Humoral and cellular immune responses to Lassa fever virus in Lassa fever survivors and their exposed contacts in Southern Nigeria.

Elucidating the adaptive immune characteristics of natural protection to Lassa fever (LF) is vital in designing and selecting optimal vaccine candidates. With rejuvenated interest in LF and a call for accelerated research on the Lassa virus (LASV) vaccine, there is a need to define the correlates of natural protective immune responses to LF. Here, we describe cellular and antibody immune responses present in survivors of LF (N = 370) and their exposed contacts (N = 170) in a LASV endemic region in Nigeria. Interestingly, our data showed comparable T cell and binding antibody responses from both survivors and their contacts, while neutralizing antibody responses were primarily seen in the LF survivors and not their contacts. Neutralizing antibody responses were found to be cross-reactive against all five lineages of LASV with a strong bias to Lineage II, the prevalent strain in southern Nigeria. We demonstrated that both T cell and antibody responses were not detectable in peripheral blood after a decade in LF survivors. Notably LF survivors maintained high levels of detectable binding antibody response for six months while their contacts did not. Lastly, as potential vaccine targets, we identified the regions of the LASV Glycoprotein (GP) and Nucleoprotein (NP) that induced the broadest peptide-specific T cell responses. Taken together this data informs immunological readouts and potential benchmarks for clinical trials evaluating LASV vaccine candidates.

Factors associated with mobile phone usage to access maternal and child healthcare among women of urban slums in Dhaka, Bangladesh: a cross-sectional study.

INTRODUCTION: With the acute shortage of human resources and infrastructure, mobile phones can be a critical tool for accessing health services and strengthening health systems in Bangladesh. Yet, there is a scarcity of evidence on the use of mobile phones in this context for accessing health services. In this study, we sought to explore the current use of mobile phones for accessing maternal and child healthcare and its determinants among recently delivered women in urban slums of Bangladesh. METHODS: The data were collected through interviewing 800 recently delivered women from eight slums of Dhaka city of Bangladesh during May and June 2018. The study followed a cross-sectional design and a two-stage cluster random sampling procedure was followed. A pretested structured questionnaire was employed to collect information. Chi square tests were performed for descriptive analyses and a multilevel binary logistic regression model was executed to explore the determinants of mobile phone usage for accessing maternal and childcare among the participants. RESULTS: Overall, 73.8% of study participants used mobile phones for accessing maternal and child healthcare. After adjusting for potential confounders, participants' age, husband's occupation, sex of household head, women's ownership of mobile phones and household wealth status were found to be significantly associated with higher odds of using mobile phones to access maternal and child healthcare. CONCLUSION: The study highlighted the possibility of implementing large-scale mobile health (mHealth) interventions in slum settlements for accessing maternal and child healthcare and is a sustainable mitigation strategy for the acute health worker crisis in Bangladesh. The findings of this study are particularly crucial for policymakers and practitioners while they revise the health policy to incorporate mHealth interventions as highlighted in the recently initiated Digital Health Strategy of Bangladesh.

Exploring Factors Associated with Women's Willingness to Provide Digital Fingerprints in Accessing Healthcare Services: A Cross-Sectional Study in Urban Slums of Bangladesh.

Digital fingerprints are increasingly used for patient care and treatment delivery, health system monitoring and evaluation, and maintaining data integrity during health research. Yet, no evidence exists about the use of fingerprinting technologies in maternal healthcare services in urban slum contexts, globally. The present study aimed to explore the recently delivered women's willingness to give digital fingerprints to community health workers to access healthcare services in the urban slums of Bangladesh and identify the associated factors. Employing a two-stage cluster random sampling procedure, we chose 458 recently delivered women from eight randomly selected urban slums of Dhaka city, Bangladesh. Chi-square tests were performed for descriptive analyses, and binary logistic regression analyses were performed to explore the factors associated with willingness to provide fingerprints. Overall, 78% of the participants reported that they were willing to provide digital fingerprints if that eased access to healthcare services. After adjusting for potential confounders, the sex of the household head, family type, and household wealth status were significantly associated with the willingness to provide fingerprints to access healthcare services. The study highlighted the potentials of using fingerprints for making healthcare services accessible. Focus is needed for female-headed households, women from poor families, and engaging husbands and in-laws in mobile health programs.

Developing and deploying a community healthcare worker-driven, digitally- enabled integrated care system for municipalities in rural Nepal.

Integrating care at the home and facility level is a critical yet neglected function of healthcare delivery systems. There are few examples in practice or in the academic literature of affordable, digitally-enabled integrated care approaches embedded within healthcare delivery systems in low- and middle-income countries. Simultaneous advances in affordable digital technologies and community healthcare workers offer an opportunity to address this challenge. We describe the development of an integrated care system involving community healthcare worker networks that utilize a home-to-facility electronic health record platform for rural municipalities in Nepal. Key aspects of our approach of relevance to a global audience include: community healthcare workers continuously engaging with populations through household visits every three months; community healthcare workers using digital tools during the routine course of clinical care; individual and population-level data generated routinely being utilized for program improvement; and being responsive to privacy, security, and human rights concerns. We discuss implementation, lessons learned, challenges, and opportunities for future directions in integrated care delivery systems.

Human Cytomegalovirus Delays Neutrophil Apoptosis and Stimulates the Release of a Prosurvival Secretome.

Human cytomegalovirus (HCMV) is a major cause of viral disease in the young and the immune-suppressed. At sites of infection, HCMV recruits the neutrophil, a cell with a key role in orchestrating the initial immune response. Herein, we report a profound survival response in human neutrophils exposed to the clinical HCMV isolate Merlin, but not evident with the attenuated strain AD169, through suppression of apoptosis. The initial survival event, which is independent of viral gene expression and involves activation of the ERK/MAPK and NF-κB pathways, is augmented by HCMV-stimulated release of a secretory cytokine profile that further prolongs neutrophil lifespan. As aberrant neutrophil survival contributes to tissue damage, we predict that this may be relevant to the immune pathology of HCMV, and the presence of this effect in clinical HCMV strains and its absence in attenuated strains implies a beneficial effect to the virus in pathogenesis and/or dissemination. In addition, we show that HCMV-exposed neutrophils release factors that enhance monocyte recruitment and drive monocyte differentiation to a HCMV-permissive phenotype in an IL-6-dependent manner, thus providing an ideal vehicle for viral dissemination. This study increases understanding of HCMV-neutrophil interactions, highlighting the potential role of neutrophil recruitment as a virulence mechanism to promote HCMV pathology in the host and influence the dissemination of HCMV infection. Targeting these mechanisms may lead to new antiviral strategies aimed at limiting host damage and inhibiting viral spread.

Eros is a novel transmembrane protein that controls the phagocyte respiratory burst and is essential for innate immunity.

The phagocyte respiratory burst is crucial for innate immunity. The transfer of electrons to oxygen is mediated by a membrane-bound heterodimer, comprising gp91phox and p22phox subunits. Deficiency of either subunit leads to severe immunodeficiency. We describe Eros (essential for reactive oxygen species), a protein encoded by the previously undefined mouse gene bc017643, and show that it is essential for host defense via the phagocyte NAPDH oxidase. Eros is required for expression of the NADPH oxidase components, gp91phox and p22phox Consequently, Eros-deficient mice quickly succumb to infection. Eros also contributes to the formation of neutrophil extracellular traps (NETS) and impacts on the immune response to melanoma metastases. Eros is an ortholog of the plant protein Ycf4, which is necessary for expression of proteins of the photosynthetic photosystem 1 complex, itself also an NADPH oxio-reductase. We thus describe the key role of the previously uncharacterized protein Eros in host defense.

Identification of LukPQ, a novel, equid-adapted leukocidin of Staphylococcus aureus.

Bicomponent pore-forming leukocidins are a family of potent toxins secreted by Staphylococcus aureus, which target white blood cells preferentially and consist of an S- and an F-component. The S-component recognizes a receptor on the host cell, enabling high-affinity binding to the cell surface, after which the toxins form a pore that penetrates the cell lipid bilayer. Until now, six different leukocidins have been described, some of which are host and cell specific. Here, we identify and characterise a novel S. aureus leukocidin; LukPQ. LukPQ is encoded on a 45 kb prophage (ΦSaeq1) found in six different clonal lineages, almost exclusively in strains cultured from equids. We show that LukPQ is a potent and specific killer of equine neutrophils and identify equine-CXCRA and CXCR2 as its target receptors. Although the S-component (LukP) is highly similar to the S-component of LukED, the species specificity of LukPQ and LukED differs. By forming non-canonical toxin pairs, we identify that the F-component contributes to the observed host tropism of LukPQ, thereby challenging the current paradigm that leukocidin specificity is driven solely by the S-component.

Evasion of Neutrophil Extracellular Traps by Respiratory Pathogens.

The release of neutrophil extracellular traps (NETs) is a major immune mechanism intended to capture pathogens. These histone- and protease-coated DNA structures are released by neutrophils in response to a variety of stimuli, including respiratory pathogens, and have been identified in the airways of patients with respiratory infection, cystic fibrosis, acute lung injury, primary graft dysfunction, and chronic obstructive pulmonary disease. NET production has been demonstrated in the lungs of mice infected with Staphylococcus aureus, Klebsiella pneumoniae, and Aspergillus fumigatus. Since the discovery of NETs over a decade ago, evidence that "NET evasion" might act as an immune protection strategy among respiratory pathogens, including group A Streptococcus, Bordetella pertussis, and Haemophilus influenzae, has been growing, with the majority of these studies being published in the past 2 years. Evasion strategies fall into three main categories: inhibition of NET release by down-regulating host inflammatory responses; degradation of NETs using pathogen-derived DNases; and resistance to the microbicidal components of NETs, which involves a variety of mechanisms, including encapsulation. Hence, the evasion of NETs appears to be a widespread strategy to allow pathogen proliferation and dissemination, and is currently a topic of intense research interest. This article outlines the evidence supporting the three main strategies of NET evasion-inhibition, degradation, and resistance-with particular reference to common respiratory pathogens.

Acute Respiratory Distress Syndrome Neutrophils Have a Distinct Phenotype and Are Resistant to Phosphoinositide 3-Kinase Inhibition.

RATIONALE: Acute respiratory distress syndrome is refractory to pharmacological intervention. Inappropriate activation of alveolar neutrophils is believed to underpin this disease's complex pathophysiology, yet these cells have been little studied. OBJECTIVES: To examine the functional and transcriptional profiles of patient blood and alveolar neutrophils compared with healthy volunteer cells, and to define their sensitivity to phosphoinositide 3-kinase inhibition. METHODS: Twenty-three ventilated patients underwent bronchoalveolar lavage. Alveolar and blood neutrophil apoptosis, phagocytosis, and adhesion molecules were quantified by flow cytometry, and oxidase responses were quantified by chemiluminescence. Cytokine and transcriptional profiling were used in multiplex and GeneChip arrays. MEASUREMENTS AND MAIN RESULTS: Patient blood and alveolar neutrophils were distinct from healthy circulating cells, with increased CD11b and reduced CD62L expression, delayed constitutive apoptosis, and primed oxidase responses. Incubating control cells with disease bronchoalveolar lavage recapitulated the aberrant functional phenotype, and this could be reversed by phosphoinositide 3-kinase inhibitors. In contrast, the prosurvival phenotype of patient cells was resistant to phosphoinositide 3-kinase inhibition. RNA transcriptomic analysis revealed modified immune, cytoskeletal, and cell death pathways in patient cells, aligning closely to sepsis and burns datasets but not to phosphoinositide 3-kinase signatures. CONCLUSIONS: Acute respiratory distress syndrome blood and alveolar neutrophils display a distinct primed prosurvival profile and transcriptional signature. The enhanced respiratory burst was phosphoinositide 3-kinase-dependent but delayed apoptosis and the altered transcriptional profile were not. These unexpected findings cast doubt over the utility of phosphoinositide 3-kinase inhibition in acute respiratory distress syndrome and highlight the importance of evaluating novel therapeutic strategies in patient-derived cells.