Adaptive immunity induces mutualism between commensal eukaryotes.

Pathogenic fungi reside in the intestinal microbiota but rarely cause disease. Little is known about the interactions between fungi and the immune system that promote commensalism. Here we investigate the role of adaptive immunity in promoting mutual interactions between fungi and host. We find that potentially pathogenic Candida species induce and are targeted by intestinal immunoglobulin A (IgA) responses. Focused studies on Candida albicans reveal that the pathogenic hyphal morphotype, which is specialized for adhesion and invasion, is preferentially targeted and suppressed by intestinal IgA responses. IgA from mice and humans directly targets hyphal-enriched cell-surface adhesins. Although typically required for pathogenesis, C. albicans hyphae are less fit for gut colonization1,2 and we show that immune selection against hyphae improves the competitive fitness of C. albicans. C. albicans exacerbates intestinal colitis3 and we demonstrate that hyphae and an IgA-targeted adhesin exacerbate intestinal damage. Finally, using a clinically relevant vaccine to induce an adhesin-specific immune response protects mice from C. albicans-associated damage during colitis. Together, our findings show that adaptive immunity suppresses harmful fungal effectors, with benefits to both C. albicans and its host. Thus, IgA uniquely uncouples colonization from pathogenesis in commensal fungi to promote homeostasis.

MicroRNA-23a Curbs Necrosis during Early T Cell Activation by Enforcing Intracellular Reactive Oxygen Species Equilibrium.

Upon antigen engagement, augmented cytosolic reactive oxygen species (ROS) are needed to achieve optimal T cell receptor (TCR) signaling. However, uncontrolled ROS production is a prominent cause of necrosis, which elicits hyper-inflammation and tissue damage. Hence, it is critical to program activated T cells to achieve ROS equilibrium. Here, we determined that miR-23a is indispensable for effector CD4(+) T cell expansion, particularly by providing early protection from excessive necrosis. Mechanistically, miR-23a targeted PPIF, gatekeeper of the mitochondria permeability transition pore, thereby restricting ROS flux and maintaining mitochondrial integrity. Upon acute Listeria monocytogenes infection, deleting miR-23a in T cells resulted in excessive inflammation, massive liver damage, and a marked mortality increase, which highlights the essential role of miR-23a in maintaining immune homeostasis.

Analysis of the Rab GTPase Interactome in Dendritic Cells Reveals Anti-microbial Functions of the Rab32 Complex in Bacterial Containment.

Dendritic cells (DCs) orchestrate complex membrane trafficking through an interconnected transportation network linked together by Rab GTPases. Through a tandem affinity purification strategy and mass spectrometry, we depicted an interactomic landscape of major members of the mammalian Rab GTPase family. When complemented with imaging tools, this proteomic analysis provided a global view of intracellular membrane organization. Driven by this analysis, we investigated dynamic changes to the Rab32 subnetwork in DCs induced by L. monocytogenes infection and uncovered an essential role of this subnetwork in controlling the intracellular proliferation of L. monocytogenes. Mechanistically, Rab32 formed a persistent complex with two interacting proteins, PHB and PHB2, to encompass bacteria both during early phagosome formation and after L. monocytogenes escaped the original containment vacuole. Collectively, we have provided a functional compartmentalization overview and an organizational framework of intracellular Rab-mediated vesicle trafficking that can serve as a resource for future investigations.

Cytomegalovirus (CMV) Reactivation and CMV-Specific Cell-Mediated Immunity After Chimeric Antigen Receptor T-Cell Therapy.

BACKGROUND: The epidemiology of cytomegalovirus (CMV) after chimeric antigen receptor-modified T-cell immunotherapy (CARTx) is poorly understood owing to a lack of routine surveillance. METHODS: We prospectively enrolled 72 adult CMV-seropositive CD19-, CD20-, or BCMA-targeted CARTx recipients and tested plasma samples for CMV before and weekly up to 12 weeks after CARTx. We assessed CMV-specific cell-mediated immunity (CMV-CMI) before and 2 and 4 weeks after CARTx, using an interferon γ release assay to quantify T-cell responses to IE-1 and pp65. We tested pre-CARTx samples to calculate a risk score for cytopenias and infection (CAR-HEMATOTOX). We used Cox regression to evaluate CMV risk factors and evaluated the predictive performance of CMV-CMI for CMV reactivation in receiver operator characteristic curves. RESULTS: CMV was detected in 1 patient (1.4%) before and in 18 (25%) after CARTx, for a cumulative incidence of 27% (95% confidence interval, 16.8-38.2). The median CMV viral load (interquartile range) was 127 (interquartile range, 61-276) IU/mL, with no end-organ disease observed; 5 patients received preemptive therapy based on clinical results. CMV-CMI values reached a nadir 2 weeks after infusion and recovered to baseline levels by week 4. In adjusted models, BCMA-CARTx (vs CD19/CD20) and corticosteroid use for >3 days were significantly associated with CMV reactivation, and possible associations were detected for lower week 2 CMV-CMI and more prior antitumor regimens. The cumulative incidence of CMV reactivation almost doubled when stratified by BCMA-CARTx target and use of corticosteroids for >3 days (46% and 49%, respectively). CONCLUSIONS: CMV testing could be considered between 2 and 6 weeks in high-risk CARTx recipients.

Heterogeneity in COVID-19 vaccine uptake within low-income minority communities: evidence from the watts neighborhood health study.

BACKGROUND: The literature on disparities in COVID-19 vaccine uptake focuses primarily on the differences between White versus non-White individuals or differences by socioeconomic status. Much less is known about disparities in vaccine uptake within low-income, minority communities and its correlates. METHODS: This study investigates disparities in COVID-19 vaccination uptake within racial and ethnic minoritized communities with similar socioeconomic backgrounds and built environments, specifically focusing on Black-Hispanic disparities and disparities within the Hispanic community by country of origin. Data are analyzed from the fourth wave (June 2021- May 2022) of the Watts Neighborhood Health Study, a cohort study of public housing residents in south Los Angeles, CA. Linear probability models estimated the association between vaccine uptake and participants' race/ethnicity, sequentially adding controls for sociodemographic characteristics, health care access and insurance, prior infection, and attitudes towards COVID-19 vaccines. Differences in reasons for vaccination status by race/ethnicity were also tested. RESULTS: Mexican Hispanic and non-Mexican Hispanic participants were 31% points (95% CI: 0.21, 0.41, p < 0.001) and 44% points (95% CI: 0.32, 0.56, p < 0.001) more likely to be vaccinated than non-Hispanic Black participants, respectively. The disparity between Black and Hispanic participants was reduced by about 40% after controlling for attitudes towards COVID-19 vaccines. Among Hispanic participants, non-Mexican participants were 13% points (95% CI: 0.03, 0.24, p = 0.01) more likely to be vaccinated than Mexican participants, however, these differences were no longer significant after controlling for individual and household characteristics (ß = 0.04, 95% CI: -0.07, 0.15, p = 0.44). CONCLUSION: There are sizeable racial and ethnic COVID-19 vaccination disparities even within low-income and minoritized communities. Accounting for this heterogeneity and its correlates can be critically important for public health efforts to ensure vaccine equity.

The cytokines IL-21 and GM-CSF have opposing regulatory roles in the apoptosis of conventional dendritic cells.

Interleukin-21 (IL-21) has broad actions on T and B cells, but its actions in innate immunity are poorly understood. Here we show that IL-21 induced apoptosis of conventional dendritic cells (cDCs) via STAT3 and Bim, and this was inhibited by granulocyte-macrophage colony-stimulating factor (GM-CSF). ChIP-Seq analysis revealed genome-wide binding competition between GM-CSF-induced STAT5 and IL-21-induced STAT3. Expression of IL-21 in vivo decreased cDC numbers, and this was prevented by GM-CSF. Moreover, repetitive α-galactosylceramide injection of mice induced IL-21 but decreased GM-CSF production by natural killer T (NKT) cells, correlating with decreased cDC numbers. Furthermore, adoptive transfer of wild-type CD4+ T cells caused more severe colitis with increased DCs and interferon-γ (IFN-γ)-producing CD4+ T cells in Il21r(-/-)Rag2(-/-) mice (which lack T cells and have IL-21-unresponsive DCs) than in Rag2(-/-) mice. Thus, IL-21 and GM-CSF exhibit cross-regulatory actions on gene regulation and apoptosis, regulating cDC numbers and thereby the magnitude of the immune response.

An intersectional approach to understanding LGBTQ+ people of color's access to LGBTQ+ community resilience.

Resiliency research suggests that connection to LGBTQ + communities helps mitigate the negative impacts of oppression (i.e., community resilience). However, due to various interlocking systems of oppression, those with multiple marginalized identities [i.e., LGBTQ + people of color (POC)] may not have equal access to LGBTQ + community resilience resources. Despite the growing body of literature, little research has explored LGBTQ + POC's experiences with the LGBTQ + community from an intersectional framework to critique systems of oppression and provide implications for social justice. Fourteen LGBTQ + POC participated in semistructured interviews to explore their experiences with protective factors of the LGBTQ + community and the barriers they face in accessing community resilience. Findings supported three broad categories with subthemes: (1) LGBTQ + Community Resilience Resources (i.e., Shared Narratives and Feeling Seen and Social Justice and Liberation), (2) Inequity to Accessing LGBTQ + Community Resilience (i.e., Alienation and Exclusion, Disempowerment and Exploitation, and Invisibility), and (3) Making Space. Utilizing our intersectional framework, we provide implications for social justice advocacy as well as clinical and educational implications for counseling psychologists and community organizations. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Simple method to extend the range of ECO-BB for waters with high backscattering coefficient.

The ECO-BB (Sea Bird Scientific) is a popular instrument used by water optics researchers to measure the backscattering coefficient of waters in the visible to near-infrared wavelengths. The ECO-BB is calibrated by default for oceanic waters where the backscattering coefficient is typically low. In inland and coastal waters however, there is a tendency for the ECO-BB to reach saturation due to the high number of suspended particles. In the paper, a simple method is presented to extend the range of the ECO-BB instrument in such waters using a nephelometric turbidimeter. The method was first tested on powdered calcium carbonate in pure freshwater, followed by collected water samples from the Singapore Straits and the Lupar River in Sarawak. All three tests confirm the correlation between the ECO-BB and turbidimeter and show that the turbidimeter is a good proxy for backscattering coefficient measurements in turbid waters.

Modeling the remote-sensing reflectance of highly turbid waters.

In ocean-color remote sensing, subsurface remote-sensing reflectance (r r s ) of optically deep waters can be linked to its absorption (a) and backscattering coefficients (b b ) by various models. The use of such models allows for quick calculations r r s from such coefficients, eliminating the need to solve the radiative transfer equation. In particular, r r s can be expressed as a function of bb/(a+bb). HydroLight and Monte Carlo simulations showed that commonly used models underestimate r r s in waters with high suspended sediment loads. Monte Carlo simulations confirmed that this issue is due to a sharp increase in multiple scattering events at high turbidity levels. A quartic polynomial model is derived relating r r s and inherent optical properties (IOPs) for waters of any turbidity, to avoid significant errors in waters of high turbidity.

Candida glabrata Binding to Candida albicans Hyphae Enables Its Development in Oropharyngeal Candidiasis.

Pathogenic mechanisms of Candida glabrata in oral candidiasis, especially because of its inability to form hyphae, are understudied. Since both Candida albicans and C. glabrata are frequently co-isolated in oropharyngeal candidiasis (OPC), we examined their co-adhesion in vitro and observed adhesion of C. glabrata only to C. albicans hyphae microscopically. Mice were infected sublingually with C. albicans or C. glabrata individually, or with both species concurrently, to study their ability to cause OPC. Infection with C. glabrata alone resulted in negligible infection of tongues; however, colonization by C. glabrata was increased by co-infection or a pre-established infection with C. albicans. Furthermore, C. glabrata required C. albicans for colonization of tongues, since decreasing C. albicans burden with fluconazole also reduced C. glabrata. C. albicans hyphal wall adhesins Als1 and Als3 were important for in vitro adhesion of C. glabrata and to establish OPC. C. glabrata cell wall protein coding genes EPA8, EPA19, AWP2, AWP7, and CAGL0F00181 were implicated in mediating adhesion to C. albicans hyphae and remarkably, their expression was induced by incubation with germinated C. albicans. Thus, we found a near essential requirement for the presence of C. albicans for both initial colonization and establishment of OPC infection by C. glabrata.

Optical coherence tomography angiography of the macula and optic nerve head: microvascular density and test-retest repeatability in normal subjects.

BACKGROUND: Despite the potential usefulness of optical coherence tomography angiography in retinal and optic disc conditions, the reliability of the imaging modality remains unclear. This study set out to measure the microvascular density of macula and optic disc by mean of optical coherence tomography angiography and report the repeatability of the vessel density measurements. METHODS: Cross sectional observational cohort study. Subjects with normal eyes were recruited. Two sets of optical coherence tomography angiography images of macula and optic nerve head were acquired during one visit. Novel in-house developed software was used to count the pixels in each images and to compute the microvessel density of the macula and optic disc. Data were analysed to determine the measurement repeatability. RESULTS: A total of 176 eyes from 88 consecutive normal subjects were recruited. For macular images, the mean vessel density at superficial retina, deep retina, outer retina and choriocapillaries segment was OD 0.113 and OS 0.111, OD 0.239 and OS 0.230, OD 0.179 and OS 0.164, OD 0.237 and OS 0.215 respectively. For optic disc images, mean vessel density at vitreoretinal interface, radial peripapillary capillary, superficial nerve head and disc segment at the level of choroid were OD 0.084 and OS 0.085, OD 0.140 and OS 0.138, OD 0.216 and OS 0.209, OD 0.227 and OS 0.236 respectively. The measurement repeatability tests showed that the coefficient of variation of macular scans, for right and left eyes, ranged from 6.4 to 31.1% and 5.3 to 59.4%. Likewise, the coefficient of variation of optic disc scans, for right and left eyes, ranged from 14.3 to 77.4% and 13.5 to 75.3%. CONCLUSIONS: Optical coherence tomography angiography is a useful modality to visualise the microvasculature plexus of macula and optic nerve head. The vessel density measurement of macular scan by mean of optical coherence tomography angiography demonstrated good repeatability. The optic disc scan, on the other hand, showed a higher coefficient of variation indicating a lower measurement repeatability than macular scan. Interpretation of optical coherence tomography angiography should take into account test-retest repeatability of the imaging system. TRIAL REGISTRATION: National Healthcare Group Domain Specific Review Board ( NHG DSRB ) Singapore. DSRB Reference: 2015/00301.

Altered signaling in systemic juvenile idiopathic arthritis monocytes.

Systemic juvenile idiopathic arthritis (sJIA) is characterized by systemic inflammation and arthritis. Monocytes are implicated in sJIA pathogenesis, but their role in disease is unclear. The response of sJIA monocytes to IFN may be dysregulated. We examined intracellular signaling in response to IFN type I (IFNα) and type II (IFNγ) in monocytes during sJIA activity and quiescence, in 2 patient groups. Independent of disease activity, monocytes from Group 1 (collected between 2002 and 2009) showed defective STAT1 phosphorylation downstream of IFNs, and expressed higher transcript levels of SOCS1, an inhibitor of IFN signaling. In the Group 2 (collected between 2011 and 2014), monocytes of patients with recent disease onset were IFNγ hyporesponsive, but in treated, quiescent subjects, monocytes were hyperresponsive to IFNγ. Recent changes in medication in sJIA may alter the IFN hyporesponsiveness. Impaired IFN/pSTAT1 signaling is consistent with skewing of sJIA monocytes away from an M1 phenotype and may contribute to disease pathology.

Adverse technical events in home hemodialysis.

BACKGROUND: There is a growing interest in home hemodialysis because of its clinical benefits. However, given that patients are responsible for performing a complex medical procedure at home, adverse-event reporting is important to ensure patient safety. The purpose of this study was to describe adverse technical events in a large cohort of home hemodialysis patients. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: All consecutive patients undergoing home hemodialysis at a large tertiary-care center from 1999 through 2011 (last follow-up, July 2012). OUTCOMES: Overall rate of adverse technical events and number/rate of severe adverse events (defined as those requiring intervention). RESULTS: The cohort consisted of 202 patients with total follow-up of 757 patient-years. The cohort underwent a median of 5 dialysis treatments per week and 8 hours per session. 22 first adverse events and 7 recurrent events were identified. Adverse event rates were 0.049 per arteriovenous fistula access-year, 0.015 per arteriovenous graft access-year, and 0.022 per dialysis catheter access-year. Event rates per 1,000 dialysis treatments were 0.208, 0.068, and 0.087 for arteriovenous fistula, arteriovenous graft, and dialysis catheter access, respectively. Most adverse events were related to needle dislodgement (n=18) or air embolism (n=6). 8 adverse events resulted in emergency department visits and 5 required hospital admission. The rate of severe adverse events was 0.009 per patient-year of home hemodialysis and 0.038 per 1,000 dialysis treatments. Interventions included 3 blood transfusions, 2 catheter changes, 1 use of intravenous fluids, and 1 need for urgent dialysis. Attempts were made to retrain or review the technique in all patients with a first adverse event. LIMITATIONS: Events that were not severe may have been under-reported by patients. CONCLUSIONS: Serious adverse technical events in home hemodialysis are relatively rare. Strategies to further prevent these events may include patient retraining and periodic vascular access technique audit.

Cirrus HD-OCT short-term repeatability of clinical retinal nerve fiber layer measurements.

PURPOSE: The detection of changes in the retinal nerve fiber layer (RNFL) as measured by optical coherence tomography (OCT) is crucial in glaucoma diagnosis and management. We investigated the short-term repeatability of peripapillary RNFL measurements in a commercially available spectral domain OCT focusing on a broad clinical spectrum of patients. METHODS: Two consecutive peripapillary RNFL measurements were taken on 227 eyes with Cirrus HD-OCT (Carl Zeiss Meditec, Version 6.5 software) using the optic disc 200 × 200 protocol. Repeatability was assessed as Bland-Altman limits of agreement and intraclass coefficients (ICCs). RESULTS: Limits of agreement showed the greatest variability in the superior RNFL quadrant at ±7.5 µm and the least variability in the temporal quadrant at ±5.2 µm. The short-term repeatability for the average RNFL thickness resulted in an ICC of 0.98 and variability of 3.81 µm. Individual quadrants were similar, excepting the nasal RNFL quadrant with an ICC of 0.94. Inferior and temporal quadrants were the most repeatable with a variability of 2 to 3% instrument error. CONCLUSIONS: Cirrus HD-OCT has excellent short-term repeatability for peripapillary RNFL measurements in a mixed patient cohort. Retinal nerve fiber layer measurements are less reliable in the nasal RNFL quadrant. As other quadrants are used in glaucoma diagnosis, the detection of glaucomatous progression would be reliable.