Insufficient yet improving involvement of the global south in top sustainability science publications.

The creation of global research partnerships is critical to produce shared knowledge for the implementation of the UN 2030 Agenda for Sustainable Development. Sustainability science promotes the coproduction of inter- and transdisciplinary knowledge, with the expectation that studies will be carried out through groups and truly collaborative networks. As a consequence, sustainability research, in particular that published in high impact journals, should lead the way in terms of ethical partnership in scientific collaboration. Here, we examined this issue through a quantitative analysis of the articles published in Nature Sustainability (300 papers by 2135 authors) and Nature (2994 papers by 46,817 authors) from January 2018 to February 2021. Focusing on these journals allowed us to test whether research published under the banner of sustainability science favoured a more equitable involvement of authors from countries belonging to different income categories, by using the journal Nature as a control. While the findings provide evidence of still insufficient involvement of Low-and-Low-Middle-Income-Countries (LLMICs) in Nature Sustainability publications, they also point to promising improvements in the involvement of such authors. Proportionally, there were 4.6 times more authors from LLMICs in Nature Sustainability than in Nature articles, and 68.8-100% of local Global South studies were conducted with host country scientists (reflecting the discouragement of parachute research practices), with local scientists participating in key research steps. We therefore provide evidence of the promising, yet still insufficient, involvement of low-income countries in top sustainability science publications and discuss ongoing initiatives to improve this.

Who is telling the story? A systematic review of authorship for infectious disease research conducted in Africa, 1980-2016.

INTRODUCTION: Africa contributes little to the biomedical literature despite its high burden of infectious diseases. Global health research partnerships aimed at addressing Africa-endemic disease may be polarised. Therefore, we assessed the contribution of researchers in Africa to research on six infectious diseases. METHODS: We reviewed publications on HIV and malaria (2013-2016), tuberculosis (2014-2016), salmonellosis, Ebola haemorrhagic fever and Buruli ulcer disease (1980-2016) conducted in Africa and indexed in the PubMed database using Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. Papers reporting original research done in Africa with at least one laboratory test performed on biological samples were included. We studied African author proportion and placement per study type, disease, funding, study country and lingua franca. RESULTS: We included 1182 of 2871 retrieved articles that met the inclusion criteria. Of these, 1109 (93.2%) had at least one Africa-based author, 552 (49.8%) had an African first author and 41.3% (n=458) an African last author. Papers on salmonellosis and tuberculosis had a higher proportion of African last authors (p<0.001) compared with the other diseases. Most of African first and last authors had an affiliation from an Anglophone country. HIV, malaria, tuberculosis and Ebola had the most extramurally funded studies (≥70%), but less than 10% of the acknowledged funding was from an African funder. CONCLUSION: African researchers are under-represented in first and last authorship positions in papers published from research done in Africa. This calls for greater investment in capacity building and equitable research partnerships at every level of the global health community.

Ontogeny of human mucosal-associated invariant T cells and related T cell subsets.

Mucosal-associated invariant T (MAIT) cells are semi-invariant Vα7.2+ CD161highCD4- T cells that recognize microbial riboflavin precursor derivatives such as 5-OP-RU presented by MR1. Human MAIT cells are abundant in adult blood, but there are very few in cord blood. We longitudinally studied Vα7.2+ CD161high T cell and related subset levels in infancy and after cord blood transplantation. We show that Vα7.2+ and Vα7.2- CD161high T cells are generated early during gestation and likely share a common prenatal developmental program. Among cord blood Vα7.2+ CD161high T cells, the minority recognizing MR1:5-OP-RU display a TRAV/TRBV repertoire very similar to adult MAIT cells. Within a few weeks of life, only the MR1:5-OP-RU reactive Vα7.2+ CD161high T cells acquire a memory phenotype. Only these cells expand to form the adult MAIT pool, diluting out other Vα7.2+ CD161high and Vα7.2- CD161high populations, in a process requiring at least 6 years to reach adult levels. Thus, the high clonal size of adult MAIT cells is antigen-driven and likely due to the fine specificity of the TCRαß chains recognizing MR1-restricted microbial antigens.

Mucosal-associated invariant T cell-rich congenic mouse strain allows functional evaluation.

Mucosal-associated invariant T cells (MAITs) have potent antimicrobial activity and are abundant in humans (5%-10% in blood). Despite strong evolutionary conservation of the invariant TCR-α chain and restricting molecule MR1, this population is rare in laboratory mouse strains (≈0.1% in lymphoid organs), and lack of an appropriate mouse model has hampered the study of MAIT biology. Herein, we show that MAITs are 20 times more frequent in clean wild-derived inbred CAST/EiJ mice than in C57BL/6J mice. Increased MAIT frequency was linked to one CAST genetic trait that mapped to the TCR-α locus and led to higher usage of the distal Vα segments, including Vα19. We generated a MAIThi congenic strain that was then crossed to a transgenic Rorcgt-GFP reporter strain. Using this tool, we characterized polyclonal mouse MAITs as memory (CD44+) CD4-CD8lo/neg T cells with tissue-homing properties (CCR6+CCR7-). Similar to human MAITs, mouse MAITs expressed the cytokine receptors IL-7R, IL-18Rα, and IL-12Rß and the transcription factors promyelocytic leukemia zinc finger (PLZF) and RAR-related orphan receptor γ (RORγt). Mouse MAITs produced Th1/2/17 cytokines upon TCR stimulation and recognized a bacterial compound in an MR1-dependent manner. During experimental urinary tract infection, MAITs migrated to the bladder and decreased bacterial load. Our study demonstrates that the MAIThi congenic strain allows phenotypic and functional characterization of naturally occurring mouse MAITs in health and disease.

Double-positive thymocytes select mucosal-associated invariant T cells.

NKT and mucosal-associated invariant T (MAIT) cells express semi-invariant TCR and restriction by nonclassical MHC class Ib molecules. Despite common features, the respective development of NKT and MAIT subsets is distinct. NKTs proliferate extensively and acquire effector properties prior to thymic export. MAIT cells exit the thymus as naive cells and acquire an effector/memory phenotype in a process requiring both commensal flora and B cells. During thymic development, NKTs are selected by CD1d-expressing cortical thymocytes; however, the hematopoietic cell type responsible for MAIT cell selection remains unresolved. Using reaggregated thymic organ culture and bone marrow chimeras, we demonstrate that positive selection of mouse iVα19 transgenic and Vß6 transgenic MAIT cell progenitors requires MHC-related 1-expressing CD4(+)CD8(+) double positive thymocytes, whereas thymic B cells, macrophages, and dendritic cell subsets are dispensable. Preincubation of double positive thymocytes with exogenous bacterial ligand increases MHC-related 1 surface expression and enhances mature MAIT cell activation in the in vitro cocultures. The revelation of a common cell type for the selection of both NKT and MAIT subsets raises questions about the mechanisms underlying acquisition of their specific features.

MAIT cells, surveyors of a new class of antigen: development and functions.

Mucosal associated invariant T (MAIT) cells are evolutionarily conserved T cells that are restricted by the non-classical MHC-1b molecule, MR1. MAIT cells are selected on hematopoietic cells, and exit the thymus with a naïve phenotype before expanding in the periphery and attaining a memory phenotype. MAIT cells represent an abundant oligoclonal population in human blood and liver. MAIT cells react against a newly identified class of antigens: vitamin B metabolites, which are found in most bacteria and yeasts. MAIT cells secrete IFN-γ and IL-17 and their frequencies are modified in several diseases. The specificity, evolutionary conservation and unique features of MAIT cells indicate important functions, either against a ubiquitous pathogen or in gut immune/epithelial homeostasis.

Human beta-defensin 3 induces maturation of human langerhans cell-like dendritic cells: an antimicrobial peptide that functions as an endogenous adjuvant.

Human beta-defensins (hBDs) are antimicrobial peptides that have an important role in innate immune responses at epithelial barriers such as the skin. However, the role that hBDs have in initiating cellular immune responses that contribute to antigen-specific adaptive immunity is not well understood. Here we show that one member of the hBD family, hBD3, can induce maturation and T-helper type 1 skewing function in human Langerhans cell-like dendritic cells (LC-DCs). Specifically, hBD3 potently induces phenotypic maturation of LC-DCs, including increased expression of CCR7, which mediates functional chemotactic responses to CCL19 and CCL21. hBD3-stimulated LC-DCs induce strong proliferation of and IFN-γ secretion by naive human T cells. hBD3 also induces phenotypic maturation of primary human skin-migratory DCs derived from human skin explants. These results suggest an important role for hBD3 in inducing DC activation, migration, and polarization. Thus, hBD3 contributes to the integration of innate and adaptive immune responses in the skin, and may be a useful adjuvant for skin immunization and an important factor in the pathophysiology of inflammatory skin diseases.

Defective NF-κB signaling in metastatic head and neck cancer cells leads to enhanced apoptosis by double-stranded RNA.

Ligands to several Toll-like receptors (TLR), which mediate innate immune responses and chronic inflammation have been used as adjuvants to immunotherapy to enhance their antitumor activity. In particular, double-stranded RNAs that are cognate ligands of TLR3 have been used to trigger proapoptotic activity in cancer cells. However, a mechanistic understanding of TLR3-mediated apoptosis and its potential involvement in controlling tumor metastasis has been lacking. In this study, we used paired cell lines and fresh tumor specimens, derived from autologous primary and metastatic head and neck squamous cell carcinoma, to investigate the role of TLR3 signaling in metastatic progression. Compared with primary tumor cells, metastatic tumor cells were highly sensitive to TLR3-mediated apoptosis after double-stranded RNA treatment. Enhanced apoptosis in metastatic cells was dependent on double-stranded RNA and TLR3 and also the TLR3 effector signaling protein TRIF. Downstream responses requiring NF-κB were critical for apoptosis in metastatic cells, the defects in which could be resuscitated by alternative pathways of NF-κB activation. By elucidating how TLR3 ligands trigger apoptosis in metastatic cells, our findings suggest insights into how to improve their clinical use.

Chemokine receptor 7 (CCR7) gene expression is regulated by NF-κB and activator protein 1 (AP1) in metastatic squamous cell carcinoma of head and neck (SCCHN).

The chemokine receptor CCR7 is a seven-transmembrane domain G-protein-coupled receptor that facilitates leukocyte migration to regional lymph nodes. Aberrant CCR7 expression in a number of human malignancies has been linked to pro-survival, -invasive, and -metastatic pathways. We demonstrate here that up-regulation of CCR7 in squamous cell carcinoma of the head and neck (SCCHN) patient tumors correlates with lower survival because of metastatic disease. Because of this important oncogenic phenotype, we investigated the mechanisms that regulate CCR7 expression in these tumors. Interestingly, the inflammatory transcription factor NF-κB has been associated with a more aggressive SCCHN phenotype. Immunohistochemical staining of a SCCHN tumor cohort (n = 47) strongly linked NF-κB staining and CCR7 expression in SCCHN. Thus, we investigated whether NF-κB contributes to metastatic disease by promoting CCR7 expression in SCCHN tumor cells. We characterized four novel, potential NF-κB binding sites in the 1000-bp promoter region upstream of the CCR7 gene, using luciferase, ChIP, and EMSA. However, NF-κB inhibition only resulted in partial reduction in CCR7 expression, prompting consideration of other co-regulators of CCR7. Indeed, cooperation between NF-κB and AP1 transcription factors, which are often co-activated, is crucial to the regulation of CCR7 mRNA expression in metastatic SCCHN cells. Thus, our findings support an important biological role for inflammatory NF-κB and AP1 in the regulation of CCR7 expression in metastatic SCCHN. As such, CCR7, NF-κB, and AP1 could be potentially useful therapeutic targets in controlling the progression and metastasis of SCCHN tumors.

Human ß-defensin 3 promotes NF-κB-mediated CCR7 expression and anti-apoptotic signals in squamous cell carcinoma of the head and neck.

The microenvironment of aerodigestive cancers contains tumor-promoting inflammatory signals often involved in innate immunity. The epithelial malignancy, squamous cell carcinoma of the head and neck (SCCHN), is characterized by secretion of inflammatory mediators that can promote tumorigenesis and lymph node metastasis. Human ß-defensin (hBD) 3 is one such antimicrobial mediator of innate immunity produced by squamous epithelial cells in response to tissue damage and inflammation. Here, we hypothesized that the observed overexpression of hBD3 in SCCHN may have a tumor-promoting effect or contribute to nodal metastasis, which has previously been linked to chemokine receptor (CCR) 7 overexpression. Indeed, treatment of non-metastatic SCCHN cells with hBD3 induced surface CCR7 expression and migration toward its ligand, CCL19. The hBD3-induced CCR7 upregulation in SCCHN cells was significantly reduced by inhibition of nuclear factor (NF)-κB, an inflammatory transcription factor known to influence CCR7 expression. Moreover, hBD3 stimulation provided anti-apoptotic signals to SCCHN cells, as evidenced by tumor resistance to cisplatin-induced cell death, which was regulated by phosphoinositide-3-kinase/Akt activation. Interestingly, the observed hBD3-mediated effects were not dependent on G-protein coupled receptors or toll-like receptors, as has been previously published, but hBD3 was internalized through endocytosis, allowing intracellular signal transduction. Our findings suggest that hBD3 represents a novel NF-κB-regulated mediator of CCR7 expression and anti-apoptotic pathways, which may be exploited by developing SCCHN tumors to enhance their survival and metastasis.

High-throughput screening for TLR3-IFN regulatory factor 3 signaling pathway modulators identifies several antipsychotic drugs as TLR inhibitors.

TLR3 is one of the major innate immune sensors of dsRNA. The signal transduction pathway activated by TLR3, upon binding to dsRNA, leads to the activation of two major transcription factors: NF-kappaB and IFN regulatory factor (IRF) 3. In an effort to identify specific chemical modulators of TLR3-IRF3 signal transduction pathway, we developed a cell-based readout system. Using the IFN-stimulated gene 56 promoter-driven firefly luciferase gene stably integrated in a TLR3-expressing HEK293 cell line, we were able to generate a cell line where treatment with dsRNA resulted in a dose-dependent induction of luciferase activity. A screen of two pharmacologically active compound libraries using this system identified a number of TLR3-IRF3 signaling pathway modulators. Among them we focused on a subset of inhibitors and characterized their mode of action. Several antipsychotic drugs, such as sertraline, trifluoperazine, and fluphenazine, were found to be direct inhibitors of the innate immune signaling pathway. These inhibitors also showed the ability to inhibit IFN-stimulated gene 56 induction mediated by TLR4 and TLR7/8 pathways. Interestingly, they did not show significant effects on TLR3-, TLR7-, and TLR8-mediated NF-kappaB activation. Detailed analysis of the signaling pathway indicated that these drugs might be exerting their inhibitory effects on IRF3 via PI3K signaling pathway. The data presented in this study provide mechanistic explanation of possible anti-inflammatory roles of some antipsychotic drugs.

CCR7 mediates inflammation-associated tumor progression.

Chemokine receptor 7 (CCR7) mediates leukocyte adhesion and chemotaxis from peripheral sites of inflammation through lymphatic channels to secondary lymphoid organs. Aberrant CCR7 expression has been identified on certain tumor types and been linked to pro-survival and invasive pathways. In metastatic squamous cell carcinoma of the head and neck (SCCHN), we have described the selective upregulation of functional CCR7. In this manuscript, we review our understanding of CCR7-mediated signaling in metastatic SCCHN and provide evidence for its involvement in tumor survival, invasion, and metastasis. Autocrine and paracrine CCR7 activation appears to propagate the response to the CCR7 ligands CCL19 and CCL21, which are expressed by the lymphatic endothelium, secondary lymphoid tissues, and CCR7-positive tumor cells. Based on our recent findings, the induction of CCR7 expression and the sustenance of the autocrine signaling pathway have been shown to be regulated by NF-kappaB, similar to several types of immune cells. While extending these observations to metastatic SCCHN tumor cells, our studies highlight the importance of downstream NF-kappaB mediated CCR7 signals in the progression of SCCHN malignancy.

Somatic mutations in the mitochondria of rheumatoid arthritis synoviocytes.

Somatic mutations have a role in the pathogenesis of a number of diseases, particularly cancers. Here we present data supporting a role of mitochondrial somatic mutations in an autoimmune disease, rheumatoid arthritis (RA). RA is a complex, multifactorial disease with a number of predisposition traits, including major histocompatibility complex (MHC) type and early bacterial infection in the joint. Somatic mutations in mitochondrial peptides displayed by MHCs may be recognized as non-self, furthering the destructive immune infiltration of the RA joint. Because many bacterial proteins have mitochondrial homologues, the immune system may be primed against these altered peptides if they mimic bacterial homologues. In addition, somatic mutations may be influencing cellular function, aiding in the acquirement of transformed properties of RA synoviocytes. To test the hypothesis that mutations in mitochondrial DNA (mtDNA) are associated with RA, we focused on the MT-ND1 gene for mitochondrially encoded NADH dehydrogenase 1 (subunit one of complex I - NADH dehydrogenase) of synoviocyte mitochondria from RA patients, using tissue from osteoarthritis (OA) patients for controls. We identified the mutational burden and amino acid changes in potential epitope regions in the two patient groups. RA synoviocyte mtDNA had about twice the number of mutations as the OA group. Furthermore, some of these changes had resulted in potential non-self MHC peptide epitopes. These results provide evidence for a new role for somatic mutations in mtDNA in RA and predict a role in other diseases.