TRAV1-2(+) CD8(+) T-cells including oligoconal expansions of MAIT cells are enriched in the airways in human tuberculosis

Mucosal-associated invariant T (MAIT) cells typically express a TRAV1-2(+) semi-invariant TCRalpha that enables recognition of bacterial, mycobacterial, and fungal riboflavin metabolites presented by MR1. MAIT cells are associated with immune control of bacterial and mycobacterial infections in murine models. Here, we report that a population of pro-inflammatory TRAV1-2(+) CD8(+) T cells are present in the airways and lungs of healthy individuals and are enriched in bronchoalveolar fluid of patients with active pulmonary tuberculosis (TB). High-throughput T cell receptor analysis reveals oligoclonal expansions of canonical and donor-unique TRAV1-2(+) MAIT-consistent TCRalpha sequences within this population. Some of these cells demonstrate MR1-restricted mycobacterial reactivity and phenotypes suggestive of MAIT cell identity. These findings demonstrate enrichment of TRAV1-2(+) CD8(+) T cells with MAIT or MAIT-like features in the airways during active TB and suggest a role for these cells in the human pulmonary immune response to Mycobacterium tuberculosis

A Tail’s Tale: Biomechanical Roles Of Dorsal Thoracic Spine Of Barnacle Nauplii

Many marine invertebrates have complex life histories that begin with a planktonic larval stage. Similar to other plankton, these larval invertebrates often possess protruding body extensions, but their function beyond predator deterrence is not well-documented. For example, the planktonic nauplii of crustaceans have spines. Using the epibiotic pedunculate barnacle Octolasmis spp., we investigated how the dorsal thoracic spine affects swimming and fluid disturbance by comparing nauplii with their spines partially removed against those with intact spines. Our motion analysis showed that amputated Octolasmis spp. swam slower, in jerkier trajectories, and were less efficient per stroke cycle than those with intact spines. Amputees showed alterations in limb beat pattern: larger beat amplitude, increased phase lag, and reduced contralateral symmetry. These changes might partially help increase propulsive force generation and streamline the flow, but were insufficient to restore full function. Particle image velocimetry further showed that amputees had a larger relative area of influence, implying elevated risk by rheotactic predator. Body extensions and their interactions with limb motion play important biomechanical roles in shaping larval performance, which likely influences the evolution of form

A PowerPack of SuperScientists: An innovative concept by African scientists to address gender bias and inequity in science [version 2; peer review: 1 approved, 1 approved with reservations]

Underrepresentation of women in scientific leadership is a global problem. To understand and counter narratives that limit gender equity in African science, we conducted a public engagement campaign. Scientists representing six sub-Saharan African countries and multiple career stages used superhero imagery to create a diverse and unified team advocating for gender equity in science. In contrast to many traditional scientific environments and global campaigns, this “PowerPack of SuperScientists” was led by early-career Black female scientists whose perspectives are often under-represented in discussions about gender equity in science. The superhero imagery served as a powerful and fun antidote to imposter syndrome and helped to subvert traditional power structures based on age, race and sex. In an interactive social media campaign, the PowerPack developed insights into three themes: a) cultural stereotypes that limit women’s scientific careers, b) the perception of a “conflict” between family and career responsibilities for women scientists, and c) solutions that can be adopted by key stakeholders to promote gender equity in African science. The PowerPack proposed solutions that could be undertaken by women working individually or collectively and interventions that require allyship from men, commitment from scientific institutions, and wider societal change. Further work is required to fully engage African scientists from even more diverse and disadvantaged backgrounds and institutions in these solutions and to enhance commitment by different stakeholders to achieving gender equity in science. Our experience suggests that creative tools should be used to subvert power dynamics and bring fresh perspectives and urgency to this topic.</ns4:p

Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control

NK cell activation has been shown to be metabolically regulated in vitro; however, the role of metabolism during in vivo NK cell responses to infection is unknown. We examined the role of glycolysis in NK cell function during murine cytomegalovirus (MCMV) infection and the ability of IL-15 to prime NK cells during CMV infection. The glucose metabolism inhibitor 2-deoxy-ᴅ-glucose (2DG) impaired both mouse and human NK cell cytotoxicity following priming in vitro. Similarly, MCMV-infected mice treated with 2DG had impaired clearance of NK-specific targets in vivo, which was associated with higher viral burden and susceptibility to infection on the C57BL/6 background. IL-15 priming is known to alter NK cell metabolism and metabolic requirements for activation. Treatment with the IL-15 superagonist ALT-803 rescued mice from otherwise lethal infection in an NK-dependent manner. Consistent with this, treatment of a patient with ALT-803 for recurrent CMV reactivation after hematopoietic cell transplant was associated with clearance of viremia. These studies demonstrate that NK cell-mediated control of viral infection requires glucose metabolism and that IL-15 treatment in vivo can reduce this requirement and may be effective as an antiviral therapy

Linkage to primary care after home-based blood pressure screening in rural KwaZulu-Natal, South Africa: a population-based cohort study

Objectives: The expanding burden of non-communicable diseases (NCDs) globally will require novel public health strategies. Community-based screening has been promoted to augment efficiency of diagnostic services, but few data are available on the downstream impact of such programmes. We sought to assess the impact of a home-based blood pressure screening programme on linkage to hypertension care in rural South Africa.  Setting: We conducted home-based blood pressure screening withinin a population cohort in rural KwaZulu-Natal, using the WHO Stepwise Approach to Surveillance (STEPS) protocol.  Participants: Individuals meeting criteria for raised blood pressure (≥140 systolic or ≥90 diastolic averaged over two readings) were referred to local health clinics and included in this analysis. We defined linkage to care based on self-report of presentation to clinic for hypertension during the next 2 years of cohort observation. We estimated the population proportion of successful linkage to care with inverse probability sampling weights, and fit multivariable logistic regression models to identify predictors of linkage following a positive hypertension screen.  Results: Of 11 694 individuals screened, 14.6% (n=1706) were newly diagnosed with elevated pressure. 26.9% (95% CI 24.5% to 29.4%) of those sought hypertension care in the following 2 years, and 38.1% (95% CI 35.6% to 40.7%) did so within 5 years. Women (adjusted OR (aOR) 2.41, 95% CI 1.68 to 3.45), those of older age (aOR 11.49, 95% CI 5.87 to 22.46, for 45–59 years vs <30) and those unemployed (aOR 1.71, 95% CI 1.10 to 2.65) were more likely to have linked to care.  Conclusions: Linkage to care after home-based identification of elevated blood pressure was rare in rural South Africa, particularly among younger individuals, men and the employed. Improved understanding of barriers and facilitators to NCD care is needed to enhance the effectiveness of blood pressure screening in the region

Participant understanding of informed consent in a multidisease community-based health screening and biobank platform in rural South Africa.

BACKGROUND: In low- and middle-income settings, obtaining informed consent for biobanking may be complicated by socio-economic vulnerability and context-specific power dynamics. We explored participants experiences and perceptions of the research objectives in a community-based multidisease screening and biospecimen collection platform in rural KwaZulu-Natal, South Africa. METHODS: We undertook semi-structured in-depth interviews to assess participant understanding of the informed consent, research objectives and motivation for participation. RESULTS: Thirty-nine people participated (individuals who participated in screening/biospecimen collection and those who did not and members of the research team). Some participants said they understood the information shared with them. Some said they participated due to the perceived benefits of the reimbursement and convenience of free healthcare. Most who did not participate said it was due to logistical rather than ethical concerns. None of the participants recalled aspects of biobanking and genetics from the consent process. CONCLUSIONS: Although most people understood the study objectives, we observed challenges to identifying language appropriate to explain biobanking and genetic testing to our target population. Engagement with communities to adopt contextually relevant terminologies that participants can understand is crucial. Researchers need to be mindful of the impact of communities' socio-economic status and how compensation can be potentially coercive

Low Levels of Peripheral CD161++CD8+ Mucosal Associated Invariant T (MAIT) Cells Are Found in HIV and HIV/TB Co-Infection

Background: High expression of CD161 on CD8+ T cells is associated with a population of cells thought to play a role in mucosal immunity. We wished to investigate this subset in an HIV and Mycobacterium tuberculosis (MTB) endemic African setting. Methods: A flow cytometric approach was used to assess the frequency and phenotype of CD161++CD8+ T cells. 80 individuals were recruited for cross-sectional analysis: controls (n = 18), latent MTB infection (LTBI) only (n = 16), pulmonary tuberculosis (TB) only (n = 8), HIV only (n = 13), HIV and LTBI co-infection (n = 15) and HIV and TB co-infection (n = 10). The impact of acute HIV infection was assessed in 5 individuals recruited within 3 weeks of infection. The frequency of CD161++CD8+ T cells was assessed prior to and during antiretroviral therapy (ART) in 14 HIV-positive patients. Results: CD161++CD8+ T cells expressed high levels of the HIV co-receptor CCR5, the tissue-homing marker CCR6, and the Mucosal-Associated Invariant T (MAIT) cell TCR Vα7.2. Acute and chronic HIV were associated with lower frequencies of CD161++CD8+ T cells, which did not correlate with CD4 count or HIV viral load. ART was not associated with an increase in CD161++CD8+ T cell frequency. There was a trend towards lower levels of CD161++CD8+ T cells in HIV-negative individuals with active and latent TB. In those co-infected with HIV and TB, CD161++CD8+ T cells were found at low levels similar to those seen in HIV mono-infection. Conclusions: The frequencies and phenotype of CD161++CD8+ T cells in this South African cohort are comparable to those published in European and US cohorts. Low-levels of this population were associated with acute and chronic HIV infection. Lower levels of the tissue-trophic CD161++ CD8+ T cell population may contribute to weakened mucosal immune defense, making HIV-infected subjects more susceptible to pulmonary and gastrointestinal infections and detrimentally impacting on host defense against TB

Gpr37l1 Modulates Seizure Susceptibility: Evidence from Mouse Studies and Analyses of a Human Gpr37l1 Variant

Progressive myoclonus epilepsies (PMEs) are disorders characterized by myoclonic and generalized seizures with progressive neurological deterioration. While several genetic causes for PMEs have been identified, the underlying causes remain unknown for a substantial portion of cases. Here we describe several affected individuals from a large, consanguineous family presenting with a novel PME in which symptoms begin in adolescence and result in death by early adulthood. Whole exome analyses revealed that affected individuals have a homozygous variant in GPR37L1 (c.1047G \u3e T [Lys349Asn]), an orphan G protein-coupled receptor (GPCR) expressed predominantly in the brain. In vitro studies demonstrated that the K349N substitution in Gpr37L1 did not grossly alter receptor expression, surface trafficking or constitutive signaling in transfected cells. However, in vivo studies revealed that a complete loss of Gpr37L1 function in mice results in increased seizure susceptibility. Mice lacking the related receptor Gpr37 also exhibited an increase in seizure susceptibility, while genetic deletion of both receptors resulted in an even more dramatic increase in vulnerability to seizures. These findings provide evidence linking GPR37L1 and GPR37 to seizure etiology and demonstrate an association between a GPR37L1 variant and a novel progressive myoclonus epilepsy

Participant recall and understandings of information on biobanking and future genomic research: experiences from a multi-disease community-based health screening and biobank platform in rural South Africa.

BACKGROUND: Limited research has been conducted on explanations and understandings of biobanking for future genomic research in African contexts with low literacy and limited healthcare access. We report on the findings of a sub-study on participant understanding embedded in a multi-disease community health screening and biobank platform study known as 'Vukuzazi' in rural KwaZulu-Natal, South Africa. METHODS: Semi-structured interviews were conducted with research participants who had been invited to take part in the Vukuzazi study, including both participants and non-participants, and research staff that worked on the study. The interviews were transcribed, and themes were identified from the interview transcripts, manually coded, and thematically analysed. RESULTS: Thirty-nine individuals were interviewed. We found that the research team explained biobanking and future genomic research by describing how hereditary characteristics create similarities among individuals. However, recollection and understanding of this explanation seven months after participation was variable. The large volume of information about the Vukuzazi study objectives and procedures presented a challenge to participant recall. By the time of interviews, some participants recalled rudimentary facts about the genetic aspects of the study, but many expressed little to no interest in genetics and biobanking. CONCLUSION: Participant's understanding of information related to genetics and biobanking provided during the consent process is affected by the volume of information as well as participant's interest (or lack thereof) in the subject matter being discussed. We recommend that future studies undertaking biobanking and genomic research treat explanations of this kind of research to participants as an on-going process of communication between researchers, participants and the community and that explanatory imagery and video graphic storytelling should be incorporated into theses explanations as these have previously been found to facilitate understanding among those with low literacy levels. Studies should also avoid having broader research objectives as this can divert participant's interest and therefore understanding of why their samples are being collected

Intracellular growth of Mycobacterium tuberculosis after macrophage cell death leads to serial killing of host cells

A hallmark of pulmonary tuberculosis is the formation of macrophage-rich granulomas. These may restrict Mycobacterium tuberculosis (Mtb) growth, or progress to central necrosis and cavitation, facilitating pathogen growth. To determine factors leading to Mtb proliferation and host cell death, we used live cell imaging to track Mtb infection outcomes in individual primary human macrophages. Internalization of Mtb aggregates caused macrophage death, and phagocytosis of large aggregates was more cytotoxic than multiple small aggregates containing similar numbers of bacilli. Macrophage death did not result in clearance of Mtb. Rather, it led to accelerated intracellular Mtb growth regardless of prior activation or macrophage type. In contrast, bacillary replication was controlled in live phagocytes. Mtb grew as a clump in dead cells, and macrophages which internalized dead infected cells were very likely to die themselves, leading to a cell death cascade. This demonstrates how pathogen virulence can be achieved through numbers and aggregation states. DOI: http://dx.doi.org/10.7554/eLife.22028.00