Lectin-Dependent Enhancement of Ebola Virus Infection via Soluble and Transmembrane C-type Lectin Receptors

Mannose-binding lectin (MBL) is a key soluble effector of the innate immune system that recognizes pathogen-specific surface glycans. Surprisingly, low-producing MBL genetic variants that may predispose children and immunocompromised individuals to infectious diseases are more common than would be expected in human populations. Since certain immune defense molecules, such as immunoglobulins, can be exploited by invasive pathogens, we hypothesized that MBL might also enhance infections in some circumstances. Consequently, the low and intermediate MBL levels commonly found in human populations might be the result of balancing selection. Using model infection systems with pseudotyped and authentic glycosylated viruses, we demonstrated that MBL indeed enhances infection of Ebola, Hendra, Nipah and West Nile viruses in low complement conditions. Mechanistic studies with Ebola virus (EBOV) glycoprotein pseudotyped lentiviruses confirmed that MBL binds to N-linked glycan epitopes on viral surfaces in a specific manner via the MBL carbohydrate recognition domain, which is necessary for enhanced infection. MBL mediates lipid-raft-dependent macropinocytosis of EBOV via a pathway that appears to require less actin or early endosomal processing compared with the filovirus canonical endocytic pathway. Using a validated RNA interference screen, we identified C1QBP (gC1qR) as a candidate surface receptor that mediates MBL-dependent enhancement of EBOV infection. We also identified dectin-2 (CLEC6A) as a potentially novel candidate attachment factor for EBOV. Our findings support the concept of an innate immune haplotype that represents critical interactions between MBL and complement component C4 genes and that may modify susceptibility or resistance to certain glycosylated pathogens. Therefore, higher levels of native or exogenous MBL could be deleterious in the setting of relative hypocomplementemia which can occur genetically or because of immunodepletion during active infections. Our findings confirm our hypothesis that the pressure of infectious diseases may have contributed in part to evolutionary selection of MBL mutant haplotypes

Computational Approaches and Analysis for a Spatio-Structural-Temporal Invasive Carcinoma Model

Spatio-temporal models have long been used to describe biological systems of cancer, but it has not been until very recently that increased attention has been paid to structural dynamics of the interaction between cancer populations and the molecular mechanisms associated with local invasion. One system that is of particular interest is that of the urokinase plasminogen activator (uPA) wherein uPA binds uPA receptors on the cancer cell surface, allowing plasminogen to be cleaved into plasmin, which degrades the extracellular matrix and this way leads to enhanced cancer cell migration. In this paper, we develop a novel numerical approach and associated analysis for spatio-structuro-temporal modelling of the uPA system for up to two-spatial and two-structural dimensions. This is accompanied by analytical exploration of the numerical techniques used in simulating this system, with special consideration being given to the proof of stability within numerical regimes encapsulating a central differences approach to approximating numerical gradients. The stability analysis performed here reveals instabilities induced by the coupling of the structural binding and proliferative processes. The numerical results expound how the uPA system aids the tumour in invading the local stroma, whilst the inhibitor to this system may impede this behaviour and encourage a more sporadic pattern of invasion.PostprintPeer reviewe

Structured models of cell migration incorporating molecular binding processes

The dynamic interplay between collective cell movement and the various molecules involved in the accompanying cell signalling mechanisms plays a crucial role in many biological processes including normal tissue development and pathological scenarios such as wound healing and cancer. Information about the various structures embedded within these processes allows a detailed exploration of the binding of molecular species to cell-surface receptors within the evolving cell population. In this paper we establish a general spatio-temporal-structural framework that enables the description of molecular binding to cell membranes coupled with the cell population dynamics. We first provide a general theoretical description for this approach and then illustrate it with two examples arising from cancer invasion

Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia

Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the β-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/β-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/β-catenin interaction

Noninvasive ventilation in critically ill patients with the Middle East respiratory syndrome

Background: Noninvasive ventilation (NIV) has been used in patients with the Middle East respiratory syndrome (MERS) with acute hypoxemic respiratory failure, but the effectiveness of this approach has not been studied.Methods: Patients with MERS from 14 Saudi Arabian centers were included in this analysis. Patients who were initially managed with NIV were compared to patients who were managed only with invasive mechanical ventilation (invasive MV).Results: Of 302 MERS critically ill patients, NIV was used initially in 105 (35%) patients, whereas 197 (65%) patients were only managed with invasive MV. Patients who were managed with NIV initially had lower baseline SOFA score and less extensive infiltrates on chest radiograph compared with patients managed with invasive MV. The vast majority (92.4%) of patients who were managed initially with NIV required intubation and invasive mechanical ventilation, and were more likely to require inhaled nitric oxide compared to those who were managed initially with invasive MV. ICU and hospital length of stay were similar between NIV patients and invasive MV patients. The use of NIV was not independently associated with 90‐day mortality (propensity score‐adjusted odds ratio 0.61, 95% CI [0.23, 1.60] P = 0.27).Conclusions: In patients with MERS and acute hypoxemic respiratory failure, NIV failure was very high. The use of NIV was not associated with improved outcomes

Corticosteroid therapy for critically ill patients with the Middle East Respiratory Syndrome.

Rationale Corticosteroid therapy is commonly used among critically ill patients with the Middle East Respiratory Syndrome (MERS), but its impact on outcomes is uncertain. Analyses of observational studies often do not account for patients’ clinical condition at the time of corticosteroid therapy initiation. Objectives To investigate the association of corticosteroid therapy on mortality and on MERS coronavirus RNA clearance in critically ill patients with MERS. Methods MERS ICU patients were included from 14 Saudi Arabian centers between September 2012 and October 2015. We carried out marginal structural modeling to account for baseline and time-varying confounders. Measurements and Main Results Of 309 patients, 151 received corticosteroids. Corticosteroids were initiated at a median of 3.0 days (Quartile Q1, 3: 1.0, 7.0) from ICU admission. Patients who received corticosteroids were more likely to receive invasive ventilation (141/151 [93.4%] vs. 121/158 [76.6%], p≤0.0001) and had higher 90-day crude mortality (112/151 [74.2%] vs. 91/158 [57.6%], p=0.002). Using marginal structural modeling, corticosteroid therapy was not significantly associated with 90-day mortality (adjusted odds ratio 0.75, 95% CI 0.52, 1.07, p=0.12), but was associated with delay in MERS coronavirus RNA clearance (adjusted hazard ratio 0.35, 95% CI: 0.17, 0.72, p=0.005). Conclusions Corticosteroid therapy in patients with MERS was not associated with a difference in mortality after adjustment for time-varying confounders, but was associated with delayed MERS coronavirus RNA clearance. These findings highlight the challenges and importance of adjusting for baseline and time-varying confounders when estimating clinical effects of treatments using observational studies

CXCR2 Signaling Protects Oligodendrocytes and Restricts Demyelination in a Mouse Model of Viral-Induced Demyelination

BACKGROUND: The functional role of ELR-positive CXC chemokines during viral-induced demyelination was assessed. Inoculation of the neuroattenuated JHM strain of mouse hepatitis virus (JHMV) into the CNS of susceptible mice results in an acute encephalomyelitis that evolves into a chronic demyelinating disease, modeling white matter pathology observed in the human demyelinating disease Multiple Sclerosis. METHODOLOGY/PRINCIPAL FINDINGS: JHMV infection induced the rapid and sustained expression of transcripts specific for the ELR+ chemokine ligands CXCL1 and CXCL2, as well as their binding receptor CXCR2, which was enriched within the spinal cord during chronic infection. Inhibiting CXCR2 signaling with neutralizing antiserum significantly (p<0.03) delayed clinical recovery. Moreover, CXCR2 neutralization was associated with an increase in the severity of demyelination that was independent of viral recrudescence or modulation of neuroinflammation. Rather, blocking CXCR2 was associated with increased numbers of apoptotic cells primarily within white matter tracts, suggesting that oligodendrocytes were affected. JHMV infection of enriched oligodendrocyte progenitor cell (OPC) cultures revealed that apoptosis was associated with elevated expression of cleaved caspase 3 and muted Bcl-2 expression. Inclusion of CXCL1 within JHMV infected cultures restricted caspase 3 cleavage and increased Bcl-2 expression that was associated with a significant (p<0.001) decrease in apoptosis. CXCR2 deficient oligodendrocytes were refractory to CXCL1 mediated protection from JHMV-induced apoptosis, readily activating caspase 3 and down regulating Bcl-2. CONCLUSION/SIGNIFICANCE: These findings highlight a previously unappreciated role for CXCR2 signaling in protecting oligodendrocyte lineage cells from apoptosis during inflammatory demyelination initiated by viral infection of the CNS

Sexual harassment in Dentistry: prevalence in dental school

OBJECTIVE: Sexual harassment is unlawful in all work and educational environments in most nations of the world. The goals of this study were to describe the sexual harassment prevalence and to evaluate the experiences and attitudes of undergraduate students in one dental school in Brazil. MATERIAL AND METHODS: An 18-item questionnaire was administered to 254 dental students with a completion rate of 82% (208). Students were requested to respond to questions about their background and academic level in dental school, their personal experiences with sexual harassment and their observation of someone else being sexually harassed. Bivariate statistical analyses were performed. RESULTS: Fifteen percent of the students reported being sexually harassed by a patient, by a relative of a patient or by a professor. Male students had 3 times higher probability of being sexually harassed than female student [OR=2.910 (1.113-7.611)]. Additionally, 25.4% of the students reported witnessing sexual harassment at the school environment. The majority of students did not feel professionally prepared to respond to unwanted sexual behaviors. CONCLUSION: These findings demonstrate that sexual harassment can occur in a dental school setting. There is a need for ongoing sexual harassment education programs for students and university staff. Increased knowledge of sexual harassment during graduation can better prepare dental professionals to respond to sexual harassment during their practice

A qualitative investigation into knowledge, beliefs, and practices surrounding mastitis in sub-Saharan Africa: what implications for vertical transmission of HIV?

BACKGROUND: Mastitis constitutes an important risk factor in HIV vertical transmission. Very little, however, is known on how women in sub-Saharan Africa conceptualise health problems related to breastfeeding, such as mastitis, and how they act when sick. We aimed at filling this gap in knowledge, by documenting the indigenous nosography of mastitis, health seeking behaviour, and remedies for prophylaxis and treatment in rural sub-Saharan Africa. METHODS: The study was conducted in the Nouna Health District, rural Burkina Faso. We employed a combination of in-depth individual interviews and focus group discussions reaching both women and guérisseuers. All material was transcribed, translated, and analysed inductively, applying data and analyst triangulation. RESULTS: Respondents perceived breast problems related to lactation to be highly prevalent and described a sequence of symptoms which resembles the biomedical understanding of pathologies related to breastfeeding, ranging from breast engorgement (stasis) to inflammation (mastitis) and infection (breast abscess). The aetiology of disease, however, differed from biomedical notions as both women and guerisseurs distinguished between "natural" and "unnatural" causes of health problems related to breastfeeding. To prevent and treat such pathologies, women used a combination of traditional and biomedical therapies, depending on the perceived cause of illness. In general, however, a marked preference for traditional systems of care was observed. CONCLUSION: Health problems related to breastfeeding are perceived to be very common in rural Burkina Faso. Further epidemiological research to assess the actual prevalence of such pathologies is urgently needed to inform the design of adequate control measures, especially given the impact of mastitis on HIV vertical transmission. Our investigation into local illness concepts and health care seeking behaviour is useful to ensure that such measures be culturally sensitive. Further research into the efficacy of local customs and traditional healing methods and their effect on viral load in breast milk is also urgently needed

Apnea of prematurity: from cause to treatment

Apnea of prematurity (AOP) is a common problem affecting premature infants, likely secondary to a “physiologic” immaturity of respiratory control that may be exacerbated by neonatal disease. These include altered ventilatory responses to hypoxia, hypercapnia, and altered sleep states, while the roles of gastroesophageal reflux and anemia remain controversial. Standard clinical management of the obstructive subtype of AOP includes prone positioning and continuous positive or nasal intermittent positive pressure ventilation to prevent pharyngeal collapse and alveolar atelectasis, while methylxanthine therapy is a mainstay of treatment of central apnea by stimulating the central nervous system and respiratory muscle function. Other therapies, including kangaroo care, red blood cell transfusions, and CO2 inhalation, require further study. The physiology and pathophysiology behind AOP are discussed, including the laryngeal chemoreflex and sensitivity to inhibitory neurotransmitters, as are the mechanisms by which different therapies may work and the potential long-term neurodevelopmental consequences of AOP and its treatment