Chan J, Tian Y, Tanaka K E, Tsang M S, Yu K, Salgame P, Carroll D, Kress Y, Teitelbaum R, Bloom B R
Department of Medicine, Montefiore Medical Center, Bronx, NY, USA.
Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14857-61. doi: 10.1073/pnas.93.25.14857.
Infectious diseases and malnutrition represent major burdens afflicting millions of people in developing countries. Both conditions affect individuals in industrialized nations, particularly the aged, the HIV-infected, and people with chronic diseases. While malnutrition is known to induce a state of immunodeficiency, the mechanisms responsible for compromised antimicrobial resistance in malnourished hosts remain obscure. In the present study, mice fed a 2% protein diet and developing protein calorie malnutrition, in contrast to well-nourished controls receiving a 20% protein diet, rapidly succumbed to infection with Mycobacterium tuberculosis. Malnourished mice exhibited a tissue-specific diminution in the expression of interferon gamma, tumor necrosis factor alpha, and the inducible form of nitric oxide synthase in the lungs, but not the liver. The expression of these molecules critical to the production of mycobactericidal nitrogen oxides was depressed in malnourished animals in the lungs specifically at early times (< 14 days) after infection. At later times, levels of expression became comparable to those in well-nourished controls, although the bacillary burden in the malnourished animals continued to rise. Nevertheless, urinary and serum nitrate contents, an index of total nitric oxide (NO) production in vivo, were not detectably diminished in malnourished, mycobacteria-infected mice. In contrast to the selective and early reduction of lymphokines and the inducible form of nitric oxide synthase in the lung, a marked diminution of the granulomatous reaction was observed in malnourished mice throughout the entire course of infection in all tissues examined (lungs, liver, and spleen). Remarkably, the progressively fatal course of tuberculosis observed in the malnourished mice could be reversed by restoring a full protein (20%) diet. The results indicate that protein calorie malnutrition selectively compromises several components of the cellular immune response that are important for containing and restricting tuberculous infection, and suggest that malnutrition-induced susceptibility to some infectious diseases can be reversed or ameliorated by nutritional intervention.
传染病和营养不良是困扰发展中国家数百万人的主要负担。这两种情况也影响工业化国家的个人，特别是老年人、艾滋病毒感染者和慢性病患者。虽然已知营养不良会导致免疫缺陷状态，但营养不良宿主中抗菌抗性受损的机制仍不清楚。在本研究中，与接受20%蛋白质饮食的营养良好的对照组相比，喂食2%蛋白质饮食并发展为蛋白质热量营养不良的小鼠迅速死于结核分枝杆菌感染。营养不良的小鼠肺部干扰素γ、肿瘤坏死因子α和诱导型一氧化氮合酶的表达出现组织特异性降低，但肝脏未出现这种情况。这些对产生杀分枝杆菌氮氧化物至关重要的分子的表达在营养不良动物的肺部感染后早期（<14天）特别受到抑制。在后期，表达水平与营养良好的对照组相当，尽管营养不良动物的细菌负荷继续上升。然而，营养不良、感染分枝杆菌的小鼠体内的尿液和血清硝酸盐含量（体内总一氧化氮（NO）产生的指标）没有明显降低。与肺部淋巴细胞因子和诱导型一氧化氮合酶的选择性早期减少相反，在所有检查的组织（肺、肝和脾）中，营养不良小鼠在整个感染过程中观察到肉芽肿反应明显减弱。值得注意的是，通过恢复全蛋白（20%）饮食，可以逆转营养不良小鼠中观察到的逐渐致命的结核病病程。结果表明，蛋白质热量营养不良选择性地损害了细胞免疫反应的几个组成部分，这些组成部分对于控制和限制结核感染很重要，并表明营养不良引起的对某些传染病的易感性可以通过营养干预来逆转或改善。
