Selective Expression of the Vβ14 T Cell Receptor on Leishmania guyanensis-Specific CD8+ T Cells during Human Infection

Peripheral blood mononuclear cells from subjects never exposed to Leishmania were stimulated with Leishmania guyanensis. We demonstrated that L. guyanensis-stimulated CD8+ T cells produced interferon (IFN)-γ and preferentially expressed the Vb14 T cell receptor (TCR) gene family. In addition, these cells expressed cutaneous lymphocyte antigen and CCR4 surface molecules, suggesting that they could migrate to the skin. Results obtained from the lesions of patients with localized cutaneous leishmaniaisis (LCL) showed that Vβ14 TCR expression was increased in most lesions (63.5%) and that expression of only a small number of Vb gene families (Vβ1, Vβ6, Vβ9, Vβ14, and Vβ24) was increased. The presence of Vβ14 T cells in tissue confirmed the migration of these cells to the lesion site. Thus, we propose the following sequence of events during infection with L. guyanensis. After initial exposure to L. guyanensis, CD8+ T cells preferentially expressing the Vb14 TCR and secreting IFN-γ develop and circulate in the periphery. During the infection, these cells migrate to the skin at the site of the parasitic infection. The role of these Vβ14 CD8+ T cells in resistance to infection remains to be determined conclusivel

In Leishmaniasis due to Leishmania guyanensis infection, distinct intralesional interleukin-10 and foxp3 mRNA expression are associated with unresponsiveness to treatment

The presence of intralesional natural regulatory T cells, characterized by the expression of Foxp3 mRNA, was analyzed in patients with localized leishmaniasis due to Leishmania guyanensis infection that was unresponsive to treatment with pentamidine isethionate. Foxp3 mRNA levels were associated with unresponsiveness to treatment among patients with a lesion duration of ⩾1 month, but this association was not observed among patients with a lesion duration of <1 month. In conclusion, high intralesional expression of Foxp3 might be an indicator of poor response to treatment, depending on the duration of lesion

Does T Helper Differentiation Correlate with Resistance or Susceptibility to Infection with L. major? Some Insights From the Murine Model

The murine model of Leishmania major infection has been an invaluable tool in understanding T helper differentiation in vivo. The initial evidence for a role of distinct CD4+ T helper subsets in the outcome of infection was first obtained with this experimental model. The development of CD4+ Th1 cells was associated with resolution of the lesion, control of parasite replication, and resistance to re-infection in most of the mouse strains investigated (i.e., C57BL/6). In contrast, differentiation of CD4+ Th2 cells correlated with the development of unhealing lesions, and failure to control parasite load in a few strains (i.e., BALB/c). Since these first reports, an incredible amount of effort has been devoted to understanding the various parameters involved in the differentiation of these, and more recently discovered T helper subsets such as Th17 and T regulatory cells. The discovery of cross-talk between T helper subsets, as well as their plasticity force us to reevaluate the events driving a protective/deleterious T helper immune response following infection with L. major in mice. In this review, we describe the individual contributions of each of these CD4+ T helper subsets following L. major inoculation, emphasizing recent advances in the field, such as the impact of different substrains of L. major on the pathogenesis of disease

Leishmaniavirus-dependent metastatic leishmaniasis is prevented by blocking IL-17A

Cutaneous leishmaniasis has various outcomes, ranging from self-healing reddened papules to extensive open ulcerations that metastasise to secondary sites and are often resistant to standard therapies. In the case of L. guyanensis (L.g), about 5-10% of all infections result in metastatic complications. We recently showed that a cytoplasmic virus within L.g parasites (LRV1) is able to act as a potent innate immunogen, worsening disease outcome in a murine model. In this study, we investigated the immunophenotype of human patients infected by L.g and found a significant association between the inflammatory cytokine IL-17A, the presence of LRV1 and disease chronicity. Further, IL-17A was inversely correlated to the protective cytokine IFN-γ. These findings were experimentally corroborated in our murine model, where IL-17A produced in LRV1+ L.g infection contributed to parasite virulence and dissemination in the absence of IFN-γ. Additionally, IL-17A inhibition in mice using digoxin or SR1001, showed therapeutic promise in limiting parasite virulence. Thus, this murine model of LRV1-dependent infectious metastasis validated markers of disease chronicity in humans and elucidated the immunologic mechanism for the dissemination of Leishmania parasites to secondary sites. Moreover, it confirms the prognostic value of LRV1 and IL-17A detection to prevent metastatic leishmaniasis in human patients

T Cell Reactivity against Mycolyl Transferase Antigen 85 of M. tuberculosis in HIV-TB Coinfected Subjects and in AIDS Patients Suffering from Tuberculosis and Nontuberculous Mycobacterial Infections

The mycolyl transferase antigen 85 complex is a major secreted protein family from mycobacterial culture filtrate, demonstrating powerful T cell stimulatory properties in most HIV-negative, tuberculin-positive volunteers with latent M.tuberculosis infection and only weak responses in HIV-negative tuberculosis patients. Here, we have analyzed T cell reactivity against PPD and Ag85 in HIV-infected individuals, without or with clinical symptoms of tuberculosis, and in AIDS patients with disease caused by nontuberculous mycobacteria. Whereas responses to PPD were not significantly different in HIV-negative and HIV-positive tuberculin-positive volunteers, responses to Ag85 were significantly decreased in the HIV-positive (CDC-A and CDC-B) group. Tuberculosis patients demonstrated low T cell reactivity against Ag85, irrespective of HIV infection, and finally AIDS patients suffering from NTM infections were completely nonreactive to Ag85. A one-year follow-up of twelve HIV-positive tuberculin-positive individuals indicated a decreased reactivity against Ag85 in patients developing clinical tuberculosis, highlighting the protective potential of this antigen

Neutrophil-Derived CCL3 Is Essential for the Rapid Recruitment of Dendritic Cells to the Site of Leishmania major Inoculation in Resistant Mice

Neutrophils are rapidly and massively recruited to sites of microbial infection, where they can influence the recruitment of dendritic cells. Here, we have analyzed the role of neutrophil released chemokines in the early recruitment of dendritic cells (DCs) in an experimental model of Leishmania major infection. We show in vitro, as well as during infection, that the parasite induced the expression of CCL3 selectively in neutrophils from L. major resistant mice. Neutrophil-secreted CCL3 was critical in chemotaxis of immature DCs, an effect lost upon CCL3 neutralisation. Depletion of neutrophils prior to infection, as well as pharmacological or genetic inhibition of CCL3, resulted in a significant decrease in DC recruitment at the site of parasite inoculation. Decreased DC recruitment in CCL3−/− mice was corrected by the transfer of wild type neutrophils at the time of infection. The early release of CCL3 by neutrophils was further shown to have a transient impact on the development of a protective immune response. Altogether, we identified a novel role for neutrophil-secreted CCL3 in the first wave of DC recruitment to the site of infection with L. major, suggesting that the selective release of neutrophil-secreted chemokines may regulate the development of immune response to pathogens

The process of developing a joint theory of change across three global entities: can this help to make their efforts to strengthen capacity for implementation research more effective?

Introduction: A theory of change is a visual representation of the pathway by which a programme anticipates it will achieve its goal. It usually starts with discussions around the goal and works backwards through outcomes and outputs to activities. // Methods: We used a theory of change to improve coherence across three research entities at the WHO. Part of the remit of all three entities is to strengthen capacity in low-income and middle-income countries for implementation research. // Results: Representatives from the three entities were able to formulate a joint goal for strengthening capacity in implementation research. They identified three pathways by which this could be achieved: (a) conducting implementation research, (b) strengthening implementation research systems and (c) using implementation research for public health priorities. // Conclusion: The process of developing the theory of change and the logic framework it created, provided a means to track progress towards the goal and to guide improvements in programmes within their lifetime. The process we used to develop the theory of change and the pathways to achieve the joint goal are adaptable and could be used by other organisations that also aim to strengthen research capacity. This would lead to more coherence, better translation of research findings into decision-making and ultimately improvements in public health

Lessons learned developing a massive open online course in implementation research in infectious diseases of poverty in low- and middle-income countries

Daniel Reidpath - ORCID: 0000-0002-8796-0420 https://orcid.org/0000-0002-8796-0420This study uses a case study approach to examine the development of a massive open online course (MOOC) on intervention and implementation research in infectious diseases of poverty for learners in low- and middle-income countries (LMICs). Implementation research (IR) seeks to understand and address barriers to effective implementation of health interventions, strategies, and policies. In recent years, IR has attracted increased interest, and corresponding demand for training, however, current training opportunities are not easily accessible to learners in LMICs. In 2017, the MOOC was introduced to a diverse range of learners to enhance access to training materials and has been offered yearly since. Findings are based on the experiences of the MOOC working group which included developers and facilitators, and on interpretations of data such as forum discussion activity and Facebook posts. The use of material from local contexts and in local languages, and professional facilitation of discussion forums was identified by the working group to be key considerations in developing the MOOC. Other findings include the importance of using clear instructions and preparing discussion questions to stimulate learner engagement. These findings add to the limited knowledge of MOOCs developed for LMICs and are of value to others developing professional development MOOCs in LMIC health contexts.http://doi.org/10.5944/openpraxis.13.1.117213pubpub

‘When she rises, we all rise’: a crowdsourcing challenge to increase women’s participation in an infectious diseases research fellowship

Background Women are under-represented in many mid-career infectious diseases research fellowships, including a TDR fellowship for low- and middle-income country (LMIC) researchers. TDR solicited creative ideas as part of a challenge contest to increase the number of women fellowship applicants. The purpose of this study is to examine themes from submitted ideas and the impact of implementing the top three ideas on the number of women applicants. Methods We solicited ideas for modifying the TDR fellowship using a crowdsourcing challenge. Then we used a mixed methods approach to evaluate texts submitted in response to the challenge. The qualitative analysis identified themes from eligible submissions. The quantitative analysis examined the mean score (1–10 scale) assigned to submitted ideas and also the number of eligible women applicants before (2014–7) and after (2018) implementing the top three ideas. Results We received 311 ideas on improving women’s participation in this fellowship from 63 countries. Among all ideas, 282 (91%) were from women and 286 (92%) were from low- and middle-income countries (LMICs). Thirty-three (17%) ideas received an overall mean score of 7.0 or greater. The top three ideas included enhanced social media communication targeting women, improving career mentorship, and creating a nomination system to nudge women applicants. These ideas were implemented as part of the 2018 fellowship application cycle. The number of eligible women applicants increased from 11 in 2016 to 48 in 2018. The number of eligible men applicants increased from 55 in 2016 to 114 in 2018. Women represent 44% (8/18) of the 2018 cohort. Conclusion This suggests that the challenge contest resulted in strong participation from women in LMICs. The three top ideas likely contributed to a greater number of women applicants to this mid-career fellowship. Further ways of enhancing women’s participation in global health training are needed