Who is at risk for weight gain after weight-gain associated treatment with antipsychotics, antidepressants, and mood stabilizers: A machine learning approach.

BACKGROUND: Weight gain is a common side effect in psychopharmacology; however, targeted therapeutic interventions and prevention strategies are currently absent in day-to-day clinical practice. To promote the development of such strategies, the identification of factors indicative of patients at risk is essential. METHODS: In this study, we developed a transdiagnostic model using and comparing decision tree classifiers, logistic regression, XGboost, and a support vector machine to predict weight gain of ≥5% of body weight during the first 4 weeks of treatment with psychotropic drugs associated with weight gain in 103 psychiatric inpatients. We included established variables from the literature as well as an extended set with additional clinical variables and questionnaires. RESULTS: Baseline BMI, premorbid BMI, and age are known risk factors and were confirmed by our models. Additionally, waist circumference has emerged as a new and significant risk factor. Eating behavior next to blood glucose were found as additional potential predictor that may underlie therapeutic interventions and could be used for preventive strategies in a cohort at risk for psychotropics induced weight gain (PIWG). CONCLUSION: Our models validate existing findings and further uncover previously unknown modifiable factors, such as eating behavior and blood glucose, which can be used as targets for preventive strategies. These findings underscore the imperative for continued research in this domain to establish effective preventive measures for individuals undergoing psychotropic drug treatments.

Deconstructing depression by machine learning: the POKAL-PSY study.

Unipolar depression is a prevalent and disabling condition, often left untreated. In the outpatient setting, general practitioners fail to recognize depression in about 50% of cases mainly due to somatic comorbidities. Given the significant economic, social, and interpersonal impact of depression and its increasing prevalence, there is a need to improve its diagnosis and treatment in outpatient care. Various efforts have been made to isolate individual biological markers for depression to streamline diagnostic and therapeutic approaches. However, the intricate and dynamic interplay between neuroinflammation, metabolic abnormalities, and relevant neurobiological correlates of depression is not yet fully understood. To address this issue, we propose a naturalistic prospective study involving outpatients with unipolar depression, individuals without depression or comorbidities, and healthy controls. In addition to clinical assessments, cardiovascular parameters, metabolic factors, and inflammatory parameters are collected. For analysis we will use conventional statistics as well as machine learning algorithms. We aim to detect relevant participant subgroups by data-driven cluster algorithms and their impact on the subjects' long-term prognosis. The POKAL-PSY study is a subproject of the research network POKAL (Predictors and Clinical Outcomes in Depressive Disorders; GRK 2621).

Suicidal behaviors and adverse childhood experiences: A cross-diagnostic study in persistent depressive disorder and borderline personality disorder.

Adverse childhood experiences (ACE) constitute a known risk factor for suicidality. There is a research gap regarding differential patterns of associations between variants of suicidal ideations and behaviors (SIB) and characteristics of ACE in severe mental disorders. This cross-diagnostic study investigates whether SIB are related to ACE subtypes in two high-risk conditions, i.e., persistent depressive disorder (PDD) and borderline personality disorder (BPD). Inpatients with PDD (n = 117; age 40.2 years ± 12.3) and BPD (n = 74; age 26.2 ± 7.9) were assessed with the Columbia-Suicide Severity Rating Scale for suicidal ideations (SI), suicidal behaviors (SB) and actual suicide attempts (SA); ACE were recorded with the Childhood Trauma Questionnaire. In PDD, SI and SA were associated with childhood physical abuse (ORs 7.2 and 2.3, respectively). In BPD, SA were associated with severe experiences of physical abuse (OR 6.5). Weaker yet significant associations were found for childhood emotional abuse in PDD with SB (including SA), and in BPD with SA. Recall of childhood physical abuse may be clinically relevant information for identifying particular risks of SIB. Future studies should investigate these differential patterns in more depth and in terms of causality.

Association between Mood and Sensation Seeking Following rTMS.

Previous studies investigating mood changes in healthy subjects after prefrontal repetitive transcranial magnetic stimulation (rTMS) have shown largely inconsistent results. This may be due to methodological issues, considerable inter-individual variation in prefrontal connectivity or other factors, e.g., personality traits. This pilot study investigates whether mood changes after rTMS are affected by personality parameters. In a randomized cross-over design, 17 healthy volunteers received three sessions of 1 Hz rTMS to Fz, F3 and T3 (10/20 system). The T3 electrode site served as the control condition with the coil angled 45° to the scalp. Subjective mood was rated at baseline and after each condition. Personality traits were assessed using the NEO Five-Factor Inventory (NEO-FFI) and the Sensation Seeking Scale (SSS). For all conditions, a significant association between mood changes towards a deterioration in mood and SSS scores was observed. There were no differences between conditions and no correlations between mood changes and NEO-FFI. The data show that sensation-seeking personality has an impact on subjective mood changes following prefrontal rTMS in all conditions. Future studies investigating the effects of rTMS on emotional paradigms should include individual measures of sensation-seeking personality. The pre-selection of subjects according to personality criteria may reduce the variability in results.

Improving mental health care in depression: A call for action.

Depressive disorders have one of the highest disability-adjusted life years (DALYs) of all medical conditions, which led the European Psychiatric Association to propose a policy paper, pinpointing their unmet health care and research needs. The first part focuses on what can be currently done to improve the care of patients with depression, and then discuss future trends for research and healthcare. Through the narration of clinical cases, the different points are illustrated. The necessary political framework is formulated, to implement such changes to fundamentally improve psychiatric care. The group of European Psychiatrist Association (EPA) experts insist on the need for (1) increased awareness of mental illness in primary care settings, (2) the development of novel (biological) markers, (3) the rapid implementation of machine learning (supporting diagnostics, prognostics, and therapeutics), (4) the generalized use of electronic devices and apps into everyday treatment, (5) the development of the new generation of treatment options, such as plasticity-promoting agents, and (6) the importance of comprehensive recovery approach. At a political level, the group also proposed four priorities, the need to (1) increase the use of open science, (2) implement reasonable data protection laws, (3) establish ethical electronic health records, and (4) enable better healthcare research and saving resources.

TDCS at home for depressive disorders: an updated systematic review and lessons learned from a prematurely terminated randomized controlled pilot study.

The application of transcranial direct current stimulation (tDCS) at home for the treatment of major depressive disorder (MDD) is the subject of current clinical trials. This is due to its positive safety profile, cost-effectiveness, and potential scalability for a wide outreach in clinical practice. Here, we provide a systematic review of the available studies and also a report on the results of a randomized controlled trial (RCT) on tDCS at home for the treatment of MDD. This trial had to be prematurely terminated due to safety concerns. The HomeDC trial is a double-blinded, placebo-controlled, parallel-group study. Patients with MDD (DSM-5) were randomized to active or sham tDCS. Patients conducted tDCS at home for 6 weeks with 5 sessions/week (30 min at 2 mA) anode over F3, cathode over F4. Sham tDCS resembled active tDCS, with ramp-in and ramp-out periods, but without intermittent stimulation. The study was prematurely terminated due to an accumulation of adverse events (AEs, skin lesions), so that only 11 patients were included. Feasibility was good. Safety monitoring was not sufficient enough to detect or prevent AEs within an appropriate timeframe. Regarding antidepressant effects, the reduction in depression scales over time was significant. However, active tDCS was not superior to sham tDCS in this regard. Both the conclusions from this review and the HomeDC trial show that there are several critical issues with the use of tDCS at home that need to be addressed. Nevertheless the array of transcranial electric simulation (TES) methods that this mode of application offers, including tDCS, is highly interesting and warrants further investigation in high quality RCTs. TRIAL REGISTRATION: www. CLINICALTRIALS: gov . TRIAL REGISTRATION NUMBER: NCT05172505. Registration date: 12/13/2021, https://clinicaltrials.gov/ct2/show/NCT05172505 . *Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers) **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. https://doi.org/10.1136/bmj.n71 . For more information, visit: http://www.prisma-statement.org/.

Outcomes of Salvage Procedures for Failed Total Ankle Arthroplasty.

BACKGROUND: The number of total ankle arthroplasty (TAA) procedures increased rapidly in the last years and so have its complications. The main pillars in treating failed TAA are revision total ankle arthroplasty (RTAA), revision total ankle arthrodesis (RAA), or revision tibiotalocalcaneal fusion (RTTC). To evaluate these options, we compared clinical, radiologic, and patient-reported outcomes. METHODS: A single-center, retrospective review of 111 cases of revision procedures of failed TAA from 2006 to 2020 was performed. Patients undergoing polyethylene exchange and revision of one metallic component were excluded. Demographic data, failure, and survival rates were analyzed. The European Foot and Ankle Society (EFAS) score and radiographic changes in the subtalar joint were evaluated. The average follow-up was 67.89 ± 40.51 months. RESULTS: One hundred eleven patients underwent removal of TAA. The procedures included 40 revisions of both metallic components, 46 revision total ankle arthrodesis and 25 revision tibiotalocalcaneal fusion. The overall failure rate in the cohort was 5.41% (6/111). The failure rate after RAA was 4.35 times higher than that of RTAA, whereas RTTC did not show failures. RTAA and RTTC lead to a 1-year and 5-year survival rate of 100%. RAA resulted in a 1-year survival rate of 90% and a 5-year survival rate of 85%. The mean EFAS score in the cohort was 12.02 ± 5.83. Analysis of the EFAS score showed that RTTC provided the most reliable pain reduction, and RTAA achieved the best gait pattern. RAA resulted in poorer clinical results. Subtalar joint degeneration occurred significantly less in the RTAA group (P = .01). CONCLUSION: This retrospective study suggests lower failure rates, increased short-term survival and a better clinical outcomes of revision arthroplasty and tibiotalocalcaneal fusion than ankle arthrodesis. Revision arthroplasty is a promising solution in treating failed total ankle arthroplasty considering lower rate of subsequent adjacent joint degeneration. LEVEL OF EVIDENCE: Level III, non-randomized observational study.

Transmission of Zika virus by dendritic cell subsets in skin and vaginal mucosa.

Zika virus is a member of the Flaviviridae family that has caused recent outbreaks associated with neurological malformations. Transmission of Zika virus occurs primarily via mosquito bite but also via sexual contact. Dendritic cells (DCs) and Langerhans cells (LCs) are important antigen presenting cells in skin and vaginal mucosa and paramount to induce antiviral immunity. To date, little is known about the first cells targeted by Zika virus in these tissues as well as subsequent dissemination of the virus to other target cells. We therefore investigated the role of DCs and LCs in Zika virus infection. Human monocyte derived DCs (moDCs) were isolated from blood and primary immature LCs were obtained from human skin and vaginal explants. Zika virus exposure to moDCs but not skin and vaginal LCs induced Type I Interferon responses. Zika virus efficiently infected moDCs but neither epidermal nor vaginal LCs became infected. Infection of a human full skin model showed that DC-SIGN expressing dermal DCs are preferentially infected over langerin+ LCs. Notably, not only moDCs but also skin and vaginal LCs efficiently transmitted Zika virus to target cells. Transmission by LCs was independent of direct infection of LCs. These data suggest that DCs and LCs are among the first target cells for Zika virus not only in the skin but also the genital tract. The role of vaginal LCs in dissemination of Zika virus from the vaginal mucosa further emphasizes the threat of sexual transmission and supports the investigation of prophylaxes that go beyond mosquito control.

Immune activation of vaginal human Langerhans cells increases susceptibility to HIV-1 infection.

Vaginal inflammation increases the risk for sexual HIV-1 transmission but underlying mechanisms remain unclear. In this study we assessed the impact of immune activation on HIV-1 susceptibility of primary human vaginal Langerhans cells (LCs). Vaginal LCs isolated from human vaginal tissue expressed a broad range of TLRs and became activated after exposure to both viral and bacterial TLR ligands. HIV-1 replication was restricted in immature vaginal LCs as only low levels of infection could be detected. Notably, activation of immature vaginal LCs by bacterial TLR ligands increased HIV-1 infection, whereas viral TLR ligands were unable to induce HIV-1 replication in vaginal LCs. Furthermore, mature vaginal LCs transmitted HIV-1 to CD4 T cells. This study emphasizes the role for vaginal LCs in protection against mucosal HIV-1 infection, which is abrogated upon activation. Moreover, our data suggest that bacterial STIs can increase the risk of HIV-1 acquisition in women.

Failure rates and patient-reported outcomes of revision of total ankle arthroplasty.

INTRODUCTION: Despite the increasing number of revision total ankle arthroplasty (TAA), the literature on indications, surgical options, and outcomes is limited. This study reports on failure rates and patient-reported outcomes (PROM) for a cohort of 122 patients who underwent revision of TAA. MATERIALS AND METHODS: A retrospective review of revision TAA between 2006 and 2020 was performed at one institution. Patient's demographics and different surgical procedures were analyzed with particular attention to comparing polyethylene exchange with revision of both metallic components and to additional interventions for axis correction. Failure rates and the European Foot and Ankle Society (EFAS) score were collected. The average follow-up period was 70.37 ± 46.76 months. RESULTS: 122 patients were treated with an exchange procedure. The surgery included 69 polyethylene exchanges, 12 revisions of one metallic component, and 41 revisions of both metallic components. The overall failure rate was 14.75%. The EFAS score, completed by 94 of the 122 patients, was used to evaluate clinical outcomes. Median EFAS score was 12.51 ± 5.53, and median EFAS sports score was 2.97 ± 3.04. Revision rates after polyethylene exchange were significantly higher than after exchanging both metallic components (p value = 0.03), while the EFAS score showed slightly better results in patients treated with polyethylene exchange. Adding procedures to induce axis correction led to significantly lower revision rates (p value = 0.03), and the EFAS score was also improved but without statistical significance. CONCLUSIONS: The high failure rate of polyethylene exchange indicates that the intervention does not address the actual cause of failed TAA in many cases. Additional axis correction should be considered more frequently. If the underlying issues of prosthesis failure can be identified and sufficiently addressed, the results of revision surgery are likely to improve.

Digital technology and mental health during the COVID-19 pandemic: a narrative review with a focus on depression, anxiety, stress, and trauma.

The sudden appearance and devastating effects of the COVID-19 pandemic resulted in the need for multiple adaptive changes in societies, business operations and healthcare systems across the world. This review describes the development and increased use of digital technologies such as chat bots, electronic diaries, online questionnaires and even video gameplay to maintain effective treatment standards for individuals with mental health conditions such as depression, anxiety and post-traumatic stress syndrome. We describe how these approaches have been applied to help meet the challenges of the pandemic in delivering mental healthcare solutions. The main focus of this narrative review is on describing how these digital platforms have been used in diagnostics, patient monitoring and as a treatment option for the general public, as well as for frontline medical staff suffering with mental health issues.

Inhalation of Low Molecular Weight Heparins as Prophylaxis against SARS-CoV-2.

New SARS-CoV-2 variants of concern and waning immunity demonstrate the need for a quick and simple prophylactic agent to prevent infection. Low molecular weight heparins (LMWH) are potent inhibitors of SARS-CoV-2 binding and infection in vitro. The airways are a major route for infection and therefore inhaled LMWH could be a prophylactic treatment against SARS-CoV-2. We investigated the efficacy of in vivo inhalation of LMWH in humans to prevent SARS-CoV-2 attachment to nasal epithelial cells in a single-center, open-label intervention study. Volunteers received enoxaparin in the right and a placebo (NaCl 0.9%) in the left nostril using a nebulizer. After application, nasal epithelial cells were retrieved with a brush for ex-vivo exposure to either SARS-CoV-2 pseudovirus or an authentic SARS-CoV-2 isolate and virus attachment as determined. LMWH inhalation significantly reduced attachment of SARS-CoV-2 pseudovirus as well as authentic SARS-CoV-2 to human nasal cells. Moreover, in vivo inhalation was as efficient as in vitro LMWH application. Cell phenotyping revealed no differences between placebo and treatment groups and no adverse events were observed in the study participants. Our data strongly suggested that inhalation of LMWH was effective to prevent SARS-CoV-2 attachment and subsequent infection. LMWH is ubiquitously available, affordable, and easy to apply, making them suitable candidates for prophylactic treatment against SARS-CoV-2. IMPORTANCE New SARS-CoV-2 variants of concern and waning immunity demonstrate the need for a quick and simple agent to prevent infection. Low molecular weight heparins (LMWH) have been shown to inhibit SARS-CoV-2 in experimental settings. The airways are a major route for SARS-CoV-2 infection and inhaled LMWH could be a prophylactic treatment. We investigated the efficacy of inhalation of the LMWH enoxaparin in humans to prevent SARS-CoV-2 attachment because this is a prerequisite for infection. Volunteers received enoxaparin in the right and a placebo in the left nostril using a nebulizer. Subsequently, nasal epithelial cells were retrieved with a brush and exposed to SARS-CoV-2. LMWH inhalation significantly reduced the binding of SARS-Cov-2 to human nasal cells. Cell phenotyping revealed no differences between placebo and treatment groups and no adverse events were observed in the participants. Our data indicated that LMWH can be used to block SARS-CoV-2 attachment to nasal cells. LMWH was ubiquitously available, affordable, and easily applicable, making them excellent candidates for prophylactic treatment against SARS-CoV-2.

SARS-CoV-2 infection activates dendritic cells via cytosolic receptors rather than extracellular TLRs.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an infectious disease characterized by strong induction of inflammatory cytokines, progressive lung inflammation, and potentially multiorgan dysfunction. It remains unclear how SARS-CoV-2 infection leads to immune activation. The Spike (S) protein of SARS-CoV-2 has been suggested to trigger TLR4 and thereby activate immunity. Here, we have investigated the role of TLR4 in SARS-CoV-2 infection and immunity. Neither exposure of isolated S protein, SARS-CoV-2 pseudovirus nor primary SARS-CoV-2 isolate induced TLR4 activation in a TLR4-expressing cell line. Human monocyte-derived DCs express TLR4 but not angiotensin converting enzyme 2 (ACE2), and DCs were not infected by SARS-CoV-2. Notably, neither S protein nor SARS-CoV-2 induced DC maturation or cytokines, indicating that both S protein and SARS-CoV-2 virus particles do not trigger extracellular TLRs including TLR4. Ectopic expression of ACE2 in DCs led to efficient infection by SARS-CoV-2 and, strikingly, efficient type I IFN and cytokine responses. These data strongly suggest that not extracellular TLRs but intracellular viral sensors are key players in sensing SARS-CoV-2. These data imply that SARS-CoV-2 escapes direct sensing by TLRs, which might underlie the lack of efficient immunity to SARS-CoV-2 early during infection.

Thinking outside the box: students positive about visionary elective curricula in medical school.

Objective: Space for personality development as well as for the development of critical, creative and interdisciplinary thinking is rarely found in medical curricula in Germany. To be prepared for the challenges of modern medicine, future physicians need a visionary mindset. The aim of this study is to determine the need for teaching such content among medical students in the context of visionary elective curricula and to examine these with regard to the desired topics and organizational structure. Methods: This is a cross-sectional study with 236 medical students from all semesters of the Ludwig-Maximilians-University Munich. The survey consists of 50 questions and includes single choice, multiple choice, matrix questions, open-ended questions and Likert scales. Responses were examined using descriptive statistics and compared parametrically in sub-aspects. Results: Three-quarters of respondents would like to see curricular content on interdisciplinary interfaces with other disciplines. A suitable framework for this is seen by 87% of the respondents in a visionary elective curriculum. Students would like to see a broad range of specific content such as global health, politics, business, and computer science. The majority of respondents would like to see 1 unit of instruction per week and would participate in an appropriate program. Such an offering would promote creative (53.6%), critical (63.7%), and interdisciplinary thinking (69.0%) and train to become better physicians (87%). Conclusion: Participants in this study are positive toward the introduction of visionary content in medical school. Faculties should build visionary elective curricula according to the graduate profile requirements of the new NKLM 2.0 to make medical education sustainable.

Infection and transmission of SARS-CoV-2 depend on heparan sulfate proteoglycans.

The current pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and outbreaks of new variants highlight the need for preventive treatments. Here, we identified heparan sulfate proteoglycans as attachment receptors for SARS-CoV-2. Notably, neutralizing antibodies against SARS-CoV-2 isolated from COVID-19 patients interfered with SARS-CoV-2 binding to heparan sulfate proteoglycans, which might be an additional mechanism of antibodies to neutralize infection. SARS-CoV-2 binding to and infection of epithelial cells was blocked by low molecular weight heparins (LMWH). Although dendritic cells (DCs) and mucosal Langerhans cells (LCs) were not infected by SARS-CoV-2, both DC subsets efficiently captured SARS-CoV-2 via heparan sulfate proteoglycans and transmitted the virus to ACE2-positive cells. Notably, human primary nasal cells were infected by SARS-CoV-2, and infection was blocked by pre-treatment with LMWH. These data strongly suggest that heparan sulfate proteoglycans are important attachment receptors facilitating infection and transmission, and support the use of LMWH as prophylaxis against SARS-CoV-2 infection.

Molecular diagnostics helps to identify distinct subgroups of spinal astrocytomas.

Primary spinal cord astrocytomas are rare, hence few data exist about the prognostic significance of molecular markers. Here we analyze a panel of molecular alterations in association with the clinical course. Histology and genome sequencing was performed in 26 spinal astrocytomas operated upon between 2000 and 2020. Next-generation DNA/RNA sequencing (NGS) and methylome analysis were performed to determine molecular alterations. Histology and NGS allowed the distinction of 5 tumor subgroups: glioblastoma IDH wildtype (GBM); diffuse midline glioma H3 K27M mutated (DMG-H3); high-grade astrocytoma with piloid features (HAP); diffuse astrocytoma IDH mutated (DA), diffuse leptomeningeal glioneural tumors (DGLN) and pilocytic astrocytoma (PA). Within all tumor entities GBM (median OS: 5.5 months), DMG-H3 (median OS: 13 months) and HAP (median OS: 8 months) showed a fatal prognosis. DMG-H3 tend to emerge in adolescence whereas GBM and HAP develop in the elderly. HAP are characterized by CDKN2A/B deletion and ATRX mutation. 50% of PA tumors carried a mutation in the PIK3CA gene which is seemingly associated with better outcome (median OS: PIK3CA mutated 107.5 vs 45.5 months in wildtype PA). This exploratory molecular profiling of spinal cord astrocytomas allows to identify distinct subgroups by combining molecular markers and histomorphology. DMG-H3 tend to develop in adolescence with a similar dismal prognosis like GBM and HAP in the elderly. We here describe spinal HAP with a distinct molecular profile for the first time.

Traces of Trauma: A Multivariate Pattern Analysis of Childhood Trauma, Brain Structure, and Clinical Phenotypes.

BACKGROUND: Childhood trauma (CT) is a major yet elusive psychiatric risk factor, whose multidimensional conceptualization and heterogeneous effects on brain morphology might demand advanced mathematical modeling. Therefore, we present an unsupervised machine learning approach to characterize the clinical and neuroanatomical complexity of CT in a larger, transdiagnostic context. METHODS: We used a multicenter European cohort of 1076 female and male individuals (discovery: n = 649; replication: n = 427) comprising young, minimally medicated patients with clinical high-risk states for psychosis; patients with recent-onset depression or psychosis; and healthy volunteers. We employed multivariate sparse partial least squares analysis to detect parsimonious associations between combinations of items from the Childhood Trauma Questionnaire and gray matter volume and tested their generalizability via nested cross-validation as well as via external validation. We investigated the associations of these CT signatures with state (functioning, depressivity, quality of life), trait (personality), and sociodemographic levels. RESULTS: We discovered signatures of age-dependent sexual abuse and sex-dependent physical and sexual abuse, as well as emotional trauma, which projected onto gray matter volume patterns in prefronto-cerebellar, limbic, and sensory networks. These signatures were associated with predominantly impaired clinical state- and trait-level phenotypes, while pointing toward an interaction between sexual abuse, age, urbanicity, and education. We validated the clinical profiles for all three CT signatures in the replication sample. CONCLUSIONS: Our results suggest distinct multilayered associations between partially age- and sex-dependent patterns of CT, distributed neuroanatomical networks, and clinical profiles. Hence, our study highlights how machine learning approaches can shape future, more fine-grained CT research.

Syndecan 4 Upregulation on Activated Langerhans Cells Counteracts Langerin Restriction to Facilitate Hepatitis C Virus Transmission.

Sexually transmitted Hepatitis C virus (HCV) infections and high reinfections are a major concern amongst men who have sex with men (MSM) living with HIV-1 and HIV-negative MSM. Immune activation and/or HIV-1 coinfection enhance HCV susceptibility via sexual contact, suggesting that changes in immune cells or external factors are involved in increased susceptibility. Activation of anal mucosal Langerhans cells (LCs) has been implicated in increased HCV susceptibility as activated but not immature LCs efficiently retain and transmit HCV to other cells. However, the underlying molecular mechanism of transmission remains unclear. Here we identified the Heparan Sulfate Proteoglycan Syndecan 4 as the molecular switch, controlling HCV transmission by LCs. Syndecan 4 was highly upregulated upon activation of LCs and interference with Heparan Sulfate Proteoglycans or silencing of Syndecan 4 abrogated HCV transmission. These data strongly suggest that Syndecan 4 mediates HCV transmission by activated LCs. Notably, our data also identified the C-type lectin receptor langerin as a restriction factor for HCV infection and transmission. Langerin expression abrogated HCV infection in HCV permissive cells, whereas langerin expression on the Syndecan 4 expressing cell line strongly decreased HCV transmission to a target hepatoma cell line. These data suggest that the balanced interplay between langerin restriction and Syndecan 4 transmission determines HCV dissemination. Silencing of langerin enhanced HCV transmission whereas silencing Syndecan 4 on activated LCs decreased transmission. Blocking Heparan Sulfate Proteoglycans abrogated HCV transmission by LCs ex vivo identifying Heparan Sulfate Proteoglycans and Syndecan 4 as potential targets to prevent sexual transmission of HCV. Thus, our data strongly suggest that the interplay between receptors promotes or restricts transmission and further indicate that Syndecan 4 is the molecular switch controlling HCV susceptibility after sexual contact.

C-Type Lectin Receptors in Antiviral Immunity and Viral Escape.

C-type lectin receptors (CLRs) are important pattern recognition receptors involved in recognition and induction of adaptive immunity to pathogens. Certain CLRs play an important role in viral infections as they efficiently interact with viruses. However, it has become clear that deadly viruses subvert the function of CLRs to escape antiviral immunity and promote infection. In particular, viruses target CLRs to suppress or modulate type I interferons that play a central role in the innate and adaptive defense against viruses. In this review, we discuss the function of CLRs in binding to enveloped viruses like HIV-1 and Dengue virus, and how uptake and signaling cascades have decisive effects on the outcome of infection.