RESUMO
Visceral leishmaniasis (VL), caused by Leishmania donovani, is a major health concern in India. It represents T-helper type 2 (Th2) bias of cytokines in active state and Th1 bias at cure. However, the role of the parasite in regulating Toll-like receptor (TLR)-mediated macrophage activation in VL patients remains elusive. In this report, we demonstrated that later stages of L. donovani infection rendered tolerance to macrophages, leading to incapability for the production of inflammatory cytokines like tumor necrosis factor (TNF)-α and interleukin (IL)-1ß in response to TLR stimulation. Overexpression of transforming growth factor (TGF)-ß(1), but not IL-10, resulted in suppressed lipopolysaccharide (LPS)-induced production of TNF-α and downregulation of TLR4 expression in L. donovani-infected macrophages. Recombinant human (rh)TGF-ß(1) markedly enhanced tyrosine phosphatase (Src homology region 2 domain-containing phosphatase-1) activity, but inhibited IL-1 receptor-activated kinase (IRAK)-1 activation. Addition of neutralizing TGF-ß(1) antibody reversed these effects, and thus suggesting the pivotal role of TGF-ß(1) in promoting refractoriness for LPS in macrophages. Surprisingly, the use of a tyrosine phosphatase inhibitor (sodium orthovanadate, Na(3)VO(4)) promoted IRAK-1 activation, confirming the negative inhibitory role of tyrosine phosphatase in macrophage activation. Furthermore, rhTGF-ß(1) induced tolerance in infected macrophages by reducing inhibitory protein (IκBα) degradation in a time-dependent manner. In addition, short interfering RNA studies proved that overexpression of A20 ubiquitin-editing protein complex induced inhibitory activity of TGF-ß(1) on LPS-mediated nuclear factor-κB activation. Thus, these findings suggest that TGF-ß(1) promotes overexpression of A20 through tyrosine phosphatase activity that ensures transient activation of inflammatory signaling pathways in macrophages in active L. donovani infection.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leishmania donovani , Leishmaniose Visceral/imunologia , Proteínas Nucleares/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Adulto , Proteínas de Ligação a DNA/genética , Ativação Enzimática , Feminino , Humanos , Quinase I-kappa B/metabolismo , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Interleucina-1beta/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/genética , Leishmania donovani/imunologia , Leishmaniose Visceral/metabolismo , Lipopolissacarídeos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , NF-kappa B/biossíntese , Proteínas Nucleares/genética , Interferência de RNA , RNA Interferente Pequeno , Transdução de Sinais , Receptor 4 Toll-Like/imunologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Fator de Necrose Tumoral alfa/biossíntese , Ubiquitina-Proteína Ligases/metabolismo , Vanadatos/farmacologiaRESUMO
A 37-year-old man was diagnosed as being infected with human immunodeficiency virus (HIV), tuberculosis (TB), tuberculoma of the brain, and visceral leishmaniasis (VL) at the Rajendra Memorial Institute of Medical Sciences in Bihar, India. He had taken anti-tuberculosis therapy (ATT) for two and a half months and had episodes of convulsions with loss of consciousness, tongue bites, and incontinence of urine. The results of a neurologic examination were normal except for a left plantar extensor. He was positive for both HIV-I (confirmed by Western blot) and VL (confirmed by splenic aspirate). Treatment was initiated with amphotericin B lipid complex, a four-drug regimen (rifampicin, isoniazid, ethambutol, and pyrazinamide) of ATT, highly active antiretroviral therapy, anti-convulsants, and other supportive therapies. A repeat computed tomography scan of the brain showed the disappearance of the lesion followed by gliosis. After six months, he was also cured of VL. The triad of infections (HIV, VL, and TB) is a real threat in Bihar as an emerging combination of diseases of public health importance. Keeping these facts in mind, efforts to develop simple and cost effective diagnostic techniques coupled with affordable therapeutic facilities are urgently needed in developing countries.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Leishmaniose/complicações , Tuberculose Pulmonar/complicações , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/imunologia , Adulto , Humanos , Índia , Leishmaniose/tratamento farmacológico , Leishmaniose/imunologia , Masculino , Tomógrafos Computadorizados , Tuberculose Pulmonar/tratamento farmacológicoRESUMO
We estimated the level of under-reporting of visceral leishmaniasis (VL) cases by comparing the actual reported cases with those expected as estimated using age- and sex-stratified incidence proportions obtained in a cohort of 31,324 persons. The average incidence proportion of VL cases in study population was 5.7/1,000 (95% confidence interval [CI] = 4.88-6.54) and 1.09/1,000 persons (95% CI = 0.99-1.20) based on the reported cases in two primary health centers. The overall magnitude of VL cases not reported to the government agencies was higher by a factor 4.17 (95% CI = 3.75-4.63) than for reported cases. The levels of under-reporting were 4.74 (95% CI = 4.11-5.47) in males and 3.51 (95% CI = 2.99-4.11) in females with no significant difference (P > 0.05). It was significantly higher in persons >or= 30 years of age than in persons 30 years of age (P < 0.05).