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Once an animal perceives a stressor, its immediate response is usually behavioral Friend an Dellmeier Early monumental burial sites. Related articles in Web of Science Google Scholar. These ill effects are preventable by supplements, fortification, and diet change. This report traces the increasing sophistication of our understanding of these relationships and their impact on susceptibility to infection through six stages to the present time. It is well known that immunological challenge in the bird is accompanied by a decrease in feed intake. Furthermore, because of the complex interplay between nutrients in the body, excessive intake of zinc may interfere with copper absorption.
Supplementation in some cases, however, may actually aggravate infection, because the malaria parasite requires iron for its multiplication in blood and thus may be less infective in the iron-deficient person.
The mechanism for this may also be related to the inhibition of zinc absorption [ 37 ]. Many microorganisms require trace elements, such as iron and zinc, for survival and replication in the host and may increase in pathogenicity with supplementation [ 38 ]; thus, there is a concern about iron supplementation in malaria chemoprophylaxis programs. In general, iron preferably with folate should be administered to all pregnant women undergoing malaria chemoprophylaxis [ 39 ], much like the need for pyridoxine B 6 supplementation during isoniazid treatment.
One billion people are infected with soil-transmitted helminths e. Humans can host as many as different types of parasites, and 1 worm can produce an average of 20, eggs per day. Intestinal parasites may be associated with a reduction in food intake, malabsorption, endogenous nutrient loss, and anemia. Although it is understood that parasites may lead to malnutrition, the extent to which malnutrition itself causes increased parasite infestation is not clearly known.
Nonetheless, the conditions so frequently coexist that they need to be considered together [ 22 ]. The evidence demonstrating that parasites damage a child's health is unambiguous. Helminth infections in school-aged children are associated with cognitive deficits [ 40 ].
Several worm infections, including hookworm, schistosomes, and Giardia , are associated with iron-deficiency anemia and a significant loss of micronutrients. Children free of parasites have better nutritional status, grow faster, learn more, and are freer of infections than are children with parasites.
Nutritional deficiencies associated with pregnancy may induce disturbances between the generation of free oxygen radicals and the production of antioxidants that scavenge free radicals, thus being associated with poor immune response to infection. This immune deficiency is partially made up for by breast-feeding. All of these strengthen the intrinsic immune response. Thus, breast milk actively enhances the immune system via transfer of antibodies and lymphocytes.
Breast milk supplies the ideal mix, density, and physiological form of nutrients to promote adequate infant growth and development. It helps reduce exposure of infants to enteropathogens because of its antibacterial and antiviral properties and diminishes the risk of developing celiac disease. Breast milk may also have a similar effect on allergic, autoimmune, and inflammatory bowel diseases and certain tumors [ 42 ]. It protects against diarrhea, respiratory tract infections, otitis media, bacteremia, bacterial meningitis, botulism, urinary tract infections, and necrotizing enterocolitis and may improve overall vaccine response.
There is enhanced protection for years after the termination of breast-feeding against pathogens such as Haemophilus influenzae type b and pneumococci, as well as the agents of otitis media, diarrhea, respiratory tract infections, and bronchitis [ 43 ]. As soon as breast-feeding is no longer adequate as the sole source of food, complementary feeding becomes imperative to avoid nutritional deficiency, particularly of iron.
For children born to poorly nourished mothers, complementary feeding is required sooner, and low-birth-weight babies may need iron supplementation by as early as age 2 months, or their susceptibility to infection will be increased. In short, breast-feeding is the single best way to protect infants from infection. Malnutrition and nutritional alterations are common complications of HIV infection and play significant and independent roles in morbidity and mortality [ 44 , 45 ].
The complex nature of AIDS wasting requires individualized strategies when providing nutritional support, and algorithms have been developed to assist in the diagnosis and treatment of malnutrition in patients with HIV infection [ 46 ]. AIDS studies initially documented weight loss and protein depletion associated with reduction in body cell mass in untreated patients. HAART has led to a decreased incidence and prevalence of malnutrition.
Nonetheless, altered body fat distribution and metabolic alterations, including hyperlipidemia and insulin resistance, may occur. The results of hypercaloric feeding studies, including the use of appetite stimulants, indicate that weight gain is predominantly fat.
In contrast, anabolic agents and resistance training exercise have been shown to promote body cell mass repletion and skeletal muscle gain [ 47 ]. The effect of treating opportunistic infections that promote wasting was shown in a study of ganciclovir therapy for cytomegalovirus colitis, in which untreated patients experienced progressive wasting, whereas treated patients replenished body mass [ 48 ].
Total parenteral nutrition had a variable effect on body composition, with repletion occurring in patients with eating disorders or malabsorption syndromes and progressive depletion occurring in patients with serious systemic infections.
Enteral nutrition also can increase body mass in patients with AIDS without severe malabsorption. Pharmacological appetite stimulation with drugs such as dronabinol also may lead to weight gain.
The results of these studies indicate that nutritional support can improve nutritional status in properly selected patients with AIDS [ 49 ]. Nonetheless, there is also a downside, as the noted physician-anthropologist Paul Farmer has pointed out: Early assessment, attention to nutritional requirements, and prompt intervention can minimize wasting and replenish body cell mass [ 51 ].
The 21st century will bring better knowledge of the dynamics and kinetics of specific immune responses; discovery of and better understanding of newer cytokines in the control of nutritional status and immune activation; more real-time noninvasive sampling methods, such as saliva or urine tests for analysis, gene sequencing, and proteomics to examine individual susceptibilities; and improvements in mass vaccination.
It may be possible to determine the specific mechanisms by which individual nutrients affect the immune system and thus to directly target activation and regulation of immune pathways.
Controlling malaria, measles, diarrhea, and parasitic infections can also help the body to absorb and retain essential vitamins and minerals. The estimated ratios of benefit to cost for such nutrition interventions range from 4: Children, who typically have less nutritional reserve than adults, are particularly susceptible to malnutrition and contaminated water. In addition to potability, water quality is also important for personal sanitation, to prevent contact spread of diarrhea and other infections.
Currently, malnutrition is to blame for more than one-half of all deaths of children around the world, primarily deaths caused by diarrhea, pneumonia, malaria, and measles. Poor nourishment leaves children underweight, weakened, and vulnerable to fatal and nonfatal infections. These conditions are preventable, providing that the insight, coordination, political will, and funding are available.
A question remains as to rising urban populations and the diminishing supply of both clean water and food. As water shortages grow, will desalination or recycling be economically feasible? Historically, food production expanded with population, but today, hunger and malnutrition are more the result of redistribution and politics than of production and natural disaster.
Infection is inevitably tied to nutrition in both the developing and the developed world. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.
Sign In or Create an Account. Close mobile search navigation Article navigation. The Cycle of Malnutrition and Infection. Abstract Infection and malnutrition have always been intricately linked. View large Download slide. Food and Agriculture Organization of the United Nations. The state of food insecurity in the world People with HIV often take micronutrient supplements, but the research has not yet proven what the most useful dosages are for these individuals.
Certain nutrients may directly influence the immune system's ability to fight infection. For example, cells that are supplemented with vitamin D appear to prevent Mycobacterium avium complex MAC from growing in macrophages from HIV-positive patients. This article will briefly review selected micronutrients and their known functions in the complex immune system.
Malnutrition and Immune Function It has long been known that malnourished individuals are at higher risk for infectious disease due to an inadequate immune response. Infection then leads to inflammation and worsening nutritional status, which further compromises the immune system.
This has been called the "vicious cycle. Protein-calorie malnutrition has a significant negative effect on various components of the immune system. Studies have shown decreased function of the organs thymus, spleen, lymph nodes of the immune system in malnourished humans. The branch of the immune system that produces antibodies is depressed in malnutrition, specifically with a decreased number of circulating B-cells and antibody responses.
Other mechanisms that kill infectious organisms are also depressed in malnutrition. The functions of cytokines, chemicals that act as cell messengers, are altered in malnourished individuals. Vitamin A deficiency can interfere with how epithelial cells function, which is vital in maintaining tissue structure. The ability of certain immune cells to kill infectious organisms and the production of B-cells and T-cells are also dependent on vitamin A status.
Blood levels of vitamin A have been shown to be lower in HIV-positive individuals compared to healthy individuals in both developing and developed countries. This is especially true in HIV-positive individuals with an opportunistic infection or cancer. Beta-carotene, a predecessor to vitamin A, has also been shown to be deficient in HIV-positive individuals despite vitamin supplementation. How Antiretrovirals May Affect Birth.
In the Hallways of the U. Science Alone Is Not the Solution. Zinc, selenium and magnesium have been shown to be deficient in some studies. When zinc was supplemented with vitamin A, an increased number of immune cells were seen in humans.
These critical mediators of cell function and host response are now known as cytokines. When it was appreciated that many of these same cytokines were involved in the activation of the immune response, it became clear that the immune and metabolic responses to infection were intimately entwined, with common pathways of activation and regulation, suggesting that both responses had survival value, and that attempts to manipulate the metabolic response to diminish the deterioration of nutritional status during infection might have potential downsides.
These discoveries began to capture the interest of immunologists to study the effects of nutrition on immune function, and the initiation of greater collaborations between immunologists and nutritionists. For example, the decades-old observation that the thymus gland involuted during childhood malnutrition led immunologists to appreciate the role of the thymus gland in the differentiation of T-lymphocytes, and the relevance of thymic involution to the decrease in the number of mature, differentiated T-cells during malnutrition.
The consequence of this was functional impairment of cell-mediated immunity and diminished antibody responses to protein antigens dependent on T-cell help. Further analysis of the mechanisms by which the thymus gland triggers differentiation of T-cells suggests that secreted thymic peptides are involved, as well as still uncharacterized signals provided by interaction of immature lymphocytes with the thymic epithelium.
This period also saw an increase in the number of studies conducted in humans, as the methodology continued to improve and new methods to obtain and purify relevant cell types from human peripheral blood and other tissues were developed, as well as new and better animal models. Some of this was ascribed to the full realization that malnutrition of a degree sufficient to impair immune function was not just confined to children in developing countries without access to nutritionally complete diets, but occurred in up to half of the adult patients hospitalized on medical or surgical services in the United States.
In fact, the same metabolic events induced by infection were found to be caused by trauma or surgery. Malnutrition was also common in the elderly, who often consumed inadequate diets because of a number of social and medical factors including disease and drug-induced anorexia. Nutritional rehabilitation during hospitalization and greater attention to nutrition and diet in general medical and surgical care became higher priorities.
In addition, there was a realization that the acute-phase response induced by infection was a closely regulated and highly complex set of events, and that further refinement in our understanding of the mechanisms and mediators involved might lead us to targeted interventions after all.
This exciting period of discovery is further discussed by Michael Powanda in this symposium. During this period the role of micronutrient deficiency as a conditioning factor in host response to infection became widely recognized, as multiple large field studies of vitamin A supplementation in different populations around the world demonstrated a marked decrease in childhood mortality attributed to all causes in children compared to those who were not supplemented.
Although it has been difficult to show that the reduction in deaths associated with supplementation of infants and young children was specifically attributable to an effect on susceptibility or the ability to respond to individual infectious diseases, with the exception of measles, there is no other plausible explanation for the large effects noted in these studies. This discrepancy between the overall effect and the lack of an explanatory mechanism has triggered considerable discussion and some degree of skepticism.
There are, however, plausible explanations that remain undocumented. For example, vitamin A deficiency is known to result in keratinization of the respiratory epithelium, leading to a decrease in mucus production and diminished capacity of the respiratory epithelium to clear bacterial pathogens.
These events have not been studied in vivo. In addition, vitamin A and other retinoids regulate the expression of the genes for multiple proteins involved in host defense; in fact, aside from its role in visual function, the major effect of vitamin A is through the regulation of genes. Although the specific pathways involved in the enhanced mortality associated with vitamin A-deficiency states remains elusive, major programs to provide vitamin A supplements to those at risk in developing countries have been initiated in many developing countries.
Deficiency of other minerals, including iron and zinc, are well documented to impair immune function in experimental animals, and to the extent studied, in humans as well. One postulated mechanism is that both of these metals are essential for the function of a number of metalloenzymes required for nucleic acid synthesis and cell replication.
This is a particularly critical barrier to an effective immune response to infectious diseases that is based on the rapid reproduction of antigen-specific responsive clones of stimulated lymphocytes and the capacity of bone marrow to churn out increasing numbers of neutrophils and monocytes. Without the ability to make new DNA and RNA for cell division the host response sputters, and this is clearly documented in a variety of in vitro studies.
It has been more difficult to demonstrate these effects in vivo in humans, however, and the clinical importance of zinc and iron deficiency remains in doubt. Interestingly, iron excess also appears to impair immune function, in this instance because of iron-catalyzed toxic oxidative reactions that physically damage immunocompetent cells. Interesting studies on Keshan disease, the cardiomyopathy ascribed to Coxsackie B virus infections in selenium-deficient individuals in Keshan province in China, demonstrated that the antioxidant deficiency acted to select for a more virulent form of the causative virus.
As is the case for many RNA viruses, including HIV, the relatively common infidelity of RNA replication leads to the production of an array of slightly different genotypes, commonly known as quasi-species. Alterations in certain specific nucleotide positions also correlate with increases or decreases in viral virulence, as tested in a mouse cardiomyopathy model.
Infection of normal mice with fully virulent, but not avirulent, forms of the virus results in disease and death. Infection of selenium-deficient mice with avirulent virus also causes disease, and when the progeny virus is reinfected into normal mice, severe disease results. Analysis of this virus before and after this serial passage in animals demonstrates the selection of virulent virus associated with nucleotide changes in the relevant virulence positions in the genome 3.
Although the precise nature of this selection for virulence in selenium deficiency remains to be determined, these studies have established another mechanism of micronutrient influence on infection. During this decade, further studies of the catabolic wasting syndrome in AIDS have suggested that the underlying mechanism involves an imbalance in the levels of pro- and antiinflammatory cytokines produced by mononuclear cells. Why these particular subjects were able to balance the increase in proinflammatory cytokines with antiinflammatory cytokines is not known at present, but of interest not only for this situation but also to the possible use of antiinflammatory cytokines in other clinical settings.
What does the new millennium portend for these areas of research? Opening on a positive note, a textbook dedicated to nutrition and immunology was published 5 , demonstrating not only the general interest in the field, but also the involvement of increasing numbers of serious immunologists as research partners. It is certainly not too much to expect that there will be an improvement in existing methods and the development of better methods to assess nutritional status as well as immune function.
As a part of this, assessment of RNA and protein synthesis can help track the activation of genes during immune responses and production of the relevant proteins that mediate the ultimate responses of the host. Interest in regulatory mechanisms, and the role of newly described cytokines in the control of nutritional status and immune activation will continue to yield new insights 7.
Explorations are much easier now with the new microchip array technology, which allows the rapid and simultaneous analysis of multiple pathways, at both the transcriptional and translational levels 8 , 9. Although there are some possibilities to use excreted samples such as saliva or urine for analysis, standardization is a problem and invasive sampling of cells and body fluids remains the standard.
Nonetheless, it is conceivable that new photolabeling and imaging techniques could make possible real-time noninvasive sampling methods. The biological revolution initiated by the Human Genome Project and the development of rapid sequencing methods have created the possibility of identifying minor sequence variations in specific genes that predict expression patterns of the proteins they encode, and thus the nature of the response at the protein and phenotypic levels Single nucleotide variations or SNPs , now readily detected, can indicate functional differences in genes between individuals.