Experimental chemotherapy against Trypanosoma cruzi infection: essential role of endogenous interferon-gamma in mediating parasitologic cure.

Studies in humans and in experimental models suggest the involvement of the immune system for efficacy of drug treatment against protozoan parasites. This study tested this hypothesis by using various cytokine and inducible nitric oxide synthase (iNOS) knockout (KO) mice infected with Trypanosoma cruzi and treated with benznidazole. In contrast with the 100% parasitologic cure rate achieved in wild-type animals, benznidazole failed to cure 100%, 42%, 35%, and 28% of interferon-gamma, interleukin-12 (protein 40), protein 55-tumor necrosis factor receptor, and iNOS KO mice, respectively. These results suggest that activation of the immune system by the parasite and endogenous interferon-gamma play a major role in the efficacy of benznidazole against infection with T. cruzi.

[1]  R. Corrêa-Oliveira,et al.  Immunological and clinical evaluation of chagasic patients subjected to chemotherapy during the acute phase of Trypanosoma cruzi infection 14-30 years ago. , 2000, The Journal of infectious diseases.

[2]  A. Romanha,et al.  In vivo activity of the bis-triazole D0870 against drug-susceptible and drug-resistant strains of the protozoan parasite Trypanosoma cruzi. , 2000, The Journal of antimicrobial chemotherapy.

[3]  D. Loebenberg,et al.  Activities of the Triazole Derivative SCH 56592 (Posaconazole) against Drug-Resistant Strains of the Protozoan ParasiteTrypanosoma (Schizotrypanum) cruzi in Immunocompetent and Immunosuppressed Murine Hosts , 2000, Antimicrobial Agents and Chemotherapy.

[4]  O. Bottasso,et al.  Protected Trypanosoma cruzi infection in rats born to mothers receiving interferon-gamma during gestation is associated with a decreased intramacrophage parasite growth and preferential synthesis of specific IgG2b antibodies. , 2000, International journal of immunopharmacology.

[5]  Murta,et al.  In‐vivo treatment with benznidazole enhances phagocytosis, parasite destruction and cytokine release by macrophages during infection with a drug‐susceptible but not with a derived drug‐resistant Trypanosoma cruzi population , 1999, Parasite immunology.

[6]  H. Masur,et al.  Trypanosoma cruzi meningoencephalitis in HIV-infected patients. , 1999, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[7]  J. McKerrow,et al.  Cysteine protease inhibitors as chemotherapy for parasitic infections. , 1999, Bioorganic & medicinal chemistry.

[8]  J. Urbina Chemotherapy of Chagas’ disease: the how and the why , 1999, Journal of Molecular Medicine.

[9]  R. Gazzinelli,et al.  Interleukin-12 Enhances In Vivo Parasiticidal Effect of Benznidazole during Acute Experimental Infection with a Naturally Drug-Resistant Strain of Trypanosoma cruzi , 1998, Antimicrobial Agents and Chemotherapy.

[10]  R. Gazzinelli,et al.  Molecular characterization of susceptible and naturally resistant strains of Trypanosoma cruzi to benznidazole and nifurtimox. , 1998, Molecular and biochemical parasitology.

[11]  R. Gazzinelli,et al.  Interleukin-12 mediates resistance to Trypanosoma cruzi in mice and is produced by murine macrophages in response to live trypomastigotes , 1996, Infection and immunity.

[12]  J. Aliberti,et al.  Tumor necrosis factor alpha mediates resistance to Trypanosoma cruzi infection in mice by inducing nitric oxide production in infected gamma interferon-activated macrophages , 1995, Infection and immunity.

[13]  C. Panosian,et al.  Human antiprotozoal therapy: past, present, and future , 1995, Clinical microbiology reviews.

[14]  O. Takayanagui,et al.  Chagasic meningoencephalitis with detection of Trypanosoma cruzi in the cerebrospinal fluid of an immunodepressed patient. , 1994, The Journal of tropical medicine and hygiene.

[15]  H. Murray Interferon-gamma and host antimicrobial defense: current and future clinical applications. , 1994, The American journal of medicine.

[16]  S. Sundar,et al.  Successful Treatment Of Refractory Visceral Leishmaniasis In India Using Antimony Plus Interferon-ã , 1994 .

[17]  K. Metze,et al.  Pathology of patients with Chagas' disease and acquired immunodeficiency syndrome. , 1994, The American journal of tropical medicine and hygiene.

[18]  L V Kirchhoff,et al.  Chagas disease. American trypanosomiasis. , 1993, Infectious disease clinics of North America.

[19]  R. Badaró,et al.  The Role of Interferon-γ in the Treatment of Visceral and Diffuse Cutaneous Leishmaniasis , 1993 .

[20]  A. Sher,et al.  The microbicidal activity of interferon‐γ‐treated macrophages against Trypanosoma cruzi involves an L‐arginine‐dependent, nitrogen oxide‐mediated mechanism inhibitable by interleukin‐10 and transforming growth factor‐β , 1992, European journal of immunology.

[21]  S. Reed,et al.  Interleukin 10 and interferon gamma regulation of experimental Trypanosoma cruzi infection , 1992, The Journal of experimental medicine.

[22]  A. Fairlamb,et al.  Interactions between immunity and chemotherapy in the treatment of the trypanosomiases and leishmaniases , 1992, Parasitology.

[23]  E. van Marck,et al.  Endogenous IFN-gamma is required for resistance to acute Trypanosoma cruzi infection in mice. , 1991, Journal of immunology.

[24]  J. Drapier,et al.  Interferon‐γ and tumor necrosis factor induce the L‐arginine‐dependent cytotoxic effector mechanism in murine macrophages* , 1988 .

[25]  S. Reed In vivo administration of recombinant IFN-gamma induces macrophage activation, and prevents acute disease, immune suppression, and death in experimental Trypanosoma cruzi infections. , 1988, Journal of immunology.

[26]  E. Camargo GROWTH AND DIFFERENTIATION IN TRYPANOSOMA CRUZI. I. ORIGIN OF METACYCLIC TRYPANOSOMES IN LIQUID MEDIA. , 1964, Revista do Instituto de Medicina Tropical de Sao Paulo.

[27]  Z. Brener Therapeutic activity and criterion of cure on mice experimentally infected with Trypanosoma cruzi. , 1962, Revista do Instituto de Medicina Tropical de Sao Paulo.