission bias evolves to encompass large genomic regions. Mus musculus (house mouse) t-haplotypes exhibit up to 99% transmission bias from heterozygous males5-14 and harbor selfish alleles9-14 genetically linked to large inversions spanning the proximal half of chromosome 1715-20. Here, by generating a high-quality, single-haplotype assembly of a t- haplotype, we reveal the evolution of eight large amplicons with known11,13,21 and candidate selfish alleles as a distinct genetic feature. Three amplicons are conserved in closely related Mus species, and two have known selfish alleles in the oldest inversion, implicating amplicons and an inversion drove the origins of a selfish chromosome 17 [~]3MYA. The remaining t- haplotype amplicons harbor gene families expressed predominantly in haploid spermatids, newly acquired retrogenes, and the most differentially expressed genes in wild-type/t-haplotype spermatids. Targeted deletion of a [~]1.8Mb amplicon with candidate selfish alleles on the t- haplotype reduces selfish transmission in heterozygous males by 3%. Notably, the evolution of selfish allele-containing amplicons and inversions on the t-haplotype parallels mammalian sex chromosome evolution as signatures of selfish transmission. We propose amplicon acquisition and large inversions initiate evolutionary arms races between selfish haplotypes and serve as genome-wide signatures of selfish transmission.

genetics↗

Enhanced Neural Speech Tracking in Aging and Hearing Loss: The Role of Stochastic Resonance

Tracking the envelope of speech in the brain is important for speech comprehension. Recent research suggests that acoustic background noise can enhance neural speech tracking, enabling the auditory system to robustly encode speech even under unfavorable conditions. Aging and hearing loss are associated with internal, neural noise in the auditory system, raising the question whether additional acoustic background noise enhances neural speech tracking in older adults. In the current electroencephalography study, younger ([~]25.5 years) and older adults ([~]68.5 years) listened to spoken stories in quiet (clear) or in the presence of background noise at a wide range of different signal-to-noise ratios. In younger adults, early neural speech tracking responses (<0.15 s) were enhanced by minimal background noise, indicating response facilitation through noise. In contrast, older adults, compared to younger adults, showed enhanced neural speech tracking for clear speech and speech masked by minimal background noise, but the acoustic noise led to little enhancement of the early neural tracking response in older people. The data demonstrate different sensitivity of the auditory cortex to speech masked by noise between younger and older adults. The results are consistent with the idea that the auditory cortex of older people exhibits more internal, neural noise that enhances neural speech tracking but that additional acoustic noise does not further support speech encoding. The work points to a highly non-linear auditory system that differs between younger and older adults.

neuroscience↗

Minimal background noise enhances neural speech tracking: Evidence of stochastic resonance

Neural activity in auditory cortex tracks the amplitude-onset envelope of continuous speech, but recent work counter-intuitively suggests that neural tracking increases when speech is masked by background noise, despite reduced speech intelligibility. Noise-related amplification could indicate that stochastic resonance - the response facilitation through noise - supports neural speech tracking, but a comprehensive account is lacking. In five human electroencephalography (EEG) experiments, the current study demonstrates a generalized enhancement of neural speech tracking due to minimal background noise. Results show that a) neural speech tracking is enhanced for speech masked by background noise at very high SNRs ([~]30 dB SNR) where speech is highly intelligible; b) this enhancement is independent of attention; c) it generalizes across different stationary background maskers, but is strongest for 12-talker babble; and d) it is present for headphone and free-field listening, suggesting that the neural-tracking enhancement generalizes to real-life listening. The work paints a clear picture that minimal background noise enhances the neural representation of the speech onset-envelope, suggesting that stochastic resonance contributes to neural speech tracking. The work further highlights non-linearities of neural tracking induced by background noise that make its use as a biological marker for speech processing challenging.

neuroscience↗

Neurophysiology of effortful listening: Decoupling motivational modulation from task demands

In demanding listening situations, a listeners motivational state may affect their cognitive investment. Here, we aim to delineate how domain-specific sensory processing, domain-general neural alpha power, and pupil size as a proxy for cognitive investment encode influences of motivational state under demanding listening. Participants performed an auditory gap-detection task while pupil size and the magnetoencephalogram (MEG) were simultaneously recorded. Task demand and a listeners motivational state were orthogonally manipulated through changes in gap duration and monetary-reward prospect, respectively. Whereas task difficulty impaired performance, reward prospect enhanced it. Pupil size reliably indicated the modulatory impact of an individuals motivational state. At the neural level, the motivational state did not affect auditory sensory processing directly but impacted attentional post-processing of an auditory event as reflected in the late evoked-response field and alpha power change. Both pre-gap pupil dilation and higher parietal alpha power predicted better performance at the single-trial level. The current data support a framework wherein the motivational state acts as an attentional top-down neural means of post-processing the auditory input in challenging listening situations. Significance StatementHow does an individuals motivational state affect cognitive investment during effortful listening? In this simultaneous pupillometry and MEG study, participants performed an auditory gap-detection task while their motivational state was manipulated through varying prospect of a monetary reward. The pupil size directly mirrored this motivational modulation of the listening demand. The individuals motivational state also enhanced top-down attentional post-processing of the auditory event but did neither change auditory sensory processing nor pre-gap parietal alpha power. These data suggest that a listeners motivational state acts as a late attentional top-down effect on auditory neural processes in challenging listening situations.

neuroscience↗

Pupil size and eye movements differently index effort in both younger and older adults

The assessment of mental effort is increasingly relevant in neuro-cognitive and lifespan domains. Pupillometry, the measure of the pupil size, is often used to assess effort but has disadvantages. Analysis of eye movements may provide an alternative, but research has been limited to easy and difficult task demands in younger adults. An effort measure must be sensitive to the whole effort profile, including giving up effort investment, and capture effort in different age groups. The current study comprised three experiments in which younger (N=66) and older adults (N=44) listened to speech masked by background babble at different signal-to-noise ratios associated with easy, difficult, and impossible speech comprehension. We expected individuals to invest little effort for easy and impossible speech ( giving up) but to exert effort for difficult speech. Indeed, pupil size was largest for difficult, but lower for easy and impossible speech. In contrast, gaze dispersion decreased with increasing speech masking in both age groups. Critically, gaze dispersion during difficult speech returned to levels similar to easy speech after sentence offset, when acoustic stimulation was similar across conditions, whereas gaze dispersion during impossible speech continued to be reduced. These findings show that a reduction in eye movements is not a byproduct of acoustic factors, but instead suggest that neuro-cognitive processes, different from arousal-related systems regulating the pupil size, drive reduced eye movements during high task demands. The current data thus show that effort in one sensory domain (audition) differentially impacts distinct functional properties in another sensory domain (vision). Significance statementThe assessment of mental effort is increasingly relevant in many domains. Here, we investigated the sensitivity of a novel measure of effort - the spatial dispersion of eye movements - and compared it to pupillometry, which is a more common effort-assessment tool. Individuals listened to speech masked by background babble at levels associated with easy, difficult, and impossible speech comprehension. Pupil size was largest for difficult, but lower for easy and impossible speech conditions (giving up listening). In contrast, the spatial dispersion of eye movements decreased with increasing speech masking, but this effect was independent of acoustic factors. Instead, the current results suggest that neuro-cognitive processes, different from arousal-related systems regulating the pupil size, drive reduced eye movements during high task demands.

neuroscience↗

Reliability and generalizability of neural speech tracking in younger and older adults

Neural tracking of continuous, spoken speech is increasingly used to examine how the brain encodes speech and is considered a potential clinical biomarker, for example, for age-related hearing loss. A biomarker must be reliable (intra-class correlation [ICC] >0.7), but the reliability of neural-speech tracking is unclear. In the current study, younger and older adults (different genders) listened to stories in two separate sessions while electroencephalography (EEG) was recorded in order to investigate the reliability and generalizability of neural speech tracking. Neural speech tracking was larger for older compared to younger adults for stories under clear and background noise conditions, consistent with a loss of inhibition in the aged auditory system. For both age groups, reliability for neural speech tracking was lower than the reliability of neural responses to noise bursts (ICC >0.8), which we used as a benchmark for maximum reliability. The reliability of neural speech tracking was moderate (ICC [~]0.5-0.75) but tended to be lower for younger adults when speech was presented in noise. Neural speech tracking also generalized moderately across different stories (ICC [~]0.5-0.6), which appeared greatest for audiobook-like stories spoken by the same person. This indicates that a variety of stories could possibly be used for clinical assessments. Overall, the current data provide results critical for the development of a biomarker of speech processing, but also suggest that further work is needed to increase the reliability of the neural-tracking response to meet clinical standards. Significance statementNeural speech tracking approaches are increasingly used in research and considered a biomarker for impaired speech processing. A biomarker needs to be reliable, but the reliability of neural speech tracking is unclear. The current study shows in younger and older adults that the neural-tracking response is moderately reliable (ICC [~]0.5-0.75), although more variable in younger adults, and that the tracking response also moderately generalize across different stories (ICC [~]0.5-0.6), especially for audiobook-like stories spoken by the same person. The current data provide results critical for the development of a biomarker of speech processing, but also suggest that further work is needed to increase the reliability of the neural-tracking response to meet clinical standards.

neuroscience↗

Pupil-size sensitivity to listening demand depends on motivational state

Motivation plays a role when a listener needs to understand speech under acoustically demanding conditions. Previous work has demonstrated pupil-linked arousal being sensitive to both listening demands and motivational state during listening. It is less clear how motivational state affects the temporal evolution of the pupil size and its relation to subsequent behavior. We used an auditory gap-detection task (N=33) to study the joint impact of listening demand and motivational state on the pupil-size response and examine its temporal evolution. Task difficulty and a listeners motivational state were orthogonally manipulated through changes in gap duration and monetary-reward prospect. We show that participants performance decreased with task difficulty, but that reward prospect enhanced performance under hard listening conditions. Pupil size increased with both increased task difficulty and higher reward prospect, and this reward-prospect effect was largest under difficult listening conditions. Moreover, pupil-size time courses differed between detected and missed gaps, suggesting that the pupil response indicates upcoming behavior. Larger pre-gap pupil size was further associated with faster response times on a trial-by-trial within-participant level. Our results reiterate the utility of pupil size as an objective and temporally sensitive measure in audiology. However, such assessments of cognitive-resource recruitment need to consider the individuals motivational state. Significance statementThe literature is inconclusive to what degree pupil size may be representing the interaction of listening task demand and an individuals motivational state. Using an auditory gap-detection task, we manipulated both the degree of listening demand and a persons motivational state, and investigated the temporal evolution of the pupil-size response and its relation to behavior. We find that the pupil size represents the interaction of demand and motivational state. These results highlight the importance of considering a persons motivational state when using pupil size as a clinical measure. Pupil size appears as a key tool when assessing the impact of motivational state on the recruiting of cognitive resources.

neuroscience↗

Blockade of IKK signaling induces RIPK1-independent apoptosis in human cells

Regulated cell death in response to microbial infection plays an important role in immune defense and is triggered by pathogen disruption of essential cellular pathways. Gramnegative bacterial pathogens in the Yersinia genus disrupt NF-{kappa}B signaling via translocated effectors injected by a type III secretion system (T3SS), thereby preventing induction of cytokine production and antimicrobial defense. In murine models of infection, Yersinia blockade of NF-{kappa}B signaling triggers cell-extrinsic apoptosis through Receptor Interacting Serine-Threonine Protein Kinase 1 (RIPK1) and caspase-8, which is required for bacterial clearance and host survival. Unexpectedly, we find that human macrophages undergo apoptosis independently of RIPK1 in response to Yersinia or chemical blockade of IKK/{beta}. Instead, IKK blockade led to decreased cFLIP expression, and overexpression of cFLIP contributed to protection from IKK blockade-induced apoptosis in human macrophages. Importantly, IKK blockade also induces RIPK1 kinase-independent apoptosis in human T cells and human pancreatic cells. Altogether, our data indicate that, in contrast to murine cells, blockade of IKK activity in human cells triggers a distinct apoptosis pathway that is independent of RIPK1. These findings have implications for the contribution of RIPK1 to cell death in humans and the efficacy of RIPK1 inhibition in human diseases.

immunology↗

A TNF-IL-1 circuit controls Yersinia within intestinal granulomas

SummaryMonocytes restrict Yersinia infection within intestinal granulomas. Here, we report that monocyte-intrinsic TNF signaling drives production of IL-1 that signals to non-hematopoietic cells to control intestinal Yersinia infection within granulomas. Tumor necrosis factor (TNF) is a pleiotropic inflammatory cytokine that mediates antimicrobial defense and granuloma formation in response to infection by numerous pathogens. Yersinia pseudotuberculosis colonizes the intestinal mucosa and induces recruitment of neutrophils and inflammatory monocytes into organized immune structures termed pyogranulomas that control the bacterial infection. Inflammatory monocytes are essential for control and clearance of Yersinia within intestinal pyogranulomas, but how monocytes mediate Yersinia restriction is poorly understood. Here, we demonstrate that TNF signaling in monocytes is required for bacterial containment following enteric Yersinia infection. We further show that monocyte-intrinsic TNFR1 signaling drives production of monocyte-derived interleukin-1 (IL-1), which signals through IL-1 receptor on non-hematopoietic cells to enable pyogranuloma-mediated control of Yersinia infection. Altogether, our work reveals a monocyte-intrinsic TNF-IL-1 collaborative circuit as a crucial driver of intestinal granuloma function, and defines the cellular target of TNF signaling that restricts intestinal Yersinia infection.

immunology↗