MMV390048, a member of a new class of inhibitors of the Plasmodium phosphatidylinositol 4-kinase, shows potential for both treatment and prophylaxis.

The pleiotropic actions of interleukin-2 (IL-2) are essential for regulation of immune responses and maintenance of immune tolerance. The IL-2 receptor (IL-2R) is composed of IL-2Rα, IL-2Rβ, and IL-2Rγ subunits, with defects in IL-2Rα and IL-2Rγ and their downstream signaling effectors resulting in known primary immunodeficiency disorders. Here, we report the first human defect in IL-2Rβ, occurring in two infant siblings with a homozygous IL2RB mutation in the WSXWS motif, manifesting as multisystem autoimmunity and susceptibility to CMV infection. The hypomorphic mutation results in diminished IL-2Rβ surface expression and dysregulated IL-2/15 signaling, with an anticipated reduction in regulatory T cells. However, in contrast to the IL-2Rβ^−/− animal model, which lacks NK cells, these siblings demonstrate an expansion of NK cells, particularly the CD56^bright subset, and a lack of terminally differentiated NK cells. Thus, the early-onset autoimmunity and immunodeficiency are linked to functional deficits arising from altered IL-2Rβ expression and signaling in T and NK cells. Graphical Abstract

In recent years, malaria (Plasmodium vivax and Plasmodium falciparum) has been successfully controlled in the Ecuador–Peru coastal border region. The aim of this study was to document this control effort and to identify the best practices and lessons learned that are applicable to malaria control and to other vector-borne diseases. A proximal outcome evaluation was conducted of the robust elimination programme in El Oro Province, Ecuador, and the Tumbes Region, Peru. Data collection efforts included a series of workshops with local public health experts who played central roles in the elimination effort, review of epidemiological records from Ministries of Health, and a review of national policy documents. Key programmatic and external factors are identified that determined the success of this eradication effort. From the mid 1980s until the early 2000s, the region experienced a surge in malaria transmission, which experts attributed to a combination of ineffective anti-malarial treatment, social-ecological factors (e.g., El Niño, increasing rice farming, construction of a reservoir), and political factors (e.g., reduction in resources and changes in management). In response to the malaria crisis, local public health practitioners from El Oro and Tumbes joined together in the mid-1990s to forge an unofficial binational collaboration for malaria control. Over the next 20 years, they effectively eradicated malaria in the region, by strengthening surveillance and treatment strategies, sharing of resources, operational research to inform policy, and novel interventions. The binational collaboration at the operational level was the fundamental component of the successful malaria elimination programme. This unique relationship created a trusting, open environment that allowed for flexibility, rapid response, innovation and resilience in times of crisis, and ultimately a sustainable control programme. Strong community involvement, an extensive microscopy network and ongoing epidemiologic investigations at the local level were also identified as crucial programmatic strategies. The results of this study provide key principles of a successful malaria elimination programme that can inform the next generation of public health professionals in the region, and serve as a guide to ongoing and future control efforts of other emerging vector borne diseases globally.

The Aedes aegypti mosquito is an efficient vector for the transmission of Zika, chikungunya, and dengue viruses, causing major epidemics and a significant social and economic burden throughout the tropics and subtropics. The primary means of preventing these diseases is household-level mosquito control. However, relatively little is known about the economic burden of Ae. aegypti control in resource-limited communities. We surveyed residents from 40 households in a high-risk community at the urban periphery in the city of Machala, Ecuador, on dengue perceptions, vector control interventions, household expenditures, and factors influencing purchasing decisions. The results of this study show that households spend a monthly median of US$2.00, or 1.90% (range: 0.00%, 9.21%) of their family income on Ae. aegypti control interventions. Households reported employing, on average, five different mosquito control and dengue prevention interventions, including aerosols, liquid sprays, repellents, mosquito coils, and unimpregnated bed nets. We found that effectiveness and cost were the most important factors that influence people’s decisions to purchase a mosquito control product. Our findings will inform the development and deployment of new Ae. aegypti control interventions by the public health and private sectors, and add to prior studies that have focused on the economic burden of dengue-like illness.

Epstein-Barr virus (EBV) is associated with a number of T-cell diseases including some peripheral T-cell lymphomas, hemophagocytic lymphohistiocytosis, and chronic active EBV. The tropism of EBV for B-cells and epithelial cell infection has been well characterized but infection of T-cells has been minimally explored. We have recently shown that the EBV type 2 (EBV-2) strain has the unique ability to infect mature T-cells. Utilizing an ex vivo infection model, we sought to understand the viral glycoprotein and cellular receptor required for EBV-2 infection of T-cells. Here we show using a neutralizing antibody assay that the viral gp350 and the complement receptor 2, CD21 are required for CD3+ T-cell infection. Using the HB5 anti-CD21 antibody clone but not the Bly-4 anti-CD21 antibody clone, we detected expression of CD21 on both CD4+ and CD8+ T-cells with the highest expression on naive CD4 and CD8+ T-cell subsets. Using CRISPR to knockout CD21, we demonstrated that CD21 is necessary for EBV entry into the Jurkat T-cell line. Together, these results indicate that EBV uses the same viral glycoprotein and cellular receptor for both T and B-cell infection. Importance Epstein-Barr virus (EBV) has a well-described tropism for B-cells and epithelial cells. More recently, we described the ability of a second strain of EBV, EBV Type 2, to infect mature peripheral T-cells. Using a neutralizing antibody assay, we identified that EBV used the viral glycoprotein, gp350, and the cellular CD21 to gain entry into mature peripheral T-cells. CRISPR-Cas9 deletion of CD21 on the Jurkat T-cell line confirmed that CD21 is required for EBV infection. This study has broad implications as we have defined a function for CD21 on mature peripheral T-cells, e.g. as a receptor for EBV. In addition, the requirement for gp350 for T-cell entry has implications for EBV vaccine studies currently targeting the gp350 glycoprotein to prevent EBV associated diseases.

The 2 strains of Epstein-Barr virus (EBV), EBV type 1 (EBV-1) and EBV-2, differ in latency genes, suggesting that they use distinct mechanisms to establish latency. We previously reported that EBV-2 infects T cells in vitro. In this study, we tested the possibility that EBV-2 infects T cells in vivo. Purified T-cell fractions isolated from children positive for EBV-1 or EBV-2 and their mothers were examined for the presence of EBV and for EBV type. We detected EBV-2 in all T-cell samples obtained from EBV-2–infected children at 12 months of age, with some children retaining EBV-2–positive T cells through 24 months of age, suggesting that EBV-2 persists in T cells. We were unable to detect EBV-2 in T-cell samples from mothers but could detect EBV-2 in samples of their breast milk and saliva. These data suggest that EBV-2 uses T cells as an additional latency reservoir but that, over time, the frequency of infected T cells may drop below detectable levels. Alternatively, EBV-2 may establish a prolonged transient infection in the T-cell compartment. Collectively, these novel findings demonstrate that EBV-2 infects T cells in vivo and suggest EBV-2 may use the T-cell compartment to establish latency.