African trypanosomes cause human sleeping sickness and livestock trypanosomiasis in sub-Saharan Africa. We present the sequence and analysis of the 11 megabase-sized chromosomes of Trypanosoma brucei. The 26-megabase genome contains 9068 predicted genes, including ∼900 pseudogenes and ∼1700 T. brucei–specific genes. Large subtelomeric arrays contain an archive of 806 variant surface glycoprotein (VSG) genes used by the parasite to evade the mammalian immune system. Most VSG genes are pseudogenes, which may be used to generate expressed mosaic genes by ectopic recombination. Comparisons of the cytoskeleton and endocytic trafficking systems with those of humans and other eukaryotic organisms reveal major differences. A comparison of metabolic pathways encoded by the genomes of T. brucei, T. cruzi, and Leishmania major reveals the least overall metabolic capability in T. brucei and the greatest in L. major. Horizontal transfer of genes of bacterial origin has contributed to some of the metabolic differences in these parasites, and a number of novel potential drug targets have been identified.

https://science.sciencemag.org/content/sci/309/5733/416.full.pdf

The Genome of the African Trypanosome Trypanosoma brucei

Mitochondrial Ca(2+) homeostasis has a key role in the regulation of aerobic metabolism and cell survival, but the molecular identity of the Ca(2+) channel, the mitochondrial calcium uniporter, is still unknown. Here we have identified in silico a protein (named MCU) that shares tissue distribution with MICU1 (also known as CBARA1), a recently characterized uniporter regulator, is present in organisms in which mitochondrial Ca(2+) uptake was demonstrated and whose sequence includes two transmembrane domains. Short interfering RNA (siRNA) silencing of MCU in HeLa cells markedly reduced mitochondrial Ca(2+) uptake. MCU overexpression doubled the matrix Ca(2+) concentration increase evoked by inositol 1,4,5-trisphosphate-generating agonists, thus significantly buffering the cytosolic elevation. The purified MCU protein showed channel activity in planar lipid bilayers, with electrophysiological properties and inhibitor sensitivity of the uniporter. A mutant MCU, in which two negatively charged residues of the putative pore-forming region were replaced, had no channel activity and reduced agonist-dependent matrix Ca(2+) concentration transients when overexpressed in HeLa cells. Overall, these data demonstrate that the 40-kDa protein identified is the channel responsible for ruthenium-red-sensitive mitochondrial Ca(2+) uptake, thus providing a molecular basis for this process of utmost physiological and pathological relevance.

/pdf/a-forty-kilodalton-protein-of-the-inner-membrane-is-the-292shih6m5.pdf

A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter

This report updates and combines earlier versions of guidelines for the prevention and treatment of opportunistic infections (OIs) in HIV-infected adults (i.e., persons aged >/=18 years) and adolescents (i.e., persons aged 13--17 years), last published in 2002 and 2004, respectively. It has been prepared by the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America (IDSA). The guidelines are intended for use by clinicians and other health-care providers, HIV-infected patients, and policy makers in the United States. These guidelines address several OIs that occur in the United States and five OIs that might be acquired during international travel. Topic areas covered for each OI include epidemiology, clinical manifestations, diagnosis, prevention of exposure; prevention of disease by chemoprophylaxis and vaccination; discontinuation of primary prophylaxis after immune reconstitution; treatment of disease; monitoring for adverse effects during treatment; management of treatment failure; prevention of disease recurrence; discontinuation of secondary prophylaxis after immune reconstitution; and special considerations during pregnancy. These guidelines were developed by a panel of specialists from the United States government and academic institutions. For each OI, a small group of specialists with content-matter expertise reviewed the literature for new information since the guidelines were last published; they then proposed revised recommendations at a meeting held at NIH in June 2007. After these presentations and discussion, the revised guidelines were further reviewed by the co-editors; by the Office of AIDS Research, NIH; by specialists at CDC; and by HIVMA of IDSA before final approval and publication. The recommendations are rated by a letter that indicates the strength of the recommendation and a Roman numeral that indicates the quality of evidence supporting the recommendation, so that readers can ascertain how best to apply the recommendations in their practice environments. Major changes in the guidelines include 1) greater emphasis on the importance of antiretroviral therapy for the prevention and treatment of OIs, especially those OIs for which no specific therapy exists; 2) information regarding the diagnosis and management of immune reconstitution inflammatory syndromes; 3) information regarding the use of interferon-gamma release assays for the diagnosis of latent Mycobacterium tuberculosis (TB) infection; 4) updated information concerning drug interactions that affect the use of rifamycin drugs for prevention and treatment of TB; 5) the addition of a section on hepatitis B virus infection; and 6) the addition of malaria to the list of OIs that might be acquired during international travel. This report includes eleven tables pertinent to the prevention and treatment of OIs, a figure that pertains to the diagnois of tuberculosis, a figure that describes immunization recommendations, and an appendix that summarizes recommendations for prevention of exposure to opportunistic pathogens.

Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.

Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. There are significant differences in the sensitivity of these species both to the standard drugs, for example, pentavalent antimonials and miltefosine, and those on clinical trial, for example, paromomycin. Over 60% of patients with visceral leishmaniasis in Bihar State, India, do not respond to treatment with pentavalent antimonials. This is now considered to be due to acquired resistance. Although this class of drugs has been used for over 60 years for leishmaniasis treatment, it is only in the past 2 years that the mechanisms of action and resistance have been identified, related to drug metabolism, thiol metabolism, and drug efflux. With the introduction of new therapies, including miltefosine in 2002 and paromomycin in 2005-2006, it is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.

/pdf/drug-resistance-in-leishmaniasis-52uqk16ezk.pdf

Drug Resistance in Leishmaniasis

In addition to malaria, tuberculosis, and human immunodeficiency virus infection, several other infectious diseases are associated with substantial morbidity and mortality. In particular, 13 tropical diseases infect billions of people and cause disabilities such as blindness and heart failure, especially in persons who live in impoverished conditions. This review article describes approaches to the global control of these diseases.

/pdf/control-of-neglected-tropical-diseases-2o2d9tvkhn.pdf

Control of Neglected Tropical Diseases

Specific chemotherapy of Chagas disease: controversies and advances.

Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches.

Chemotherapy of trypanosomiases and leishmaniasis

Molecular order and dynamics of phosphatidylcholine bilayer membranes in the presence of cholesterol, ergosterol and lanosterol: a comparative study using 2H-, 13C- and 31p-NMR spectroscopy

Through its impact on worker productivity, premature disability, and death, Chagas disease accounts for 670,000 disability-adjusted life years per annum [1]. This makes it the most important parasitic disease of the Americas. It is both a disease of poverty (Figures 1 and ​and2)2) and, like other neglected tropical diseases, also “poverty promoting” [2]. Traditionally confined to Latin America, Chagas disease is becoming an important health issue in the United States and Europe. First, due to the continuous influx of immigrants from disease-endemic countries in Latin America, a proportion of whom are infected with Trypanosoma cruzi, an increasing number of infected subjects are seen in clinical practice, whether, for example, through routine screening of US blood and organ banks [3] or physicians' offices in Europe [4]. The appearance of T. cruzi in US blood banks led to the implementation of the first Food and Drug Administration–approved diagnostic blood screening test for Chagas disease earlier this year [5]. Second, an increasing number of autochthonous Chagas disease cases have been reported in the US [6,7], which may mirror the increased reporting of T. cruzi infection in domestic animals and wildlife. Recognizing that Chagas disease can no longer be considered an “exotic” disease in the US, the American Society of Tropical Medicine and Hygiene held a clinical course in Chagas disease prior to its 2007 annual meeting (http://www.astmh.org/meetings/premeeting.cfm#clinical).



Figure 1

Chagas Disease Is Closely Linked to Poverty and Socioeconomic Development, and Poor Housing In Particular





Figure 2

Interior of House Showing the Type of Wall Construction Often Found in Households in Many Endemic Areas



Despite estimates of up to 15 million existing cases and 50,000–200,000 new infections per year, funding for research, prevention, and control has been limited, and therapeutic options remain unsatisfactory. Consequently, several editorials and perspectives have recently drawn attention to Chagas disease and T. cruzi [8–10]. While these papers highlighted the impact of this disease on public health in the Americas, and rightly pointed out that major achievements have been made in its control, they failed to emphasize several key challenges that are currently undermining these achievements and that must be urgently addressed in order to move to the next stage: ensuring the long-term and sustainable control of this devastating disease.

Julio A. Urbina

Papers

Specific chemotherapy of Chagas disease: controversies and advances.

Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches.

Chemotherapy of trypanosomiases and leishmaniasis

Molecular order and dynamics of phosphatidylcholine bilayer membranes in the presence of cholesterol, ergosterol and lanosterol: a comparative study using 2H-, 13C- and 31p-NMR spectroscopy

The challenges of Chagas Disease-- grim outlook or glimmer of hope.