Visceral Leishmaniasis in Muzaffarpur District, Bihar, India from 1990 to 2008

BACKGROUND: Visceral Leishmaniasis (VL) is a vector-borne disease transmitted by Phlebotomus argentipes. To understand the VL seasonality, annual and monthly variations of VL incidence and its relationship to meteorological variables, the numbers of VL cases reported in Muzaffarpur district, Bihar, India from 1990 to 2008 were studied. METHODS: Annual VL incidence per 10,000 and the total number of annual VL cases reported at block Community Health Centres (CHC), Public Hospitals or Non-Governmental Organisations (NGO) and the number of VL cases per month from 2000 to 2008 as well as the monthly average of cases for 2000-08, 2000-04 and 2005-08 periods along with the monthly averages of temperature, rainfall and relative humidity were plotted. VL Standardised Incidence Ratios per block were computed for the periods of 1990-1993, 1994-1998, 1999-2004 and 2005-2008 and month wise from 2002 to 2008. A negative binomial regression model was used to evaluate the association between meteorological variables and the number of VL cases per month from 2000 to 2008. RESULTS: A total of 68,358 VL cases were reported in Muzaffarpur district from 1990 to 2008, ranging from 1,2481 in 1992 to 1,161 in 2001. The blocks with the highest number of cases shifted from East (1990-98) to West (1999-2008). Monthly averages of cases ranged from 149 to 309, highest peak in March-April and another one in July. Monthly VL incidence was associated positively to rainfall and negatively to relative humidity and the numbers of VL cases in the previous month. INTERPRETATION: The number of cases reported to the public health sector allowed the describing of the spatial distribution and temporal variations in the Muzaffarpur from 1990 to 2008. However, to assess the actual VL burden, as well as the efficacy of the control measures applied in the district, reporting from private practices and NGOs should be encouraged

Options for Active Case Detection of Visceral Leishmaniasis in Endemic Districts of India, Nepal and Bangladesh, Comparing Yield, Feasibility and Costs

For the elimination of any infectious disease (i.e., reduction of the burden of a serious public health problem to a minor problem which can be managed by the general health services) the right mix of public health tools has to be identified for the early detection and successful treatment of new cases as well as effective vector control (in the case of vector borne diseases) at affordable costs. The paper provides a powerful example of evidence building for cost-effective early case detection in the visceral leishmaniasis elimination initiative of Bangladesh, India and Nepal. It compares the camp approach (mobile teams testing in chronic fever camps for spleen enlargement and rapid diagnostic tests) with the index case approach (screening for new cases in the neighbourhood of reported visceral leishmaniasis patients) and the incentive based approach (where basic health workers receive an allowance for detecting a new case) using subsequent house-to-house screening for the identification of the real number of un-detected cases. By applying a mix of different study methods and an itinerate research process to identify the most effective, feasible and affordable case detection method, under different environmental conditions, recommendations could be developed which help governments in shaping their visceral leishmaniasis elimination strategy

Increased Memory Conversion of Naïve CD8 T Cells Activated during Late Phases of Acute Virus Infection Due to Decreased Cumulative Antigen Exposure

Background: Memory CD8 T cells form an essential part of protective immunity against viral infections. Antigenic load, costimulation, CD4-help, cytokines and chemokines fluctuate during the course of an antiviral immune response thus affecting CD8 T cell activation and memory conversion. Methodology/Principal Findings: In the present study, naïve TCR transgenic LCMV-specific P14 CD8 T cells engaged at a late stage during the acute antiviral LCMV response showed reduced expansion kinetics but greater memory conversion in the spleen. Such late activated cells displayed a memory precursor effector phenotype already at the peak of the systemic antiviral response, suggesting that the environment determined their fate during antigen encounter. In the spleen, the majority of late transferred cells exhibited a central memory phenotype compared to the effector memory displayed by the early transferred cells. Increasing the inflammatory response by exogenous administration of IFNc, PolyI:C or CpG did not affect memory conversion in the late transferred group, suggesting that the diverging antigen load early versus later during acute infection had determined their fate. In agreement, reduction in the LCMV antigenic load after ribavirin treatment enhanced the contribution of early transferred cells to the long lasting memory pool. Conclusions/Significance: Our results show that naïve CD8 cells, exposed to reduced duration or concentration of antigen during viral infection convert into memory more efficiently, an observation that could have significant implications fo

B7-H1 Blockade Increases Survival of Dysfunctional CD8+ T Cells and Confers Protection against Leishmania donovani Infections

Experimental visceral leishmaniasis (VL) represents an exquisite model to study CD8+ T cell responses in a context of chronic inflammation and antigen persistence, since it is characterized by chronic infection in the spleen and CD8+ T cells are required for the development of protective immunity. However, antigen-specific CD8+ T cell responses in VL have so far not been studied, due to the absence of any defined Leishmania-specific CD8+ T cell epitopes. In this study, transgenic Leishmania donovani parasites expressing ovalbumin were used to characterize the development, function, and fate of Leishmania-specific CD8+ T cell responses. Here we show that L. donovani parasites evade CD8+ T cell responses by limiting their expansion and inducing functional exhaustion and cell death. Dysfunctional CD8+ T cells could be partially rescued by in vivo B7-H1 blockade, which increased CD8+ T cell survival but failed to restore cytokine production. Nevertheless, B7-H1 blockade significantly reduced the splenic parasite burden. These findings could be exploited for the design of new strategies for immunotherapeutic interventions against VL

Epitope Density Influences CD8+ Memory T Cell Differentiation

The generation of long-lived memory T cells is critical for successful vaccination but the factors controlling their differentiation are still poorly defined. We tested the hypothesis that the strength of T cell receptor (TCR) signaling contributed to memory CD8(+) T cell generation.We manipulated the density of antigenic epitope presented by dendritic cells to mouse naïve CD8(+) T cells, without varying TCR affinity. Our results show that a two-fold decrease in antigen dose selectively affects memory CD8(+) T cell generation without influencing T cell expansion and acquisition of effector functions. Moreover, we show that low antigen dose alters the duration of the interaction between T cells and dendritic cells and finely tunes the expression level of the transcription factors Eomes and Bcl6. Furthermore, we demonstrate that priming with higher epitope density results in a 2-fold decrease in the expression of Neuron-derived orphan nuclear receptor 1 (Nor-1) and this correlates with a lower level of conversion of Bcl-2 into a pro-apoptotic molecule and an increased number of memory T cells.Our results show that the amount of antigen encountered by naïve CD8(+) T cells following immunization with dendritic cells does not influence the generation of functional effector CD8(+) T cells but rather the number of CD8(+) memory T cells that persist in the host. Our data support a model where antigenic epitope density sensed by CD8(+) T cells at priming influences memory generation by modulating Bcl6, Eomes and Nor-1 expression

Selected MicroRNAs Define Cell Fate Determination of Murine Central Memory CD8 T Cells

During an immune response T cells enter memory fate determination, a program that divides them into two main populations: effector memory and central memory T cells. Since in many systems protection appears to be preferentially mediated by T cells of the central memory it is important to understand when and how fate determination takes place. To date, cell intrinsic molecular events that determine their differentiation remains unclear. MicroRNAs are a class of small, evolutionarily conserved RNA molecules that negatively regulate gene expression, causing translational repression and/or messenger RNA degradation. Here, using an in vitro system where activated CD8 T cells driven by IL-2 or IL-15 become either effector memory or central memory cells, we assessed the role of microRNAs in memory T cell fate determination. We found that fate determination to central memory T cells is under the balancing effects of a discrete number of microRNAs including miR-150, miR-155 and the let-7 family. Based on miR-150 a new target, KChIP.1 (K + channel interacting protein 1), was uncovered, which is specifically upregulated in developing central memory CD8 T cells. Our studies indicate that cell fate determination such as surface phenotype and self-renewal may be decided at the pre-effector stage on the basis of the balancing effects of a discrete number of microRNAs. These results may have implications for the development of T cell vaccines and T cell-based adoptive therapies

Estimating the Global Clinical Burden of Plasmodium falciparum Malaria in 2007

Simon Hay and colleagues derive contemporary estimates of the global clinical burden of Plasmodium falciparum malaria (the deadliest form of malaria) using cartography-based techniques

CD40-Activated B Cells Can Efficiently Prime Antigen-Specific Naïve CD8+ T Cells to Generate Effector but Not Memory T cells

Background: The identification of the signals that should be provided by antigen-presenting cells (APCs) to induce a CD8 + T cell response in vivo is essential to improve vaccination strategies using antigen-loaded APCs. Although dendritic cells have been extensively studied, the ability of other APC types, such as B cells, to induce a CD8 + T cell response have not been thoroughly evaluated. Methodology/Principal Findings: In this manuscript, we have characterized the ability of CD40-activated B cells, stimulated or not with Toll-like receptor (TLR) agonists (CpG or lipopolysaccharide) to induce the response of mouse naïve CD8 + T cells in vivo. Our results show that CD40-activated B cells can directly present antigen to naïve CD8 + T cells to induce the generation of potent effectors able to secrete cytokines, kill target cells and control a Listeria monocytogenes infection. However, CD40-activated B cell immunization did not lead to the proper formation of CD8 + memory T cells and further maturation of CD40-activated B cells with TLR agonists did not promote the development of CD8 + memory T cells. Our results also suggest that inefficient generation of CD8 + memory T cells with CD40-activated B cell immunization is a consequence of reduced Bcl-6 expression by effectors and enhanced contraction of the CD8 + T cell response. Conclusions: Understanding why CD40-activated B cell immunization is defective for the generation of memory T cells and gaining new insights about signals that should be provided by APCs are key steps before translating the use of CD40-B cel

Dissociating Markers of Senescence and Protective Ability in Memory T Cells

No unique transcription factor or biomarker has been identified to reliably distinguish effector from memory T cells. Instead a set of surface markers including IL-7Rα and KLRG1 is commonly used to predict the potential of CD8 effector T cells to differentiate into memory cells. Similarly, these surface markers together with the tumor necrosis factor family member CD27 are frequently used to predict a memory T cell's ability to mount a recall response. Expression of these markers changes every time a memory cell is stimulated and repeated stimulation can lead to T cell senescence and loss of memory T cell responsiveness. This is a concern for prime–boost vaccine strategies which repeatedly stimulate T cells with the aim of increasing memory T cell frequency. The molecular cues that cause senescence are still unknown, but cell division history is likely to play a major role. We sought to dissect the roles of inflammation and cell division history in developing T cell senescence and their impact on the expression pattern of commonly used markers of senescence. We developed a system that allows priming of CD8 T cells with minimal inflammation and without acquisition of maximal effector function, such as granzyme expression, but a cell division history similar to priming with systemic inflammation. Memory cells derived from minimal effector T cells are fully functional upon rechallenge, have full access to non-lymphoid tissue and appear to be less senescent by phenotype upon rechallenge. However, we report here that these currently used biomarkers to measure senescence do not predict proliferative potential or protective ability, but merely reflect initial priming conditions

Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at √s = 7 TeV with the ATLAS detector

This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of √s = 7 TeV;{\rm Te}{\rm V}$and correspond to an integrated luminosity of$4.6\;{\rm f}{{{\rm b}}^{-1}}$. The measurement is performed by reconstructing the boosted W or Z bosons in single jets. The reconstructed jet mass is used to identify the W and Z bosons, and a jet substructure method based on energy cluster information in the jet centre-of-mass frame is used to suppress the large multi-jet background. The cross-section for events with a hadronically decaying W or Z boson, with transverse momentum${{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}$and pseudorapidity$|\eta |\lt 1.9$, is measured to be${{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques