SUMMARY Tissue effector cells of the monocyte lineage can differentiate into different cell types with specific cell function depending on their environment. The phenotype, developmental requirements, and functional mechanisms of immune protective macrophages that mediate the induction of transplantation tolerance remain elusive. Here, we demonstrate that costimulatory blockade favored accumulation of DC-SIGN-expressing macrophages that inhibited CD8+ T cell immunity and promoted CD4+Foxp3+ Treg cell expansion in numbers. Mechanistically, that simultaneous DC-SIGN engagement by fucosylated ligands and TLR4 signaling was required for production of immunoregulatory IL-10 associated with prolonged allograft survival. Deletion of DC-SIGN-expressing macrophages in vivo, interfering with their CSF1-dependent development, or preventing the DC-SIGN signaling pathway abrogated tolerance. Together, the results provide new insights into the tolerogenic effects of costimulatory blockade and identify DC-SIGN+ suppressive macrophages as crucial mediators of immunological tolerance with the concomitant therapeutic implications in the clinic.

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A double-blind phase III malaria prevention trial was conducted in two refugee camps using pre-manufactured insecticide-treated plastic sheeting (ITPS) or untreated polyethylene sheeting (UPS) randomly deployed to defined sectors of each camp. In Largo camp the ITPS or UPS was attached to inner walls and ceilings of shelters, whereas in Tobanda the ITPS or UPS was used to line only the ceiling and roof. In Largo the Plasmodium falciparum incidence rate in children up to 3 years of age who were cleared of parasites and monitored for 8 months was 163/100 person-years under UPS and 63 under ITPS (adjusted odds ratio [AOR] = 0.40, 95% confidence interval [CI] = 0.33–0.47). In Tobanda incidence was 157/100 person-years under UPS and 134 under ITPS (AOR = 0.85, 95% CI = 0.75–0.95). Protective efficacy was 61% under fully lined ITPS and 15% under roof lined ITPS. Anemia rates improved under ITPS in both camps. This novel tool proved to be a convenient, safe, and long-lasting method of malaria control when used as a full shelter lining in an emergency setting.

The HIF (hypoxia-inducible factor) plays a central regulatory role in oxygen homoeostasis. HIF proteins are regulated by three Fe(II)- and α-KG (α-ketoglutarate)-dependent prolyl hydroxylase enzymes [PHD (prolyl hydroxylase domain) isoenzymes 1-3 or PHD1, PHD2 and PHD3] and one asparaginyl hydroxylase [FIH (factor inhibiting HIF)]. The prolyl hydroxylases control the abundance of HIF through oxygen-dependent hydroxylation of specific proline residues in HIF proteins, triggering subsequent ubiquitination and proteasomal degradation. FIH inhibits the HIF transcription activation through asparagine hydroxylation. Understanding the precise roles and regulation of these four Fe(II)- and α-KG-dependent hydroxylases is of great importance. In the present paper, we report the biochemical characterization of the first HIF protein substrates that contain the CODDD (C-terminal oxygen-dependent degradation domain), the NODDD (N-terminal oxygen-dependent degradation domain) and the CAD (C-terminal transactivation domain). Using LC-MS/MS (liquid chromatography-tandem MS) detection, we show that all three PHD isoenzymes have a strong preference for hydroxylation of the CODDD proline residue over the NODDD proline residue and the preference is observed for both HIF1α and HIF2α protein substrates. In addition, steady-state kinetic analyses show differential substrate selectivity for HIF and α-KG in reference to the three PHD isoforms and FIH.

BackgroundAccurate and timely malaria data are crucial to monitor the progress towards and attainment of elimination. Lusaka, the capital city of Zambia, has reported very low malaria prevalence in Malaria Indicator Surveys. Issues of low malaria testing rates, high numbers of unconfirmed malaria cases and over consumption of anti-malarials were common at clinics within Lusaka, however. The Government of Zambia (GRZ) and its partners sought to address these issues through an enhanced surveillance and feedback programme at clinic level.MethodsThe enhanced malaria surveillance programme began in 2011 to verify trends in reported malaria, as well as to implement a data feedback loop to improve data uptake, use, and quality. A process of monthly data collection and provision of feedback was implemented within all GRZ health clinics in Lusaka District. During clinic visits, clinic registers were accessed to record the number of reported malaria cases, malaria test positivity rate, malaria testing rate, and proportion of total suspected malaria that was confirmed with a diagnostic test.Results and discussionFollowing the enhanced surveillance programme, the odds of receiving a diagnostic test for a suspected malaria case increased (OR = 1.54, 95 % CI = 0.96–2.49) followed by an upward monthly trend (OR = 1.05, 95 % CI = 1.01–1.09). The odds of a reported malaria case being diagnostically confirmed also increased monthly (1.09, 95 % CI 1.04–1.15). After an initial 140 % increase (95 % CI = 91–183 %), costs fell by 11 % each month (95 % CI = 5.7–10.9 %). Although the mean testing rate increased from 18.9 to 64.4 % over the time period, the proportion of reported malaria unconfirmed by diagnostic remained high at 76 %.ConclusionsEnhanced surveillance and implementation of a data feedback loop have substantially increased malaria testing rates and decreased the number of unconfirmed malaria cases and courses of ACT consumed in Lusaka District within just two years. Continued support of enhanced surveillance in Lusaka as well as national scale-up of the system is recommended to reinforce good case management and to ensure timely, reliable data are available to guide targeting of limited malaria prevention and control resources in Zambia.