Interaction between infection, nutrition and immunity in tropical medicine

REVIEW ARTICLE

Interaction between infection, nutrition and immunity in tropical medicine

P. C. M. Pereira

Departamento de Doenças Tropicais e Diagnóstico por Imagem, Faculdade de Medicina de Botucatu, UNESP, Botucatu, SP, Brasil

^{Correspondence}

ABSTRACT

Host nutritional state has an important role in susceptibility to bacteria, parasites, and viral infections. Infection precipitates the appearance of signs and symptoms of nutrition deficiencies in the undernourished; this can aggravate infection evolution. Infection stimulates specific and non-specific host defense mechanisms; these are directly influenced by the nutritional state of micro- and macronutrients. Immune alterations, which are closely related to nutritional status, markedly contribute to a higher susceptibility to infectious agents and can also contribute to worsening nutritional state, forming a vicious cycle.

Key words: infection, nutrition, immunity, tropical diseases.

INTRODUCTION

The interaction between nutrition and infection has been considered one of the major problems for the development and survival of humans. Some of the main observations on the association between nutrition and bacterial infections have referred to the effects of typhoid fever and other enteric infections on the excretion of nitrogen (4,5).

Undernourishment is considered a major cause of the high prevalence of acquired immunodeficiency in the world, followed by high morbidity and mortality (30). Various natural biological factors, including illness causing micro and macro-organisms, such as viruses, bacteria, protozoa, and parasitic worms may have the power to infect and/or pathogenically modify in individuals submitted to different diets (20). Serious illness and changes in metabolic equilibrium in a host could be associated to his nutritional state (1).

Infectious agents and parasites can interfere in the equilibrium between the external and internal environment, determining major or minor actuation of factors related to the nutritional state. Host nutritional state has an important role in susceptibility to bacteria, parasites, and viral infections. Infection precipitates the appearance of signs and symptoms of nutrition deficiencies in the undernourished; this can aggravate infection process evolution (20). Both interact synergetically and are a public health problem, mainly in areas of poor basic sanitation; poverty and ignorance also influence eating habits (12).

The infection process stimulates specific and non-specific host defense mechanisms; these are directly influenced by the nutritional state of micro and macronutrients (1). In addition, generalized infection is usually followed by hypercatabolism aggravated by anorexia resulting in the loss and consequent depletion of body nutrient reserves (9,12). The higher energy demand during infection is followed by marked alterations in host metabolism, preparing to fight the aggressor agent. These alterations vary according to micro-organism type, disease severity, the presence of certain complications, or the compromise of certain organs or systems (20).

Alterations in protein synthesis and degradation, complex modifications in amino acid metabolism, alterations in nutrients including electrolytes, minerals, oligoelements and vitamins, and changes in the type and magnitude of cell energy production and its utilization have been seen (15). Hormone participation and the influence of fever contribute to these metabolic responses and alterations. Food consumption, body nutrient reserves, and their loss actively interfere in the nutrition balance and infection (9,15).

Immune alterations, which are closely related to nutritional status, markedly contribute to a higher susceptibility to infectious agents and can also contribute to worsening nutritional state, forming a vicious cycle (5,6,12,15,18,30).

The triangle formed by the interaction between nutrition, infection, and immunity must remain balanced, since alterations in these factors maybe responsible for high morbidity and mortality especially in poorer regions (15).

The effect of infections on nutritional state

Acute infections trigger responses to stress caused in the body, producing metabolic alterations that strengthen the host to fight the aggressor. In contrast to what occurs in fasting and undernutrition, aggressions caused by infections trigger a characteristic protein hypermetabolic state with high resting energy expenditure (3). However there is a higher nutrient requirement speeding up active and passive host resistance to aggressor mechanisms which when associated with anorexia following infection may result in losses and consequent depletion of body nutrient reserves (21,22).

The increase in energy demand and hypercatabolism, associated to a lower nutrient intake, may trigger latent or clinical states of malnutrition. Therefore, in an attempt to provide an increase in energy demand, there is an increase in glucose and the patients may show hyperglycemia (3). Both the lesion repair and immunostimulation involve a higher glucose consumption that during anorexia has hepatic neoglycogenesis as its main source and muscular amino acids as its precursor. Amino acid redistribution from peripheral tissue proteolysis to bone marrow and Endothelium Reticulum System organs, favors not only neogycogenesis, but also granulopoiesis, synthesis of immunoglobulins and acute-phase positive proteins (10,29).

The acute-phase response is an early complex and non-specific body reaction to aggressions caused by factors such as: bacterial, viral, or parasitic infections (29). These responses start locally and then become systemic. The secondary systemic reaction includes neurological, endocrine, and metabolic alterations such as fever, leukocytosis, increased hormone levels, activation of hemostasis and the complement system, formation of kinines, and rearrangement of the plasma protein pattern (22). This entire process is accompanied by increase in energy demand and lower ingestion, which may affect the host nutritional state (20).

The acute-phase response (APR) is triggered by the action of proinflammatory cytokines, interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) which are responsible for a series of metabolic changes, following pathogen invasion, to strengthen the host in relation to immunocompetence or lesion repair (30).

The behavior of hepatic plasma proteins to aggression, responsive to the positive acute phase (higher synthesis) has the following main functions: antiproteasic, antioxidant, and cell debris clearance. With this, the body tries to circumscribe the aggression area inactivating the bacterial agents released in the extracellular by the phagocyte (22,29). In man, the main representative of positive acute phase protein response are: reactive C protein (RCP), a1-acid glycoprotein, a1-antitrypsin, a1-antichemotrypsin, haptoglobin, ceruloplasmin, fibrinogin, and serum amyloid A (10).

The main functions of negative acute phase proteins are the transport of substances, maintenance of oncotic pressure, and amino acid reservoir such as: albumin, transtiretin, retinol binding protein (RBP), and transferin (10).

Cortisone and insulin participate in the mediation of amino acid mobilization saving them for liver glycogenesis. This promotes protein consumption in the body because the mobilized amino acids are deaminated to provide glucose carbons, and nitrogen is excreted in the urine, mainly as urea. The new protein synthesis by the liver substantially increases during infection using the amino acids released from the muscles. Some of these new synthesized proteins are defense mechanism components such as the C3 and complement factor B. Some of these proteins, produced in large quantity during infection, are found in very low concentrations in normal hosts. This includes C reactive protein and serum amyloid, which may have immunoregulatory functions (10). Other proteins are used as protein carriers, such as hepatoglobulin or copper transporting protein, ceruloplasmin or with enzymatic inhibiting functions such as a-1 antitrypsin or a1-antichemotrypsin. Simultaneously, maybe as a compensating response, there is a reduction in the pattern of protein synthesis exported by the liver such as albumin and transferin (22). Their in serum quantity decreases to very low levels, inversely proportional to severity, and may give an idea of infection prognosis (22). In this sense, Pereira et al. (23) found very low albumin and transferin levels in malaria patients compared to normal groups in a malaria endemic region study. In some infections, for example Gram-negative bacterial sepsis, the serum may become milky due to an increase in triglyceride concentration. There is a defect in lipid cleansing by low-density lipoproteins caused by the decrease of lipoproteic lipase enzyme activity. This inhibits fat storage capacity contributing to excessive serum lipid levels. Although there are many lipids, they cannot be effectively used for energy production via ketone oxidation. Pereira et al. (23), studying malaria repercussion on nutritional state in Humaitá, Amazonas, found lower cholesterol and total lipid levels in malaria patients compared to normal people in the region. Triglycerate levels were higher especially in patients infected by P. falciparum, which was a more severe infection.

Reduced serum levels of iron and zinc and increased copper levels are seen in patients with severe acute infections (14). These result from level in changes of their binding protein cations. The function of these alterations is to strengthen the host and weaken the aggressor.

Therefore, cytokines are responsible for many changes observed in metabolic alterations during host infection (11,16). Pro-inflammatory cytokines such as IL-1, IL-6 and TNF-a, regulate the metabolic rhythm, the immune response, and body composition; they directly and indirectly affect metabolism. Cytokine participation is clear in acute or even in chronic inflammatory processes (24). They also show endocrine action on distant organs or tissues (25). There are groups of cytokines with synergistic and others with antagonistic effects on the metabolism or even between themselves.

In severe bacteria infections, sepsis, we see hyperglycaemia, insulin resistance, and a strongly negative nitrogen balance, with a diversion of amino acid from the skeletal muscle to splanchic tissues. These inflammatory responses are primarily mediated by cytokines (TNF-a, IL-1 e IL-6) and, secondarily (to cytokine primary action) by the action of catecholamines, cortisol, and glucagon (19). Increased muscular proteolysis, in sepsis, is partially regulated by IL-1, while TNF-a induces higher energy consumption and increased protein and lipid metabolism. This mobilization of energy substrates is the response to aggression with the aim of adapting to survive (27), but consequential nutritional damage may occur in the host especially if the process is perpetuated.

TNF shares many biological properties with IL-1 and is one of its inducers. In experimental studies with animals, TNF was responsible for anorexia and weight loss (27). It produces severe depletion in fat reserves, inhibiting lipoprotein lipase production. Excessive TNF-a may induce sceptic shock or sustain hypermetabolic stress (25). Variation in TNF-a levels is related to infection severity (19).

Due to its early appearance, TNF-a is considered a primary sign of metabolic responses. Although its infusion results in fever, tachicardia, and shivering, its most potent effects are on carbon and nitrogen mobilization from the periphery to the splanchic circulation (25).

TNF-a therefore, is the cytokine involved in septic shock pathogenesis and is the indicator of septic complications or multiple organ failure.

IL-6 is described as the major acute-phase response regulator in human hepatocytes (13). This cytokine activates the hepatocyte nuclear factor, induces the synthesis of fibrinogen, a1-antichemotrypsin, a1–acid glycoprotein, haptoglobin, a2-macroglobulin, and protease inhibitors (13). Redistribution of nutrients in infection includes the participation, biofeedback of IL-6 and glycocorticoids (2).

IL-6 induces the genic expression of proteins participating in defense mechanisms, especially hematological and immune responses. Its continued production may weaken host functions (8). Therefore, IL-6 acts on hematopoiesis, immune reactions, and acute-phase responses. Anorexia and muscular hypercatabolism are predisposing factors to energy protein undernutrition and immunosuppression (13).

Early secretion of IL-1 and TNF-a seem to participate in IL-6 induction and protein catabolism initiation. Thus, data report that IL-6 would be the key cytokine in the synthesis of acute phase proteins in humans, with the other cytokines potentializing or inhibiting this stimulus (13).

The metabolic modifications that occur in the fever patient result in loss of proteins and energy reserves evolving to the consumption of nutrient reserves. This may have very serious consequences since an inadequate diet is not able to replace the lost reserves. The high prevalence of infections may lead to new nutrient losses that may culminate in severe undernutrition.

Effects of undernutrition in relation to infections

The effect of poor nutrition on infections may be observed in the host and the infectious agent facilitating or impeding its growth and pathogenic potential. Infection may aggravate pre-existing poor nutrition or impede proliferation of the pathogenic agent. A major characteristic of living beings is their capacity to regulate the main metabolic processes. During fluctuations in protein ingestion levels, the body, up to a certain point, manages a favorable balance between the anabolic and catabolic phases (3).

Individual proteins are catabolized at different velocities; some have an average life of 10 minutes while others live for days (3). Most organic proteins are subject to these mechanisms and healthy adults maintain a constant body protein because synthesis velocity is sufficient to replace degradation – synthesis and catabolism are equivalent (3).

The undernourished patient displays a lower capacity of specific antibody formation, phagocyte activity reduction, alteration in tissue integrity, reduction or lack of mucous secretion, loss of respiratory tract ciliated epithelium, nutritional oedema, alterations of inflammatory reaction, alterations in intestinal flora, etc. All these proteins, positive and negative, which are synthesized in the liver, are affected in different proportions by the body energy-protein status (12). This probably occurs due to the hepatic capacity of producing them in the presence of a lower amino acid supply.

The impact of undernutrition on the immune system has been demonstrated both clinically and experimentally. Nutrients have a profound effect the production and action of cytokines (12).

The lack of nutrients in severely undernourished patients is known as protein energy malnutrition (PEM). This includes deficiency of iron, zinc, selenium, copper, other minerals, vitamin A, and other lipo and hydrosoluble vitamins (15). These deficiencies may compromise the inflammatory responses exerting a modulatory effect (12,26).

The host defense system suffers a great impact in PEM. Functions depending on cell maturation, such as proliferative response to mitogens, are decreased. Tests of late hypersensitivity in PEM patients show decreased response. Defects in cell immunity in these PEM patients increase susceptibility to intracellular infections such as measles (4,5,16).

Although the B cells and immunoglobulin levels are normal in PEM patients, there is a decrease in the production of certain antibodies. The responses or activation of many antigens depend on the T cells to start the responses in these cells. This interdependence may reflect a problem in the immune system (5).

In PEM patients, the complement system is usually depressed; both the classical and alternative route are compromised. This deficiency in the complement system may predispose the host to Gram-negative infections (11).

There have been several reports in literature about the synergism observed in infectious diseases. Leitch (17) reported the incidence of tuberculosis in Norwegian naval cadets prior to 1925 and when their diet was supplemented with margarine, cod liver oil, wholemeal bread, fruit, vegetables, and milk, there was a rapid decrease in the incidence of this disease. The study between tuberculosis and nutritional state was also performed by Deodato (7), who concluded that TB in itself does not cause alterations in protein and/or iron metabolism and that these changes are primarily due to nutritional deficiency. Other authors have shown that severe diarrhea and acute upper respiratory tract diseases are more frequent and prolonged in undernourished children (20). Pereira et al. (23), studying nutrition and malaria found indices of parasitosis in the most debilitated malaria patients. Measles has been described by several authors as responsible for the high number of deaths, which may be attributed to undernutrition in measles children. Supplementary diet may reduce deaths from measles in younger children and decrease complications (1,12,15). Diets poor in nutrients are known to contribute to a decreased resistance in the host to infections (14). In PEM (kwashiorkor), we can observe absence of fever leukocyte response to infections (1-3).

Synergy between nutrition, infection, and immunity is of utmost importance being responsible for high morbidity and mortality especially in needy and underdeveloped regions (20).

Success in fighting infection largely depends on the speed and efficacy of the host defense system response. Under nutrition causes disorganization in the host defense system being responsible for asymptomatic infections and even severe diseases. Maintenance of the nutritional state is therefore highly important to strengthen the host and supply elements for its defense providing then a better quality of life. In this sense, the patient’s approach must always involve the three areas simultaneously: early nutritional support, specific treatment of infection, and restoration of the immune system (28).

Received May 14, 2003

Accepted May 14, 2003

• 1 BEISEL WR. Nutrition and immune function: overview. J. Nutr., 1996, 126, 2611S-5S.
• 2 BRODSKY IG. Hormone, cytokine, and nutrient interactions. In: SHILS ME., OLSON JA., SHIKE M., ROSS AC. Modern nutrition in healthy and disease. 9ed. Baltimore: Willians & Wilkins, 1999: 699-724.
• 3 CHAMPE PC., HARVEY RA. Metabolismo no jejum, diabetis melito e trauma. In: ________. Bioquímica ilustrada. 2ed. Porto Alegre: Artes Médicas, 1996: 297-308.
• 4 CHANDRA RK. Symposium on nutrition and immunity in serious illness. Proc. Nutr. Soc., 1993, 52, 77-84.
• 5 CHANDRA RK., KUMARI S. Nutrition and immunity: an overview. J. Nutr., 1994, 124, 1433S-5S.
• 6 CUNNINGHAN-RUNDLES S., KIM SH., DNISTRIAN A., NOROSKI L., MENENDEZ-BOTET C., GRASSEY CB., HINDSG., CERVIA JS. Micronutrient and cytokine interaction in congenital pediatric HIV infection. J. Nutr., 1996, 126, 2674S-9S.
• 7 DEODATO F. Interaccion entre estado nutricional e infeccion tuberculosa. (Estudio en adultos atraves de indicadores bioquimicos). Medicina (Buenos Aires), 1980, 40, 15-20.
• 8 DINARELLO CA. Interleukin and interleukin-1 antagonism. Blood, 1991, 77, 1627-52.
• 9 FILTEAU SM., TOMKINS AM. Micronutrients and tropical infectious. Trans. R. Soc. Trop. Med. Hyg., 1994, 88, 1-3826.
• 10 FLECK A. Clinical and nutritional aspects of change in acute-phase proteins during inflammation. Proc. Nutr. Soc., 1989, 48, 347-54.
• 11 FRESNO M., KOPF M., RIVAS L. Cytokines and infectious diseases. Immunol. Today, 1997, 18, 56-8.
• 12 GRIMBLE RF. Malnutrition and the immune response. Trans. R. Soc. Trop. Med. Hyg., 1994, 88, 615-9.
• 13 HEINIRICH PC., CASTEL JV., ANDUS T. Interleukin-6 and the acute-phase response. Biochem. J., 1990, 265, 621-36.
• 14 HERSHKO C. Iron, infection and immune function. Proc. Nutr. Soc., 1993, 52, 165-74.
• 15 KEUSCH GT. Micronutrients and susceptibility to infection. Ann. N. Y. Acad. Sci., 1990, 587, 181-8.
• 16 LANDERS DV. Nutrition and immune function II: maternal factors influencing transmission. J. Nutr., 1996, 126, 2637S-40S.
• 17 LEITCH J. Diet and tuberculosis. Proc. Nutr. Soc., 1945, 3, 156.
• 18 LENNARD TWJ., BROWEL DA. The immunological effects of trauma. Proc. Nutr. Soc., 1993, 52, 85-90.
• 19 MICHIE HR. Metabolism of sepsis and multiple organ failure. World J. Surg., 1996, 20, 460-4.
• 20 PEREIRA PCM. Nutrição e infecção. In: MEIRA DA. Clínica de doenças tropicais e infecciosas. Rio de Janeiro: Interlivros, 1991: 29-32.
• 21 PEREIRA PCM., BURINI PC. Resposta do hospedeiro à infecção. Sistema de defesa e mediadores químicos. Arq. Bras. Med., 1991, 65, 403-10.
• 22 PEREIRA PCM., BURINI RC. Reação metabólica à infecção no hospedeiro. Rev. Hosp. Clin. Fac. Med. São Paulo, 1992, 47, 111-6.
• 23 PEREIRA PCM., MEIRA DA., CURI PR., SOUZA N., BURINI RC. The malarial impact on the nutritional status of Amazonian adult subjects. Rev. Inst. Med. Trop. São Paulo, 1995, 37, 19-24.
• 24 ROUBENOFF R. Inflammatory and hormonal mediators of cachexia. J. Nutr., 1997, 127, 10145-65.
• 25 SMITH MK., LOWRYSF. The hypercatabolic state. In: SHILS ME., OLSON JA., SHIKE M., ROSS AC. Modern nutrition in health and disease. 9ed Baltimore: Willians & Wilkins, 1999: 1555-68.
• 26 SOLIS-PEREYRA B., AATTOURI N., LEMONNIER D. Role of food in the stimulation of cytokine production. Am. J. Clin. Nutr., 1997, 66, 521S5S.
• 27 STARNES JR HF., WARREN RS., JEEVANANDAN M., GABRILOVE JL., LARCHIAN W. Tumor necrosis factor and the acute metabolic response to tissue injury in man. J. Clin. Invest., 1988, 82, 1321-5.
• 28 SOUZA LR., MEIRA DA., MENDES RP., MARCONDES-MACHADO J., PEREIRA PCM. Emprego da glucana como imunoestimulante e da zidovudina (AZT) em doentes com Aids. JBM, 1995, 69, 126-38.
• 29 VAN LEEUWEN MA., VAN RIJSWIJK MH. Acute phase proteins in the monitoring of inflammatory disorders. Baillieres Clin. Reumatol., 1994, 8, 531-52.
• 30 WOLF L., KEUSCH GT. Nutrition and Infection. In: SHILS ME., OLSON JA., SHIKE M., ROSS AC. Modern nutrition in health and disease. 9ed Baltimore: Willians & Wilkins, 1999: 1569-88.

Publication Dates

• Publication in this collection
  09 Dec 2003
• Date of issue
  2003

History

• Accepted
  14 May 2003
• Received
  14 May 2003