Cytokines in the treatment of leishmaniasis: From studies of immunopathology to patient therapy

The genusLeishmania, an obligate intramacrophage parasite, causes a wide spectrum of clinical diseases. It is worldwide in distribution and causes 20 million new cases annually with an at risk population of approximately 1.5 billion persons. The most severe forms are associated with high morbidity, mortality and relapses with conventional therapy. The therapeutic issues and responses to standard and alternative therapies are reviewed. Recent developments in molecular biology and immunology methods employed in the study of leishmaniasis have defined an intricate interaction of the parasite with host immune system. Perturbation of the host immune responses may be part of the survival mechanisms ofLeishmania. In murine model, the finding of T helper cells that differ by their panel of cytokines has allowed a more precise definition of immunopathogenesis of leishmaniasis. Preliminary data from leishmaniasis patients lend support to this concept of altered immunomodulation. Furthermore, the enhancement of therapeutic response by interferon- has provided a new approach for treatment of patients using recombinant cytokines and for the study of the disease. Current research for early diagnosis, alternative therapies and need for vaccines are reviewed in the context of the immunopathology of leishmaniasis.     

Antiproliferative Activity and Ultrastructural Changes in Promastigote and Amastigote forms of Leishmania amazonensis Caused by Limonene-Acylthiosemicarbazide Hybrids

Leishmaniasis is a tropical zoonotic disease. It is found in 98 countries, with an estimated 1.3 million people being affected annually. During the life cycle, the Leishmania parasite alternates between promastigote and amastigote forms. The first line treatment for leishmaniasis are the pentavalent antimonials, such as N-methylglucamine antimoniate (Glucantime®) and sodium stibogluconate (Pentostam®). These drugs are commonly related to be associated with dangerous side effects such as cardiotoxicity, nephrotoxicity, hepatotoxicity, and pancreatitis. Considering these aspects, this work aimed to obtain a new series of limonene-acylthiosemicarbazides hybrids as an alternative for the treatment of leishmaniasis. For this, promastigotes, axenic amastigotes, and intracellular amastigotes of Leishmania amazonensis were used in the antiproliferative assay; J774-A1 macrophages for the cytotoxicity assay; and electron microscopy techniques were performed to analyze the morphology and ultrastructure of parasites. ATZ−S-04 compound showed the best result in both tests. Its IC₅₀, in promastigotes, axenic amastigotes and intracellular amastigotes was 0.35±0.08 μM, 0.49±0.06 μM, and 15.90±2.88 μM, respectively. Cytotoxicity assay determined a CC₅₀ of 16.10±1.76 μM for the same compound. By electron microscopy, it was observed that ATZ−S-04 affected mainly the Golgi complex, in addition to morphological changes in promastigote forms of L. amazonensis.     

Human leishmaniasis vaccines: Use cases,target population and potential global demand

The development of vaccines against one or all forms of human leishmaniasis remains hampered by a paucity of investment, at least in part resulting from the lack of well-evidenced and agreed estimates of vaccine demand. Starting from the definition of 4 main use cases (prevention of visceral leishmaniasis, prevention of cutaneous leishmaniasis, prevention of post-kala-azar dermal leishmaniasis and treatment of post-kala-azar dermal leishmaniasis), we have estimated the size of each target population, focusing on those endemic countries where incidence levels are sufficiently high to justify decisions to adopt a vaccine. We assumed a dual vaccine delivery strategy, including a wide age-range catch-up campaign before the start of routine immunisation. Vaccine characteristics and delivery parameters reflective of a target product profile and the likely duration of the clinical development effort were considered in forecasting the demand for each of the four indications. Over a period of 10 years, this demand is forecasted to range from 300–830 million doses for a vaccine preventing visceral leishmaniasis and 557–1400 million doses for a vaccine preventing cutaneous leishmaniasis under the different scenarios we simulated. In a scenario with an effective prophylactic visceral leishmaniasis vaccine, demand for use to prevent or treat post-kala-azar dermal leishmaniasis would be more limited (over the 10 years ~160,000 doses for prevention and ~7,000 doses for treatment). Demand would rise to exceed 330,000 doses, however, in the absence of an effective vaccine for visceral leishmaniasis. Because of the sizeable demand and potential for public health impact, a single-indication prophylactic vaccine for visceral or cutaneous leishmaniasis, and even more so a cross-protective prophylactic vaccine could attract the interest of commercial developers. Continuous refinement of these first-of-their kind estimates and confirmation of country willingness and ability to pay will be paramount to inform the decisions of policy makers and developers in relation to a leishmaniasis vaccine. Positive decisions can provide a much-needed contribution towards the achievement of global leishmaniasis control.     

Pancreatic Cancer Genetics

Although relatively rare, pancreatic tumors are highly lethal [1]. In the United States, an estimated 48,960 individuals will be diagnosed with pancreatic cancer and 40,560 will die from this disease in 2015 [1]. Globally, 337,872 new pancreatic cancer cases and 330,391 deaths were estimated in 2012 [2]. In contrast to most other cancers, mortality rates for pancreatic cancer are not improving; in the US, it is predicted to become the second leading cause of cancer related deaths by 2030 [3, 4]. The vast majority of tumors arise in the exocrine pancreas, with pancreatic ductal adenocarcinoma (PDAC) accounting for approximately 95% of tumors. Tumors arising in the endocrine pancreas (pancreatic neuroendocrine tumors) represent less than 5% of all pancreatic tumors [5]. Smoking, type 2 diabetes mellitus (T2D), obesity and pancreatitis are the most consistent epidemiological risk factors for pancreatic cancer [5]. Family history is also a risk factor for developing pancreatic cancer with odds ratios (OR) ranging from 1.7-2.3 for first-degree relatives in most studies, indicating that shared genetic factors may play a role in the etiology of this disease [6-9]. This review summarizes the current knowledge of germline pancreatic cancer risk variants with a special emphasis on common susceptibility alleles identified through Genome Wide Association Studies (GWAS).     

Interpretation of laboratory data during cryptic leishmaniasis in dog

Leishmaniasis is a zoonosis caused by an intracellular parasite belonging to the genus Leishmania. In Europe, Africa, South America and China, visceral leishmaniasis is caused by L. infantum. The vectors of leishmaniasis are phlebotomine sandflies belonging to the genera Phlebotomus. According to the World Health Organization there are 2 million new cases each year and 1/10 of the world's population is at risk of infection. Leishmaniasis is considered a zoonosis and human are generally accidental hosts. The animal reservoir includes rodents, dog and other mammals. Several studies have indicate that half of the dogs with antileishmanial antibodies have no signs of disease although, animal with subclinical infections are potentially infectious to sand flies. The factors determining susceptibility or resistence to visceral leishmaniasis remain unclear, but the genetics of the host may play a major role. Clinical signs are: intermittent fever, hepatosplenomegaly, skin lesions and ulcers, alopecia, onychogryphosis, anemia, thrombocytopenia and hypergammaglobulinemia. In mice, the outcome of infection depends on the polarized activation of one of two subsets of CD4+ T cells, Th1 or Th2, the subdivision into Th1 and Th2 cells is based on the pattern of cytokines that they produce. Th1 cells produce gamma interferon (IFN-gamma) and interleukin -2 (IL-2), whereas Th2 cells produce IL-4, IL-5, and IL-10. An important difference between susceptible and resistant mice is that the resistant mice are able to switch to a Th1 profile and control the disease. An important factor in the "decision" to form a Th1 or Th2 phenotype is the early cytokine environment, and IL-12 is one of the cytokines that contributes significantly to the establishment of the Th1 phenotype. Canine leishmaniosis is endemic in the Mediterranean basin and, in most cases is caused by the parasite Leishmania infantum. The main clinical findings are skin lesions, local or generalized lymphoadenopathy, loss of body weight, glomerulopathy, ocular lesions, epistaxis and lameness. Non pruritic skin lesions are the usual manifestation and several forms have been described, such as exfoliative dermatitis and alopecia, and ulcerative, nodular and pustular dermatitis. Seroepidemiological studies of canine leishmaniasis have revealed a large number of asymptomatic seropositive animals. Moreover in areas where leishmaniasis is highly endemic, high proportion of apparently healthy animals show low levels of anti-Leishmania antibodies. Others have regressive forms of the desease, and their antibody levels will decrease in the following months or years; still others maintain low levels of antibodies without developing the desease for many years. However, the total number of infected animals is unknown. Canine leishmaniasis is a major zoonosic parasitic disease, enzootic in the Mediterranean area, caused by the intracellular protozoan Leishmania infantum. The dog is the main reservoir host of the parasite. However, most infected dogs do not present any clinical signs, and there is evidence that Leishmania infection prevalence rates in areas of endemicity are higher than those ascertained by serological studies. Visceral leishmaniasis is becoming a real problem of public health because it is an opportunistic infection in immunocompromised patients and in human immunodeficiency virus-positive subjects. The detection of the extent of the infection, particularly among asymptomatic dogs, is of great importance for the control of leishmaniasis. PCR has been applied successfully in recent years to detect Leishmania spp. even in the cases with any of the clinical manifestation of leishmaniasis. Very recently, real-time PCR for Leishmania has been applied to evaluate the parasitic load of dog tissues both at the time of the diagnosis and during follow-up of the therapy and to measure cytokine mRNA levels in different clinical samples of infected and uninfected dogs.     

Leishmanicidal activity of synthetic antimicrobial peptides in an infection model with human dendritic cells

Different species of Leishmania are responsible for cutaneous, mucocutaneous or visceral leishmaniasis infections in millions of people around the world [14]. The adverse reactions caused by antileishmanial drugs, emergence of resistance and lack of a vaccine have motivated the search for new therapeutic options to control this disease. Different sources of antimicrobial molecules are under study as antileishmanial agents, including peptides with antimicrobial and/or immunomodulatory activity, which have been considered to be potentially active against diverse species of Leishmania [7] and [39]. This study evaluated the cytotoxicity on dendritic cells, hemolytic activity, leishmanicidal properties on Leishmania panamensis and Leishmania major promastigotes and effectiveness on parasite intracellular forms (dendritic cells infected with L. panamensis and L. major promastigotes), when each parasite in culture was exposed to different concentrations of a group of synthetic peptides with previously reported antimicrobial properties, which were synthesized based on their naturally occurring reported sequences. Dermaseptin, Pr-2 and Pr-3 showed inhibitory activity on the growth of L. panamensis promastigotes, while Andropin and Cecropin A (with a selectivity index of 4 and 40, respectively) showed specific activity against intracellular forms of this species. The activities of Andropin and Cecropin A were exclusively against the intracellular forms of the parasite, therefore indicating the relevance of these two peptides as potential antileishmanial agents. In the case of L. major promastigotes, Melittin and Dermaseptin showed inhibitory activity, the latter also showed a selectivity index of 8 against intracellular forms. These findings suggest Andropin, Cecropin A and Dermaseptin as potential therapeutic tools to treat New and Old World cutaneous leishmaniasis.     

Streptococcal Superantigen,Mitogenic Factor,and Pyrogenic Exotoxin B Expressed by Streptococcus pyogenes

Abstract

Streptococcus pyogenes is a Gram-positive human bacterial pathogen that causes pharyngitis, tonsillitis, skin infections (impetigo, erysipelis, and other forms of pyoderma), acute rheumatic fever (ARF), scarlet fever (SF), poststreptococcal glomerulonephritis (PSGN), a streptococcal toxic shock syndrome (STSS), and necrotizing fasciitis. These infections are some of the most economically and medically important conditions that affect humans. For example, globally, ARF is the most common cause of pediatric heart disease. It is estimated that in India more than six million school-aged children suffer from rheumatic heart disease (1). In the United States, “sore throat” is the third most common reason for physician office visits and S. pyogenes is recovered from about 30% of children with this complaint (2). It has been estimated that there are 25–35 million cases of streptococcal pharyngitis per year in the United States, and these infections cause 1–2 billion dollars per year in direct health care costs (3,4). Although the continued great morbidity and mortality caused by S. pyogenes in developing nations, the significant health care financial burden attributable to group A streptococci in the United States, and increasing levels of antibiotic resistance (5), have highlighted the need for a fuller understanding of the molecular pathogenesis of streptococcal infection, it has been the relatively recent intercontinental increase in streptococcal disease frequency and severity (6,7) that has resulted in renewed interest in S. pyogenes virulence factors and host-parasite interactions.     

Visceral Leishmaniasis in Ethiopia: An Evolving Disease

Visceral leishmaniasis (also known as kala-azar) is classified as one of the most neglected tropical diseases. It is becoming a growing health problem in Ethiopia, with endemic areas that are continually spreading. The annual burden of visceral leishmaniasis (VL) in Ethiopia is estimated to be between 4,500 and 5,000 cases, and the population at risk is more than 3.2 million. There has been a change in the epidemiology of VL in Ethiopia. Over the last decades, almost all cases and outbreaks of VL were reported from arid and semi-arid parts of the country; however, recent reports indicated the introduction of this disease into the highlands. Migration of labourers to and from endemic areas, climatic and environmental changes, and impaired immunity due to HIV/AIDS and malnutrition resulted in the change of VL epidemiology. HIV spurs the spread of VL by increasing the risk of progression from asymptomatic infection towards full VL. Conversely, VL accelerates the onset of AIDS. In Ethiopia, VL epidemiology remains complex because of the diversity of risk factors involved, and its control is becoming an increasing challenge. This paper reviews the changes in epidemiology of VL in Ethiopia and discusses some of the possible explanations for these changes. The prospects for novel approaches to VL control are discussed, as are the current and future challenges facing Ethiopia''s public health development program.     

Neglected Tropical Diseases in Sub-Saharan Africa: Review of Their Prevalence,Distribution, and Disease Burden

The neglected tropical diseases (NTDs) are the most common conditions affecting the poorest 500 million people living in sub-Saharan Africa (SSA), and together produce a burden of disease that may be equivalent to up to one-half of SSA''s malaria disease burden and more than double that caused by tuberculosis. Approximately 85% of the NTD disease burden results from helminth infections. Hookworm infection occurs in almost half of SSA''s poorest people, including 40–50 million school-aged children and 7 million pregnant women in whom it is a leading cause of anemia. Schistosomiasis is the second most prevalent NTD after hookworm (192 million cases), accounting for 93% of the world''s number of cases and possibly associated with increased horizontal transmission of HIV/AIDS. Lymphatic filariasis (46–51 million cases) and onchocerciasis (37 million cases) are also widespread in SSA, each disease representing a significant cause of disability and reduction in the region''s agricultural productivity. There is a dearth of information on Africa''s non-helminth NTDs. The protozoan infections, human African trypanosomiasis and visceral leishmaniasis, affect almost 100,000 people, primarily in areas of conflict in SSA where they cause high mortality, and where trachoma is the most prevalent bacterial NTD (30 million cases). However, there are little or no data on some very important protozoan infections, e.g., amebiasis and toxoplasmosis; bacterial infections, e.g., typhoid fever and non-typhoidal salmonellosis, the tick-borne bacterial zoonoses, and non-tuberculosis mycobaterial infections; and arboviral infections. Thus, the overall burden of Africa''s NTDs may be severely underestimated. A full assessment is an important step for disease control priorities, particularly in Nigeria and the Democratic Republic of Congo, where the greatest number of NTDs may occur.     

Therapeutic approaches for prion and Alzheimer's diseases

Alzheimer's and prion diseases belong to a category of conformational neurodegenerative disorders [Prusiner SB (2001) N Eng J Med344, 1516-1526; Sadowski M & Wisniewski T (2007) Curr Pharm Des 13, 1943-1954; Beekes M (2007) FEBS J 274, 575]. Treatments capable of arresting or at least effectively modifying the course of disease do not yet exist for either one of these diseases. Alzheimer's disease is the major cause of dementia in the elderly and has become an ever greater problem with the aging of Western societies. Unlike Alzheimer's disease, prion diseases are relatively rare. Each year only approximately 300 people in the USA and approximately 100 people in the UK succumb to various forms of prion diseases [Beekes M (2007) FEBS J 274, 575; Sigurdsson EM & Wisniewski T (2005) Exp Rev Vaccines 4, 607-610]. Nevertheless, these disorders have received great scientific and public interest due to the fact that they can be transmissible among humans and in certain conditions from animals to humans. The emergence of variant Creutzfeld-Jakob disease demonstrated the transmissibility of the bovine spongiform encephalopathy to humans [Beekes M (2007) FEBS J 274, 575]. Therefore, the spread of bovine spongiform encephalopathy across Europe and the recently identified cases in North America have put a large human population at risk of prion infection. It is estimated that at least several thousand Britons are asymptomatic carriers of prion infections and may develop variant Creutzfeld-Jakob disease in the future [Hilton DA (2006) J Pathol 208, 134-141]. This delayed emergence of human cases following the near elimination of bovine spongiform encephalopathy in the UK may occur because prion disease have a very prolonged incubation period, ranging from months to decades, which depends on the amount of inoculum, the route of infection and the genetic predisposition of the infected subject [Hilton DA (2006) J Pathol 208, 134-141]. Therefore, there is a great need for effective therapies for both Alzheimer's disease and prion diseases.     

Regulation of Leishmania (L.) amazonensis Protein Expression by Host T Cell Dependent Responses: Differential Expression of Oligopeptidase B,Tryparedoxin Peroxidase and HSP70 Isoforms in Amastigotes Isolated from BALB/c and BALB/c Nude Mice

Leishmaniasis is an important disease that affects 12 million people in 88 countries, with 2 million new cases every year. Leishmania amazonensis is an important agent in Brazil, leading to clinical forms varying from localized (LCL) to diffuse cutaneous leishmaniasis (DCL). One interesting issue rarely analyzed is how host immune response affects Leishmania phenotype and virulence. Aiming to study the effect of host immune system on Leishmania proteins we compared proteomes of amastigotes isolated from BALB/c and BALB/c nude mice. The athymic nude mice may resemble patients with diffuse cutaneous leishmaniasis, considered T-cell hyposensitive or anergic to Leishmania´s antigens. This work is the first to compare modifications in amastigotes’ proteomes driven by host immune response. Among the 44 differentially expressed spots, there were proteins related to oxidative/nitrosative stress and proteases. Some correspond to known Leishmania virulence factors such as OPB and tryparedoxin peroxidase. Specific isoforms of these two proteins were increased in parasites from nude mice, suggesting that T cells probably restrain their posttranslational modifications in BALB/c mice. On the other hand, an isoform of HSP70 was increased in amastigotes from BALB/c mice. We believe our study may allow identification of potential virulence factors and ways of regulating their expression.     

Epidemiology of leishmaniasis in Ecuador: current status of knowledge -- a review

Although leishmaniasis is regarded as a significant health problem in Ecuador by the Ministry of Health, and the incidence has increased over the last years, an official map on the geographic distribution of disease and sand fly vectors or a control strategy do not exist yet. This article reviews the current situation based on published information to improve our knowledge and understand the epidemiological situation of leishmaniasis in Ecuador in order to help future research and to develop a national control strategy. The disease is endemic in most provinces throughout Pacific coastal region, Amazonian lowlands, and some inter-Andean valleys with a total 21,805 cases reported during 1990-2003. Whereas cutaneous leishmaniasis (CL) is found throughout Ecuador, mucocutaneous leishmaniasis (MCL) appears to be restricted to the Amazon region; one, parasitologically unconfirmed case of visceral form was reported in 1949. Most human infections are caused by Leishmania (Viannia) spp., which is distributed in the subtropical and tropical lowlands; infections due to L. (Leishmania) spp. are found in the Andean highlands and in the Pacific lowlands as well. The proven vectors are Lutzomyia trapidoi and Lu. ayacuchensis. Canis familiaris, Sciurus vulgaris, Potos flavus, and Tamandua tetradactyla have been found infected with Leishmania spp. It is estimated that around 3000-4500 people may be infected every year, and that 3.1 to 4.5 millions people are estimated to be at risk of contracting leishmaniasis.     

Host genetic factors in American cutaneous leishmaniasis: a critical appraisal of studies conducted in an endemic area of Brazil

American cutaneous leishmaniasis (ACL) is a vector-transmitted infectious disease with an estimated 1.5 million new cases per year. In Brazil, ACL represents a significant public health problem, with approximately 30,000 new reported cases annually, representing an incidence of 18.5 cases per 100,000 inhabitants. Corte de Pedra is in a region endemic for ACL in the state of Bahia (BA), northeastern Brazil, with 500-1,300 patients treated annually. Over the last decade, population and family-based candidate gene studies were conducted in Corte de Pedra, founded on previous knowledge from studies on mice and humans. Notwithstanding limitations related to sample size and power, these studies contribute important genetic biomarkers that identify novel pathways of disease pathogenesis and possible new therapeutic targets. The present paper is a narrative review about ACL immunogenetics in BA, highlighting in particular the interacting roles of the wound healing gene FLI1 with interleukin-6 and genes SMAD2 and SMAD3 of the transforming growth factor beta signalling pathway. This research highlights the need for well-powered genetic and functional studies on Leishmania braziliensis infection as essential to define and validate the role of host genes in determining resistance/susceptibility regarding this disease.     

Orchid Mimics Honey Bee Alarm Pheromone in Order to Attract Hornets for Pollination

Approximately one-third of the world's estimated 30,000 orchid species are deceptive and do not reward their pollinators with nectar or pollen [1]. Most of these deceptive orchids imitate the scent of rewarding flowers or potential mates [2] and [3]. In this study, we investigated the floral scent involved in pollinator attraction to the rewardless orchid Dendrobium sinense, a species endemic to the Chinese island Hainan that is pollinated by the hornet Vespa bicolor. Via chemical analyses and electrophysiological methods, we demonstrate that the flowers of D. sinense produce (Z)-11-eicosen-1-ol and that the pollinator can smell this compound. This is a major compound in the alarm pheromones of both Asian (Apis cerana) and European (Apis mellifera) honey bees [4] and [5] and is also exploited by the European beewolf (Philanthus triangulum) to locate its prey [6]. This is the first time that (Z)-11-eicosen-1-ol has been identified as a floral volatile. In behavioral experiments, we demonstrate that the floral scent of D. sinense and synthetic (Z)-11-eicosen-1-ol are both attractive to hornets. Because hornets frequently capture honey bees to feed to their larvae, we suggest that the flowers of D. sinense mimic the alarm pheromone of honey bees in order to attract prey-hunting hornets for pollination.     

World Health Organization Estimates of the Global and Regional Disease Burden of 11 Foodborne Parasitic Diseases, 2010: A Data Synthesis

Background

Foodborne diseases are globally important, resulting in considerable morbidity and mortality. Parasitic diseases often result in high burdens of disease in low and middle income countries and are frequently transmitted to humans via contaminated food. This study presents the first estimates of the global and regional human disease burden of 10 helminth diseases and toxoplasmosis that may be attributed to contaminated food.

Methods and Findings

Data were abstracted from 16 systematic reviews or similar studies published between 2010 and 2015; from 5 disease data bases accessed in 2015; and from 79 reports, 73 of which have been published since 2000, 4 published between 1995 and 2000 and 2 published in 1986 and 1981. These included reports from national surveillance systems, journal articles, and national estimates of foodborne diseases. These data were used to estimate the number of infections, sequelae, deaths, and Disability Adjusted Life Years (DALYs), by age and region for 2010. These parasitic diseases, resulted in 48.4 million cases (95% Uncertainty intervals [UI] of 43.4–79.0 million) and 59,724 (95% UI 48,017–83,616) deaths annually resulting in 8.78 million (95% UI 7.62–12.51 million) DALYs. We estimated that 48% (95% UI 38%-56%) of cases of these parasitic diseases were foodborne, resulting in 76% (95% UI 65%-81%) of the DALYs attributable to these diseases. Overall, foodborne parasitic disease, excluding enteric protozoa, caused an estimated 23.2 million (95% UI 18.2–38.1 million) cases and 45,927 (95% UI 34,763–59,933) deaths annually resulting in an estimated 6.64 million (95% UI 5.61–8.41 million) DALYs. Foodborne Ascaris infection (12.3 million cases, 95% UI 8.29–22.0 million) and foodborne toxoplasmosis (10.3 million cases, 95% UI 7.40–14.9 million) were the most common foodborne parasitic diseases. Human cysticercosis with 2.78 million DALYs (95% UI 2.14–3.61 million), foodborne trematodosis with 2.02 million DALYs (95% UI 1.65–2.48 million) and foodborne toxoplasmosis with 825,000 DALYs (95% UI 561,000–1.26 million) resulted in the highest burdens in terms of DALYs, mainly due to years lived with disability. Foodborne enteric protozoa, reported elsewhere, resulted in an additional 67.2 million illnesses or 492,000 DALYs. Major limitations of our study include often substantial data gaps that had to be filled by imputation and suffer from the uncertainties that surround such models. Due to resource limitations it was also not possible to consider all potentially foodborne parasites (for example Trypanosoma cruzi).

Conclusions

Parasites are frequently transmitted to humans through contaminated food. These estimates represent an important step forward in understanding the impact of foodborne diseases globally and regionally. The disease burden due to most foodborne parasites is highly focal and results in significant morbidity and mortality among vulnerable populations.     

Immune response to leishmania: paradox rather than paradigm

The leishmaniases are a group of diseases caused by protozoan parasites of the genus Leishmania. Various Leishmania species can cause human infection, producing a spectrum of clinical manifestations. It is estimated that 350 million people are at risk, with a global yearly incidence of 1-1.5 million for cutaneous and 500,000 for visceral leishmaniasis (VL). VL is a major cause of morbidity and mortality in East Africa and the Indian subcontinent. Coinfection with HIV enhances the risk of the disease. The only control measure currently available in India is case detection and treatment with antimonial drugs, which are expensive, not always available and cannot be self-administered. Newer drugs like oral miltefosine have not become widely available. Vector and reservoir control is difficult due to the elusive nature of the vector and the diversity of the animal reservoir. A detailed knowledge of immune response to the parasite would help in designing prophylactic and therapeutic strategies against this infection.     

Leishmaniasis with oral mucosa involvement

doi: 10.1111/j.1741‐2358.2011.00512.x Leishmaniasis with oral mucosa involvement Introduction: The term leishmaniasis comprises a group of diseases caused by different protozoan species of the genus Leishmania. There are three main clinical forms of leishmaniasis: visceral, cutaneous and mucocutaneous. Exclusive involvement of the mucosa is very rare. Objectives: To present a case of mucocutaneous leishmaniasis in an elderly patient, discuss the clinical presentation, diagnostic process and treatment emphasizing the distinctions from other granulomatous lesions. Case report: A 71‐year‐old male presenting with a symptomatic lesion on the hard and soft palate, which had developed over a period of 6 months was evaluated. The oral exam revealed a lesion with multiple ulcerated nodules on the hard and soft palate extending to the oropharynx. The diagnostic hypothesis was chronic infectious disease (paracoccidioidomycose, tuberculosis and leishmaniasis) or squamous cell carcinoma. Histopathological, histochemical and immunohistochemical analysis were performed. A chest x‐ray revealed a normal pulmonary pattern. The Montenegro skin test was positive. The definitive diagnosis was leishmaniasis with exclusive oral manifestation and the patient was treated with liposomal amphotericin. Conclusions: Localized oral mucosa leishmaniasis is an uncommon event in an immunocompetent patient. Dentists play an important role in the diagnosis of oral leishmaniasis, which has systemic repercussions.     

Progress and Impact of 13 Years of the Global Programme to Eliminate Lymphatic Filariasis on Reducing the Burden of Filarial Disease

Background

A Global Programme to Eliminate Lymphatic Filariasis was launched in 2000, with mass drug administration (MDA) as the core strategy of the programme. After completing 13 years of operations through 2012 and with MDA in place in 55 of 73 endemic countries, the impact of the MDA programme on microfilaraemia, hydrocele and lymphedema is in need of being assessed.

Methodology/Principal findings

During 2000–2012, the MDA programme made remarkable achievements – a total of 6.37 billion treatments were offered and an estimated 4.45 billion treatments were consumed by the population living in endemic areas. Using a model based on empirical observations of the effects of treatment on clinical manifestations, it is estimated that 96.71 million LF cases, including 79.20 million microfilaria carriers, 18.73 million hydrocele cases and a minimum of 5.49 million lymphedema cases have been prevented or cured during this period. Consequently, the global prevalence of LF is calculated to have fallen by 59%, from 3.55% to 1.47%. The fall was highest for microfilaraemia prevalence (68%), followed by 49% in hydrocele prevalence and 25% in lymphedema prevalence. It is estimated that, currently, i.e. after 13 years of the MDA programme, there are still an estimated 67.88 million LF cases that include 36.45 million microfilaria carriers, 19.43 million hydrocele cases and 16.68 million lymphedema cases.

Conclusions/Significance

The MDA programme has resulted in significant reduction of the LF burden. Extension of MDA to all at-risk countries and to all regions within those countries where MDA has not yet reached 100% geographic coverage is imperative to further reduce the number of microfilaraemia and chronic disease cases and to reach the global target of interrupting transmission of LF by 2020.     

Reactive oxygen species production by human dendritic cells involves TLR2 and dectin‐1 and is essential for efficient immune response against Mycobacteria

Tuberculosis remains the single largest infectious disease with 10 million new cases and two million deaths that are estimated to occur yearly, more than any time in history. The intracellular replication of Mycobacterium tuberculosis (Mtb) and its spread from the lungs to other sites occur before the development of adaptive immune responses. Dendritic cells (DC) are professional antigen‐presenting cells whose maturation is critical for the onset of the protective immune response against tuberculosis disease and may vary depending on the nature of the cell wall of Mtb strain. Here, we describe the role of the endogenous production of reactive oxygen species (ROS) on DC maturation and expansion of Mtb‐specific lymphocytes. Here, we show that Mtb induces DC maturation through TLR2/dectin‐1 by generating of ROS and through Dendritic Cell‐Specific Intercellular adhesion molecule‐3‐Grabbing Non‐integrin (DC‐SIGN) in a ROS independently manner. Based on the differences observed in the ability to induce DC maturation, ROS production and lymphocyte proliferation by those Mtb families widespread in South America, i.e., Haarlem and Latin American Mediterranean and the reference strain H37Rv, we propose that variance in ROS production might contribute to immune evasion affecting DC maturation and antigen presentation.     

The molecular pathology of Kaposi’s sarcoma-associated herpesvirus

Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is the eighth and most recently identified human herpesvirus (HHV-8). KSHV was discovered in 1994 by Chang et al. who used representational difference analysis to search for DNA sequences present in AIDS-associated KS but not in adjacent normal skin [1]. The virus has since been shown to be specifically associated with all forms of this disease and has fulfilled all of Hill’s criteria for causation (reviewed in [2]). KSHV is also found in all cases of primary effusion lymphoma [3] and in a plasmablastic variant of multicentric Castleman’s disease [4], [5]. Over the last few years a wealth of data has been gained on the role of KSHV genes during infection. This review is an attempt to assemble this information into a more complete picture of how KSHV may cause disease.