Monocyte subpopulations as important biomarkers of resistence and susceptibility during experimental infection with Leishmania (Leishmania) major.

Visceral Leishmaniasis is a chronic and lethal, parasitic disease. In the later infection stages, it is known that expressive hematological disorders can be observed, including changes in the frequency and phenotype of certain leukocytes. There is a lack of good prognostic indicators to characterize the on-goin clinical status of the patient. In this study, we have analyzed the frequency of monocyte subpopulations in mice infected with Leishmania major (L. major). Our results show a significant correlation between increased blood monocyte frequency and lesion development in both BALB/c and in the C57BL/6 mice infected with L. major. In BALB/c mice we observed a significant correlation between the frequency of GR1+ monocytes and lesion size. Furthermore, treatment of infected BALB/c mice with Anfotericin B, to resolve lesions, resulted in a lower frequency of GR1+ monocytes compared to untreated infected BALB/c mice. C57BL/6 infected mice, which normally resolve infections, show decreased numbers of monocytes during the healing phase of infection. The results indicate that disease severity can be predicted by analyzing monocyte frequency. Thus, we propose that the frequency of monocytes, can be used to define the severity of the disease as well as the success of the treatment in experimental leishmaniasis.

Myocardial scars correlate with eletrocardiographic changes in chronic Trypanosoma cruzi infection for dogs treated with Benznidazole.

OBJECTIVES: The cardiac form of Chagas disease is evidenced by a progressive cardiac inflammation that leads to myocarditis, fibrosis and electrocardiographic (ECG) conduction abnormalities. Considering these characteristics, the aim of this study was to prospectively evaluate the early ECG changes in dogs that were experimentally inoculated with Benznidazole (Bz)-susceptibly (Berenice-78) and Bz-resistant (VL-10, and AAS) Trypanosoma cruzi strains and, later, evaluate the efficacy of Bz treatment for preventing these ECG alterations. METHODS: Electrocardiographic changes of treated and untreated animals were prospectively evaluated for up to 270 days after infection, at which point collagen (right atrium) quantification was performed. RESULTS: All infected dogs had a high intensity of heart fibrosis (4616.00 ± 1715.82 collagen/74931 µm(2) in dogs infected with Berenice-78 strain, 5839.2 ± 1423.49 collagen/74931 µm(2) in infected by AAS and 6294.40 ± 896.04 collagen/74931 µm(2) in animals infected with VL-10 strain), while 78.57% of all infected dogs showed ECG alterations. Bz Therapy reduced or prevented fibrosis in Bz-susceptible Berenice-78 (2813.00 ± 607.13 collagen/74931 µm(2) ) and Bz-resistant AAS strains (4024 ± 1272.44 collagen/74931 µm(2) ), coincident with only 10% de ECG alterations at 270 days. However, in those animals infected with a Bz-resistant VL-10 strain, specific treatment did not alter collagen deposition (6749.5 ± 1596.35 collagen/74931 µm(2) ) and there was first atrioventricular block and chamber overload at 120 and 270 days after infection, with 75% abnormal ECG exams. CONCLUSIONS: These findings indicate that an effective antiparasitic treatment in the early stage of Chagas disease can lead to a significant reduction in the frequency and severity of the parasite-induced cardiac disease, even if parasites are not completely eliminated.

Fexinidazole: a potential new drug candidate for Chagas disease.

BACKGROUND: New safe and effective treatments for Chagas disease (CD) are urgently needed. Current chemotherapy options for CD have significant limitations, including failure to uniformly achieve parasitological cure or prevent the chronic phase of CD, and safety and tolerability concerns. Fexinidazole, a 2-subsituted 5-nitroimidazole drug candidate rediscovered following extensive compound mining by the Drugs for Neglected Diseases initiative and currently in Phase I clinical study for the treatment of human African trypanosomiasis, was evaluated in experimental models of acute and chronic CD caused by different strains of Trypanosoma cruzi. METHODS AND FINDINGS: We investigated the in vivo activity of fexinidazole against T. cruzi, using mice as hosts. The T. cruzi strains used in the study were previously characterized in murine models as susceptible (CL strain), partially resistant (Y strain), and resistant (Colombian and VL-10 strains) to the drugs currently in clinical use, benznidazole and nifurtimox. Our results demonstrated that fexinidazole was effective in suppressing parasitemia and preventing death in infected animals for all strains tested. In addition, assessment of definitive parasite clearance (cure) through parasitological, PCR, and serological methods showed cure rates of 80.0% against CL and Y strains, 88.9% against VL-10 strain, and 77.8% against Colombian strain among animals treated during acute phase, and 70% (VL-10 strain) in those treated in chronic phase. Benznidazole had a similar effect against susceptible and partially resistant T. cruzi strains. Fexinidazole treatment was also shown to reduce myocarditis in all animals infected with VL-10 or Colombian resistant T. cruzi strains, although parasite eradication was not achieved in all treated animals at the tested doses. CONCLUSIONS: Fexinidazole is an effective oral treatment of acute and chronic experimental CD caused by benznidazole-susceptible, partially resistant, and resistant T. cruzi. These findings illustrate the potential of fexinidazole as a drug candidate for the treatment of human CD.