Nutrition in pediatric HIV infection: setting the research agenda. Nutrition and immune function: overview.

Malnutrition can have adverse, even devastating effects on the antigen-specific arms of the immune system and on generalized host defensive mechanisms. Protein/energy malnutrition and/or deficiencies of single nutrients that assist in nucleic acid metabolism generally lead to atrophy of lymphoid tissues and dysfunctions of cell-mediated immunity. Deficiencies of single nutrients can impair production of key proteins. Trace element deficiencies are often multifactorial. Essential fatty acid deficiencies can reduce or perturb the synthesis of cytokine-induced eicosanoids. Arginine deficiency can diminish the production of nitric oxide, and deficiencies of antioxidant nutrients can allow increases in the damaging effects of free oxygen radicals. Humoral immunity continues to be maintained, although new primary responses to T-cell-dependent antigens are generally subnormal in both magnitude and quality. Immunological dysfunctions associated with malnutrition have been termed Nutritionally Acquired Immune Deficiency Syndromes (NAIDS). Infants and small children are at great risk because they possess only immature, inexperienced immune systems and very small protein reserves. The combination of NAIDS and common childhood infections is the leading cause of human mortality. NAIDS can generally be corrected by appropriate nutritional rehabilitation, but from a viewpoint highly important to this Workshop, AIDS and NAIDS are intensely synergistic. AIDS-induced malnutrition can lead to the secondary development of NAIDS, with its much broader array of additional immunological dysfunctions. The complex and far reaching insults to the immune system caused by NAIDS, and the synergistic combination of NAIDS and AIDS, thereby hasten the demise of many victims of AIDS. Aggressive nutritional support for children with HIV infections could delay, or lessen, the development of NAIDS and avoidance of NAIDS would improve both quality and length of life.

Herman Award Lecture, 1995: infection-induced malnutrition--from cholera to cytokines.

Infection-induced malnutrition, the most common form of cytokine-induced malnutrition, results from the actions of proinflammatory cytokines, ie, tumor necrosis factor (TNF) and interleukins 1,6, and 8 (IL-1, IL-6, and IL-8). During acute generalized infections, these cytokines initiate the acute-phase reaction. This reaction is quite stereotyped, and includes fever, malaise, myalgia, headaches, cellular hypermetabolism, and multiple endocrine and enzyme responses. In addition, there is heightened catabolism of muscle proteins and many amino acids; flux of free amino acids into the liver; hepatic synthesis of acute-phase plasma proteins; sequestration of iron and zinc; gluconeo-genesis; insulin resistance; impaired cellular uptake of fatty acids from plasma triglycerides; sizable losses of body nitrogen, potassium, magnesium, phosphate, and zinc; retention of body salt and water; heightened metabolic degradation and/or loss of vitamins; and an activation of the immune system. The pathogenesis of cytokine-induced malnutrition is thus vastly different from the malnutrition caused by uncomplicated starvation. Cytokine-induced malnutrition can have a devastating effect on the immune system and its functions. Although proinflammatory cytokines are found in mucosal fluids, where they contribute to the pathogenesis of inflammatory bowel diseases, it is not known whether cytokines play a role in toxigenic, secretory diarrheas such as cholera, which cause huge losses of body water, electrolytes, and bicarbonate while exhibiting no systemic manifestations of an acute-phase reaction.

History of nutritional immunology: introduction and overview.

Nutritional immunology is a newly recognized subdiscipline of vast clinical and public health importance. Its history began in 1810 with recognition of lymphoid tissue atrophy due to malnutrition. Discovery of vitamins in the early 1900s was followed by reports on their contribution to immunity and other host defenses. A hiatus in immunonutritional progress occurred during World War II and the "antibiotic era," but a worldwide rebirth of interest began in the 1960s and early 1970s. The current logarithmic growth of nutritional immunology was triggered by increased medical interest, plus the introduction of new concepts and investigative research methodologies from both parent sciences.

Future role of micronutrients on immune functions.

The future is bright in the field of micronutrients and immunity. New advances in technology now permit the design of many new research studies, and an increased application of the findings to clinical and public health practices. More investigators will need to be trained in the fundamentals of both nutritional and immunological sciences. More basic information will be needed in both fields, but the scientific and clinical values of merging these two fields are already well established. The development of additional animal models will be needed to dissect out the role of each essential micronutrient and its potential importance in each step of the immune response. Based on future studies, new RDAs must be formulated and applied widely in medical and public health practices and in public education.

The effects of space flight on immunocompetence.

The National Aeronautics and Space Administration (NASA) conducts a research program in the biological and medical aspects of space flight and funds research proposals submitted by interested scientists. Changes that could influence immune status and possibly impair host resistance to infections have been noted and are summarized in a report prepared by the Life Sciences Research Office of the Federation of American Societies for Experimental Biology and a working group of eminent scientists.

Does fever or myalgia indicate reduced physical performance capacity in viral infections?

To study prospectively the effects of a brief febrile viral infection on parameters of muscle and circulatory function, seven volunteers were inoculated with sandfly fever virus and two control subjects with sterile saline. During but not after fever, decreased isometric and dynamic strength and endurance were recorded in various muscles. Impairment could not be explained by altered activities of relevant muscle enzymes in serum or muscle tissue or by altered muscle ultrastructure, but correlated with the severity of perceived symptoms, including myalgia, as rated by each subject. Compared to baseline, cardiac stroke volume was lower during and after fever. During fever, an increased heart rate maintained cardiac output at pre-inoculation values, whereas cardiac output fell in early convalescence. This decrease in cardiac output correlated significantly with the severity of fever. Thus, in brief viral infections a transient impairment of muscle performance capacity is correlated to subjective symptoms such as myalgia, rather than to fever, whereas a decreased cardiac output following such infections seems to be associated with the fever reaction.

Sequential metabolic alterations in the myocardium during influenza and tularemia in mice.

Mice with generalized influenza or tularemia of similar lethality were studied in an effort to compare biochemical responses of the myocardium during infections of viral and bacterial etiology. A progressive loss of body weight characterized the course of both infections. Accompanying this, the myocardial content of protein and the activities of lactate dehydrogenase, citrate synthase, and cytochrome c oxidase all decreased. However, myocardial protein degradation appeared earlier and was more pronounced in influenza, and the protein changes were accompanied by a rapid decline of myocardial RNA. Activation of acid hydrolases, such as cathepsin D and beta-glucuronidase, occurred in tularemia but not in influenza, whereas leakage of beta-glucuronidase into the plasma occurred in both infections. Conversely, there was a considerably greater activation of myocardial catalase in influenza. These findings suggested that different control mechanisms or metabolic pathways were operative in the degradation of myocardial constituents in influenza as compared with tularemia. The absence of histological signs of myocarditis in either infection appeared to exclude any direct local effects of an inflammatory process on myocardial cells. Since the infections were of comparable lethality (based upon the inoculated dose of organisms), the observed differences in pattern and extent of metabolic responses of the myocardium to these infections may be attributed to different pathophysiological mechanisms evoked by the different microorganisms.

Modifying effects of exercise on clinical course and biochemical response of the myocardium in influenza and tularemia in mice.

For a study of the interactions of strenuous physical exercise (daily swimming to exhaustion) and a viral as compared with a bacterial infection with regard to the clinical course and the biochemical response of the myocardium, influenza and tularemia of similar lethality were used in mice. In both infections, expected infection-induced catabolic alterations in the ventricular myocardium were evident 2 days before median lethality was achieved, with a more pronounced wasting in influenza than in tularemia. Exercise before inoculation (preconditioning) was beneficial in that the catabolic effects of both infections were limited and lethality in influenza was reduced. Thus, the myocardial protein-degrading effect of influenza did not occur with preconditioning, and oxidative tissue enzyme activities decreased less. In tularemia, cytochrome c oxidase activity was fully preserved with preconditioning, and activation of catalase was less pronounced. Exercise during ongoing infection counteracted the infection-induced decrease in the activities of glycolytic and oxidative enzymes in tularemia, but lethality and bacterial counts in the spleen were uninfluenced. Conversely, exhaustive exercise in influenza increased lethality and had no significant effect on cardiac enzymes. These exercise models caused no major alterations in activation of lysosomal enzymes (beta-glucuronidase and cathepsin D).

The effect of exercise and fasting on the myocardial protein and lipid metabolism in experimental bacterial myocarditis.

A generally nonlethal Salmonella typhimurium infection in weanling rats produced bacterial myocarditis and myocardial hyperplasia. Myocardial lesions were characterized by focal infiltrates of inflammatory cells (predominantly mononuclear), segmental myocyte necrosis, and incipient fibrosis. Although bacterial infections are infrequently associated with myocarditis, the S. typhimurium infection in young rats produced a new experimental model of diffuse myocardial inflammatory foci. Biochemical changes in the myocardium included great increases in total myocardial contents of protein (23%), RNA (39%) and DNA (43%) and several lipid fractions (35-55%) as well as in tissue activities of acid hydrolases, such as cathepsin D (124%) and beta-glucuronidase (135%), all of which contrasted with the relatively limited areas of histologic involvement (1.5%). To study the effects of additional stress in this model infection, some rats were exercised by forced running in wheels for 2 hours and others were fasted for 24 hours before samples were obtained. The short period of forced exercise in this infection caused an additional increase of myocardial protein content (47%) but with no additional change in histology. The expected fasting-induced degradation of protein as well as an infection-associated increase in myocardial lipids were each prevented when rats were fasted during ongoing acute infection. Protein degradation, as reflected by heightened acid hydrolase activities, seemed to occur at a similar rate regardless of other stresses, whereas the rate of myocardial protein synthesis appeared to be alterable.

Effects of Streptococcus pneumoniae, Salmonella typhimurium and Francisella tularensis infections on oxidative, glycolytic and lysosomal enzyme activity in red and white skeletal muscle in the rat.

Since opinions differ as to whether the oxidative and glycolytic capabilities of skeletal muscle are altered in acute infection, enzyme activities in oxidative, glycolytic and degradative (acid hydrolases) pathways and total protein and DNA were determined in skeletal muscle of rats infected with Streptococcus pneumoniae, Salmonella typhimurium or Francisella tularensis. Studies were performed separately in red (slow twitch) and white (fast twitch) muscle tissue because these fibers function during different types of exercise. In the salmonella- and tularemia-infected rats, the intramitochondrially located oxidative enzymes of muscle were decreased to 56-83% of controls whereas the glycolytic enzyme situated in the cytosol showed an earlier and more pronounced loss of activity, 30-75% of controls. In the pneumococcal infection, only reduced glycolytic activity was significant. DNA concentrations were unchanged in any infection. Reductions during tularemia were statistically correlated with whole-cell protein degradation, while that of the glycolytic enzyme was parallelled by activation of lysosomal enzymes. Red and white muscle tissues responded similarly, in contrast to several other pathologic states that involve a catabolic component of muscle with a predominant response (or damage) in one or the other fiber type.

Metabolic effects of infection.

The metabolic effects of infection influence a wide variety and number of host biochemical pathways and molecular mechanisms. These responses function in support of the many diverse defense systems used by the body to control or eliminate invading microorganisms. Despite their complexity and diversity, these responses develop in relatively consistent, almost stereotypic pattern of progression during the course of generalized febrile infections caused by many kinds of different agents. If an infection localizes within an organ system, derangements of function of that organ may be superimposed upon the generalized responses. These general metabolic responses are initiated and modulated by the release of endogenous mediators, hormones, and by central nervous system stimuli as well. The magnitude of these metabolic changes can be influenced by the severity and duration of the illness. Clinically, the most visible metabolic effects of an infectious disease are catabolic. They can be documented by measurable losses of body constituents and nutrients. However, it must be kept in mind that equally important anabolic processes are taking place at the same time. It is these latter anabolic events that are of importance in host defensive mechanisms.

Biochemical responses of the myocardium and red skeletal muscle to Salmonella typhimurium infection in the rat.

Previous studies with bacterial infections have demonstrated a reduced exercise capacity and equally pronounced catabolic responses in red and white skeletal muscle. In the present study, red skeletal muscle and heart ventricular muscle were compared in a S. typhimurium model in rats. Two days before median lethality was achieved, the activities of one oxidative (cytochrome c oxidase), one glycolytic (glyceraldehyde-3-phosphate dehydrogenase) and one lysosomal (beta-glucuronidase) enzyme were determined in the two tissues. The contents of protein, RNA and DNA were also determined. The oxidative and glycolytic capacity decreased 24-29% in red skeletal muscle but only 7-20% in the myocardium. However, the decrease in oxidative capacity in skeletal muscle and myocardium was statistically correlated. The protein synthetic capacity (RNA) also decreased and was correlated to the protein concentration in both tissues. This metabolic impairment of both skeletal and heart muscle probably contributes to the deterioration of the physical performance capacity previously observed to follow acute infectious diseases. This study emphasizes the importance of the choice of reference, such as 'wet' weight, DNA or the entire organ, when evaluating metabolic results in biologic tissues and that biochemical alterations in skeletal muscle biopsies in bacterial infections do not reflect alterations in myocardium reliably.