Perturbation of the dimer interface of triosephosphate isomerase and its effect on trypanosoma cruzi

Chagas disease affects around 18 million people in the American continent. Unfortunately, there is no satisfactory treatment for the disease. The drugs currently used are not specific and exert serious toxic effects. Thus, there is an urgent need for drugs that are effective. Looking for molecules to eliminate the parasite, we have targeted a central enzyme of the glycolytic pathway: triosephosphate isomerase (TIM). The homodimeric enzyme is catalytically active only as a dimer. Because there are significant differences in the interface of the enzymes from the parasite and humans, we searched for small molecules that specifically disrupt contact between the two subunits of the enzyme from Trypanosoma cruzi but not those of TIM from Homo sapiens (HTIM), and tested if they kill the parasite

Leishmania (L.) mexicana infected bats in Mexico: novel potential reservoirs

Leishmania (Leishmania) mexicana causes cutaneous leishmaniasis, an endemic zoonosis affecting a growing number of patients in the southeastern states of Mexico. Some foci are found in shade-grown cocoa and coffee plantations, or near perennial forests that provide rich breeding grounds for the sand fly vectors, but also harbor a variety of bat species that live off the abundant fruits provided by these shade-giving trees. The close proximity between sand flies and bats makes their interaction feasible, yet bats infected with Leishmania (L.) mexicana have not been reported. Here we analyzed 420 bats from six states of Mexico that had reported patients with leishmaniasis. Tissues of bats, including skin, heart, liver and/or spleen were screened by PCR for Leishmania (L.) mexicana DNA. We found that 41 bats (9.77%), belonging to 13 species, showed positive PCR results in various tissues. The infected tissues showed no evidence of macroscopic lesions. Of the infected bats, 12 species were frugivorous, insectivorous or nectarivorous, and only one species was sanguivorous (Desmodus rotundus), and most of them belonged to the family Phyllostomidae. The eco-region where most of the infected bats were caught is the Gulf Coastal Plain of Chiapas and Tabasco. Through experimental infections of two Tadarida brasiliensis bats in captivity, we show that this species can harbor viable, infective Leishmania (L.) mexicana parasites that are capable of infecting BALB/c mice. We conclude that various species of bats belonging to the family Phyllostomidae are possible reservoir hosts for Leishmania (L.) mexicana, if it can be shown that such bats are infective for the sand fly vector. Further studies are needed to determine how these bats become infected, how long the parasite remains viable inside these potential hosts and whether they are infective to sand flies to fully evaluate their impact on disease epidemiology

Perturbation of the Dimer Interface of Triosephosphate Isomerase and its Effect on Trypanosoma cruzi

Most of the enzymes of parasites have their counterpart in the host. Throughout evolution, the three-dimensional architecture of enzymes and their catalytic sites are highly conserved. Thus, identifying molecules that act exclusively on the active sites of the enzymes from parasites is a difficult task. However, it is documented that the majority of enzymes consist of various subunits, and that conservation in the interface of the subunits is lower than in the catalytic site. Indeed, we found that there are significant differences in the interface between the two subunits of triosephosphate isomerase from Homo sapiens and Trypanosoma cruzi (TcTIM), which causes Chagas disease in the American continent. In the search for agents that specifically inhibit TcTIM, we found that 2,2′-dithioaniline (DTDA) is far more effective in inactivating TcTIM than the human enzyme, and that its detrimental effect is due to perturbation of the dimer interface. Remarkably, DTDA prevented the growth of Escherichia coli cells that had TcTIM instead of their own TIM and killed T. cruzi epimastigotes in culture. Thus, this study highlights a new approach base of targeting molecular interfaces of dimers

NEW WILDLIFE HOSTS OF Leptospira interrogans IN CAMPECHE, MEXICO

Lepstospira interrogans ha sido identificada como uno de los agentes causantes de la leptospirosis, una zoonosis ampliamente distribuida, la cual se ha identificado en numerosos animales domésticos y silvestres. En este trabajo se analizaron los riñones de dos especies de roedores silvestres procedentes del estado de Campeche, México mediante la técnica de PCR con iniciadores específicos para la detección de DNA de Leptospira interrogans. Las especies de roedores que resultaron positivas corresponden a Heteromys gaumeri y Ototylomys phyllotis, ambas representan nuevos registros de huéspedes para la bacteria en el sureste de México. Estos nuevos huéspedes deberán ser estudiados cuidadosamente con el fin de determinar la posibilidad de que otras especies de animales, y en particular los humanos, entren en contacto con el patógeno presente en animales silvestres.Leptospira interrogans has been identified to cause leptospirosis, a widespread zoonotic disease that has been identified in domestic and wild animals. This work analyzed kidneys from two species of wild rodents from the state of Campeche, Mexico. Analyses were made by PCR using specific primers for detection of Leptospira interrogans DNA. The rodent species that tested positive were Heteromys gaumeri and Ototylomys phyllotis, both of which are new hosts for the bacteria in Southeastern Mexico. These records provide new insights into the disease’s transmission that should be studied carefully in order to identify other potential host species, including humans, which are at risk of becoming infected if they are in contact with infected wildlife

Leptospirosis in Mexico: Epidemiology and Potential Distribution of Human Cases.

Leptospirosis is widespread in Mexico, yet the potential distribution and risk of the disease remain unknown.We analysed morbidity and mortality according to age and gender based on three sources of data reported by the Ministry of Health and the National Institute of Geography and Statics of Mexico, for the decade 2000-2010. A total of 1,547 cases were reported in 27 states, the majority of which were registered during the rainy season, and the most affected age group was 25-44 years old. Although leptospirosis has been reported as an occupational disease of males, analysis of morbidity in Mexico showed no male preference. A total number of 198 deaths were registered in 21 states, mainly in urban settings. Mortality was higher in males (61.1%) as compared to females (38.9%), and the case fatality ratio was also increased in males. The overall case fatality ratio in Mexico was elevated (12.8%), as compared to other countries. We additionally determined the potential disease distribution by examining the spatial epidemiology combined with spatial modeling using ecological niche modeling techniques. We identified regions where leptospirosis could be present and created a potential distribution map using bioclimatic variables derived from temperature and precipitation. Our data show that the distribution of the cases was more related to temperature (75%) than to precipitation variables. Ecological niche modeling showed predictive areas that were widely distributed in central and southern Mexico, excluding areas characterized by extreme climates.In conclusion, an epidemiological surveillance of leptospirosis is recommended in Mexico, since 55.7% of the country has environmental conditions fulfilling the criteria that favor the presence of the disease

Cases and infection rates according to age.

<p>The bars represent the number of cases for each age group that was registered during the decade. The solid line represents the incidence rate per 100,000 inhabitants).</p

Distribution of cases and incidence rate of leptospirosis registered in Mexico during the period 2000–2010.

<p>Number of cases are represented by bars and the incidence rate is represented by the solid line.</p

Bioclimatic variables derived from temperature and precipitation.

<p>Bioclimatic variables derived from temperature and precipitation.</p