August Stich

Human African trypanosomiasis

The re-emergence of sleeping sickness presents a major public health problem Human African trypanosomiasis or sleeping sickness is one of the most important but equally most neglected tropical infections. It is caused by a protozoan, Trypanosoma brucei ,which is transmitted to humans through the bite of a tsetse fly ( Glossina spp).1 Patchy distribution of the various vector species confines the disease to some 200 microfoci in sub-Saharan Africa (fig 1). The disease had been successfully controlled by a combination of approaches, including treatment of patients, active case finding, and measures to deal with the vector.2 Since the 1970s, however, the disease has re-emerged as a new epidemic of immense proportions, which, until recently, received little attention from the international community (fig 2). According to the World Health Organization, about 500 000 people already carry trypanosomes and will die if left untreated.3 ### Summary points Human African trypanosomiasis is a re-emerging public health problem of epidemic proportions in many parts of rural Africa The disease is caused by subspecies of Trypanosoma brucei and is transmitted by tsetse flies Treatment requires admission to hospital and is costly, potentially dangerous, and limited by the widespread appearance of drug resistances Investment in clinical and pathophysiological research and a broad international commitment to fight trypanosomiasis in Africa are urgently needed Fig 1 Distribution of human African trypanosomiasis in sub-Saharan Africa Extensive literature exists on human African trypanosomiasis and trypanosomes, but it is mostlyconfined to basic sciences and neglects clinical research and the impact of the disease on large parts of the population in rural Africa. One of the countries most affected is Angola. In the north, local health professionals are involved in a control programme implemented through the Catholic charity, Caritas. Some 14 000 patients have already been treated and more than 100 000 examined for the …

Evidence for trafficking of PfEMP1 to the surface of P. falciparum-infected erythrocytes via a complex membrane network

The human malarial parasite Plasmodium falciparum exports virulence determinants, such as the P. falciparum erythrocyte membrane protein 1 (PfEMP1), beyond its own periplasmatic boundaries to the surface of its host erythrocyte. This is remarkable given that erythrocytes lack a secretory pathway. Here we present evidence for a continuous membrane network of parasite origin in the erythrocyte cytoplasm. Co-localizations with antibodies against PfEMP1, PfExp-1, Pf332 and PfSbpl at the light and electron microscopical level indicate that this membrane network is composed of structures that have been previously described as tubovesicular membrane network (TVM), Maurers clefts and membrane whorls. This membrane network could also be visualized in vivo by vital staining of infected erythrocytes with the fluorescent dye LysoSensor Green DND-153. At sites where the membrane network abuts the erythrocyte plasma membrane we observed small vesicles of 15-25 nm in size, which seem to bud from and/or fuse with the membrane network and the erythrocyte plasma membrane, respectively. On the basis of our data we hypothesize that this membrane network of parasite origin represents a novel secretory organelle that is involved in the trafficking of PfEMP1 across the erythrocyte cytoplasm.

New drugs for the treatment of human African trypanosomiasis: research and development.

Chemotherapy of human African trypanosomiasis is problematic because of the high frequency of severe adverse events, the long duration and high cost of treatment, and an increasing number of treatment-refractory cases. New cost-efficient, easy-to-use drugs are urgently needed. Whereas basic research on potential drug targets is anchored in academia, the complex, highly regulated and very expensive process of preclinical and clinical drug development is almost exclusively in the hands of pharmaceutical companies. Jennifer Keiser, August Stich and Christian Burri here review, from the angle of industrial drug research and development, the past ten years of research activities at different stages of the development of trypanocidal drugs, and assess future prospects. The absence of compounds in clinical development Phases I-III indicates no new drugs will become available in the next few years.

Waking up to sleeping sickness

Devastating epidemics of human African trypanosomiasis are currently re-emerging in many sub-Saharan countries. In the past three decades, clinical research into this important disease has been neglected, as have urgently needed initiatives on drug development, disease surveillance and vector control. Recent impetus has aimed to provide a free supply of antitrypanosomal drugs, to develop a new orally active trypanocidal agent and to attack the tsetse vector with modern technology. In addition, pan-African initiatives to co-ordinate control efforts have begun. These all provide some hope for the future, but they might not be enough to reverse the resurgence of this deadly disease in the heart of Africa.

Allicin and derivates are cysteine protease inhibitors with antiparasitic activity.

Allicin and derivatives thereof inhibit the CAC1 cysteine proteases falcipain 2, rhodesain, cathepsin B and L in the low micromolar range. The structure-activity relationship revealed that only derivatives with primary carbon atom in vicinity to the thiosulfinate sulfur atom attacked by the active-site Cys residue are active against the target enzymes. Some compounds also show potent antiparasitic activity against Plasmodium falciparum and Trypanosoma brucei brucei.

Bacteremia and Antimicrobial Drug Resistance over Time, Ghana

Bacterial distribution and antimicrobial drug resistance were monitored in patients with bacterial bloodstream infections in rural hospitals in Ghana. In 2001–2002 and in 2009, Salmonella enterica serovar Typhi was the most prevalent pathogen. Although most S. enterica serovar Typhi isolates were chloramphenicol resistant, all isolates tested were susceptible to ciprofloxacin.

Michael Acceptor Based Antiplasmodial and Antitrypanosomal Cysteine Protease Inhibitors with Unusual Amino Acids

New peptidic Michael acceptor based cysteine protease inhibitors displaying antiparasitic activity were identified by testing a broad series of 45 compounds in total, containing Asn, Gln, or Phe. As target enzymes, falcipain-2 and -3 from P. falciparum and rhodesain from T. b. rhodesiense were used. In the case of the Asn/Gln containing compounds, the trityl-protected, diastereomeric E-configured vinylogous dipeptide esters 16 (Boc-(S)-Phg-(R/S)-vGln(Trt)-OEt) were discovered as most active inhibitors concerning both protease inhibition and antiparasitic acitivity, with inhibition constants in the submicromolar range. The compounds were shown to display time-dependent and competitive inhibition. In the case of the Phe containing compounds, the maleic acid derivatives 42 and 43 (BnO-Phe<--Mal-Phe-OBn, BnO-Phe<--Mal-Phe-Ala-OBn, Mal = maleic acid) displayed good inhibition of rhodesain as well as good antitrypanosomal activity, while the fumaric acid derived E-analogue 14 (BnO-Phe<--Fum-Phe-OBn) only displayed inhibition of the target enzymes but no antiparasitic activity. Inhibition by these Phe derivatives was shown to be time-independent and competitive.

Retaking sleeping sickness control in Angola

Africa is severely affected by a resurgence of human African trypanosomiasis (HAT) at epidemic proportions. We report the results of the first 5 years of a HAT control programme in northern Angola run by the non‐governmental organization (NGO) ANGOTRIP. In the period between 1996 and 2001, 13 426 patients were screened for HAT. The mortality rate of patients in stage II who were treated with melarsoprol fell from 7.5% to 2.9%, possibly as a result of training and the standardization of treatment protocols. A total of 191 578 people in three provinces of Angola were screened for HAT. Vector control activities were initiated using Lancien traps. Our experiences reflect the connection between war and the increasing incidence of disease, but also demonstrate that HAT control is possible by dedicated NGOs in close cooperation with national institutions even under extremely difficult circumstances.

Diagnosing human African trypanosomiasis in Angola using a card agglutination test: observational study of active and passive case finding strategies.

Abstract Objective To assess the operational feasibility of detecting human African trypanosomiasis by active and passive case finding using the card agglutination test with serial dilution of serum to guide treatment. Setting Trypanosomiasis control programme in the Negage focus, northern Angola, during a period of civil war. Design Observational study. Participants 359 patients presenting themselves to health centres with symptoms (passive case finding) and 14 446 people actively screened in villages. Main outcome measures Whole blood and serological tests at different dilutions using the card agglutination test, and detection of parasites by microscopy. Results Active case finding identified 251 people with a positive card agglutination test result, 10 of whom had confirmed parasites. In those presenting for investigation 34 of 51 with a positive card agglutination test result at the dilution of 1:8 or more used to guide treatment had parasites in blood, lymph node fluid, or cerebrospinal fluid, compared with 10 of 76 in those detected by active case finding: positive predictive values of 67% for passive case detection and 13% for active case detection. Only at a cut-off dilution more than 1:32 was the positive predictive value in active case detection reasonable (46%) and at this dilution 40% of microscopically proved cases were missed. Conclusions The card agglutination test is useful for initial screening in active detection of cases with human African trypanosomiasis but, given the toxicity of the drugs, serology using the card agglutination test should be not used alone to guide treatment after active case finding. A second confirmatory test is needed.

Potent and selective inhibition of cysteine proteases from Plasmodium falciparum and Trypanosoma brucei

Treating tropical diseases: Structure‐based design afforded highly active triazine nitrile inhibitors of the protozoan cysteine proteases falcipain‐2 and rhodesain. Optimization of the occupancy of the S1, S2, and S3 pockets of these enzymes yielded inhibitory constants in the low nanomolar activity range. The new ligands are selective against other related proteases and exhibit in vitro activities against the protozoan parasites.WILEY-VCHThis article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.