Last updated on April 16, 2014 at 17:34 EDT

Interactions Among Infections, Nutrients and Xenobiotics

July 10, 2007

By Ilback, Nils-Gunnar Friman, Goran

During recent years there have been several incidents in which symptoms of disease have been linked to consumption of food contaminated by chemical substances (e.g., 2,3,7,8- tetrachlorodibenzo-p-dioxin, TCDD). Furthermore, outbreaks of infections in food-producing animals have attracted major attention regarding the safety of consumers, e.g., Bovine Spongiform Encephalitis (BSE) and influenza in chicken. As shown for several xenobiotics in an increasing number of experimental studies, even low-dose xenobiotic exposure may impair immune function over time, as well as microorganism virulence, resulting in more severe infectious diseases and associated complications. Moreover, during ongoing infection, xenobiotic uptake and distribution are often changed resulting in increased toxic insult to the host. The interactions among infectious agents, nutrients, and xenobiotics have thus become a developing concern and new avenue of research in food toxicology as well as in food-borne diseases. From a health perspective, in the risk assessment of xenobiotics in our food and environment, synergistic effects among microorganisms, nutrients, and xenobiotics will have to be considered. Otherwise, such effects may gradually change the disease panorama in society. Keywords Infection, nutrients, risk assessment, xenobiotics


Interactions among infectious agents, nutrients, and xenobiotics are a developing concern in both food safety and foodborne diseases in which xenobiotics may affect host resistance and microorganism virulence. These interactions include a delicate balance between the infected host and the microorganism, including their nutritional requirements, as well as competition between nutrients and xenobiotics in both the host and the microorganism (Fig. 1). Consequently, both the course of the dis ease and the toxicity of the xenobiotic could be influenced by how this pattern of interactions is balanced.

Although most infections go undiagnosed and unreported (McDade, 1997), food-borne infections cause millions of illnesses and thousands of deaths every year in the US and Western Europe. Occurrence of disease is a function of several variables, including the virulence of the microorganism, its mode of transmission, and host susceptibility. A theory has been advanced that certain new “emerging” infections may reflect a more contaminated environment and a changed nutritional and immunological status of the population (Gauntt and Tracy, 1995). For instance, an increased incidence of common cold and influenza in Pb-exposed workers (Ewers et al., 1982) and of malaria in Hg-exposed workers (Crompton et al., 2002) has been reported. Respiratory infections were also more frequently found in children after prenatal exposure to PCB (Dallaire et al., 2006) and in humans accidentally exposed to PCB than in non-exposed individuals (Shigematsu et al., 1978), whereas such a difference could not be confirmed in humans exposed to TCDD (Evans et al., 1988). Recently, a higher postnatal PCB exposure among healthy Dutch preschool children was found to be associated with a higher prevalence of recurrent middle ear infections and chicken pox (Weisglas-Kuperus et al., 2004).

Infections are common in our societies and new emerging infections appear at regular intervals worldwide (McDade, 1997). In addition to the number of newly discovered infections, old pathogens with new properties (re-emerging infections) have increased in recent years (Drancourt et al., 1995; Spach et al., 1995). Furthermore, “old” diseases, long thought to be noninfectious, have recently been found to have an infectious aetiology (Blaser, 1990). Because microorganisms adapt to changes in the surroundings more quickly than people (McDade, 1997), it cannot be ruled out that a more contaminated environment may promote the development of pathogens in an unfavorable direction.

Figure 1 Potential interactions among infection, nutrients, and xenobiotics. Interactions include a delicate balance between the infected host and the microorganism, including their nutritional requirements and competition between nutrients and xenobiotics, both in the host and the microorganism.

We are often infected but our host defense, in most instances, protects us from developing any clinical illness. Adults and children in the United States experience from two to six colds per year (Prasad et al., 2000). Although most respiratory infections cause only mild to moderate symptoms in a majority of cases, they sometimes give rise to aggravated disease as well as such complications as pneumonia, myocarditis, pancreatitis, meningoencephalitis, and even atherosclerotic lesions (Ilback et al., 1990; Nystrom-Rosander et al., 2003; Woodruff, 1980).

In developing countries and poor communities micronutrient deficiencies and infectious diseases often co-exist and exhibit complex interactions, many times resulting in severe complications. From epidemiological studies, it is well known that malnourished children develop a greater severity of measles and many other infections (Beisel, 1991 ; Bhaskaram, 2002). It is apparent from a number of clinical studies that suppression of the immune system is characteristically associated with increased susceptibility to different infectious diseases as well as an aggravated clinical course once disease develops. A few experimental studies already during the 1970s-80s showed increased lethality in infected individuals when exposed to immunotoxic chemicals (Friend and Trainer, 1970; Imanishi et al., 1980; Thigpen et al., 1975) or when fed a nutritionally deficient diet (Woodruff, 1970; Woodruff and Kilbourne, 1970).

From the above findings, a hypothesis has developed that an interaction among infections, nutrients, and potentially harmful chemical substances in food and in the environment can result in a changed illness panorama. One example is the supposition that PCB- and TCDD-related substances were the cause of the high death rate that appeared in the early 1990s among morbillivirusinfected seals living in the contaminated waters around Scandinavia (Ross et al., 1996; Van Loveren et al., 2000) and in harbor porpoises from England and Wales (Jepson et al., 1999; Jepson et al., 2005). Other examples are early studies using a lymphocytic choriomeningitis virus in mice, suggesting that cumulative environmental insults from chemicals can potentiate a persistent virus to induce diabetes (Tishon and Oldstone, 1987; Toniolo et al., 1980).

The combined effect of micronutrient deficiencies and exposure to low concentrations of xenobiotics can be assumed to adversely interact in our defense against infections and therefore constitute a potentially increased health risk. These and other data also raise concern that the toxicity of xenobiotics may increase during ongoing infection because of increased uptake and redistribution of previously accumulated xenobiotics from storage tissues to target organs of infection and toxicity.


To attain a satisfactory functioning of the immune defense system a large number of nutrients are required (Beisel, 1998), which is also likely true for active and replicating microorganisms in infected tissues. To meet the needs of the activated immune defense the host metabolic rate starts to increase: the general estimation is that for every centigrade of increase in fever, the metabolic rate increases by about 13% (Beisel, 1998). The number of microorganisms in the infected host can increase from just a few to literally millions during the course of a few days. Thus, the host and the microorganisms’ demands for nutrients run much in parallel.

Despite a dramatically increased need for certain nutrients, the infected individual loses appetite, a condition that most often leads to a decreased intake of food. The body’s own resources must therefore be mobilized, resulting in a changed metabolism of fat, protein, and carbohydrates (Fig. 2). The increased energy needed during infection is initially provided by a decrease in the normal protein synthesis rate and subsequently through a simultaneous increased degradation of somatic tissues, including muscle protein from the heart muscle (Friman et al., 1982; Ilback et al., 1984a; Ilback et al., 1984b) and both red and white skeletal muscle (Friman et al., 1984; Ilback et al., 1983). Wasting of muscle tissue in infection is the result of a complex course of events in which classical hormones act in concert with proinflammatory cytokines, such as interleukins (IL-1, IL-6) and TNF, with the purpose of inhibiting protein synthesis and activating proteolysis in muscle (Fig. 2).

The estimated amount of protein required to produce and maintain an increase in circulating leukocytes and acute phase proteins participating in host defense during major infections in man is 45 g/ day (Grimble, 1996). Rats infected with Streptococcus pneumoniae or Salmonella typhimurium showed a marked increase (up to 5 times) in the uptake of amino acids by the liver, whereas amino acids were lost from muscle tissue (Powanda and Beisel, 2003). Free amino acids released from this degradation of muscle protein can be used in gluconeogenesis for energy production and also be recycled for de novo synthesis of, for example, acute phase proteins, antibodies, and cytokines (Beisel and Wannemacher, 1980). Thus, regardless of the reduced intake of nutrients in infection, acute phase proteins are produced in excess by the liver (Beisel, 1998). Figure 2 Characteristic metabolic responses in a generalised infection involve changes in protein, carbohydrate, lipid and trace element metabolism (Friman and Ilback, 1998).

The increased energy demand in infection is initially covered by carbohydrate fuels. This results in early hyperglycemia and hyperinsulinemia, followed by a progressive decrease of glucose from blood and glycogen in tissue stores (Beisel, 1991). Because stored carbohydrates can only fuel the host for a short period, endocrine responses to infection (insulin, glucagons, growth hormone) activate the liver to use body resources of triglycerides, lactic acid, and gluconeogeneic amino acids for glucose production (Beisel and Wannemacher, 1980). The accelerated use of carbohydrates is important for host defense mechanisms, such as the respiratory burst associated with phagocytic activity of neutrophils and macrophages (Beisel, 1998). If the production of glucose is disturbed, for example, because of a toxic insult of liver cells by xenobiotics, this may have severe consequences on the host defense, associated complications, and survival.

The infection-induced metabolic responses in lipid metabolism are complex and less well-defined than those involving proteins and carbohydrates. TNF stimulates the release of free fatty acids from adipose tissue cells and thereby contributes to the weight loss observed in chronic or repeated infections (Beisel, 1998). However, in most acute infections the increased blood insulin concentration counteracts the release of fatty acids from fat depots, which deprive the liver of substrate for the synthesis of energy-rich ketone bodies. Ketone bodies are an important metabolic fuel for the brain and other tissues during fasting and malnutrition in the absence of infection. In some infections triglycerides increase in blood, probably due to increased liver production in combination with a decrease in peripheral utilization. In such infections fatty acids accumulate in hepatocytes in the form of lipid droplets that eventually may result in fatty metamorphosis or lipid degeneration (Beisel, 1998). A similar lipid accumulation also occurs in inflammatory lesions (Raymond et al., 1985) in target organs of infection, such as in the heart during coxsackievirus (Ilback et al., 1990) and Salmonella typhimurium infections (Ilback et al., 1983).

An infectious disease, as well as inflammation, is often accompanied by changes in several trace elements (Beisel, 1998; Chaturvedi et al., 2004; Shankar and Prasad, 1998; Shenkin, 1995). However, the pattern of trace element changes is not the same in different infections. For example, clinical studies in patients with brucellosis show changes in Cu and Zn (Cesur et al., 2005c), whereas hepatitis B (Cesur et al., 2005a) and C (Cesur et al., 2005b) infections does not affect these elements. The most consistent responses include a decrease in plasma levels of Fe and Zn and an increase in Cu (Beisel, 1998; Ilback et al., 2003b; Ilback et al., 2004; Pekarek and Engelhardt, 1981). However, plasma changes in Mn, Mg, Co, Cr, I, and Gl have been described (Fisk et al., 2007; Funseth et al., 2000a; Pekarek and Engelhardt, 1981).


The objectives of the acute phase responses are to disadvantage and destroy the invading microorganisms, repair damaged tissue, and restore tissue function to allow a return to the normal condition. The course of a generalized infection can be divided into three phases: the incubation period, the acute dis ease phase, and the recovery period (Fig. 3). Host responses are similar in mammals and man in a majority of acute infections (Beisel, 1998) and includes an array of responses, including fever, hormonal changes, immune cell activation, increased synthesis and release of cytokines, antibodies, complement and acute phase proteins, and a simultaneous flow of trace elements between blood and tissues, as well as extensive changes in various metabolic pathways (Beisel, 1998; Friman and Ilback, 1998; Friman et al., 1982; Grimble, 1996; Ilback et al., 1984a).

Figure 3 The acute phase reaction modified from Beisel (Beisel, 1998). A generalised infectious disease can be divided into three parts: the incubation period, the acute illness and the convalescent period.

The acute phase reaction of the host is mediated by cytokines (e.g., IL-I, IL-6, TNFalpha), which, during infection, are secreted by activated immune cells, including macrophages (Beisel, 1998; Powanda and Beisel, 2003). The T-helper 1 (Th1) cytokines, represented by IFNgamma and IL-2, favor cytotoxic T-cell responses, whereas the T-helper 2 (Th2) cytokines IL-4, IL-5 and IL-10 are thought to dampen cellular immunity and favor antibody responses (Naniche and Oldstone, 2000). IL-I stimulates the secretion of IL-6 and glucocorticoides, both activating hepatic synthesis of metallothionein and acute phase proteins (Brown, 1998; Coyle et al., 2002; Grimble, 1996; Liuzzi et al., 2005). A five-fold increase in plasma proteins, consistent with the increase in acute phase proteins, has been detected in the early phase of lethal Streptococcus pneumoniae and Salmonella typhimurium infections in the rat (Powanda and Beisel, 2003). Macrophages/monocytes and lymphocytes are able to bind, catabolize and even synthesize a variety of acute phase proteins which appear to occur in proportion to the infectious dose and to the likelihood of death (Powanda and Beisel, 2003).

Acute phase proteins are metal-binding proteins and include Fe- binding ferritin (Beisel, 1998), Cu-binding ceruloplasmin (Friman et al., 1982; Ilback et al., 1983),andCd-andZn-binding metallothioneins (Funseth et al., 2002a; Ilback et al., 2004). Metallothioneins are regulated by cytokines (Borghesi et al., 1996; Palmiter, 1998), expressed to a certain extent in almost all mammalian tissues (Nordberg and Nordberg, 2000) and directly involved in Cd detoxification, Zn homeostasis, and protection of the cell from oxidative stress (Sous et al., 2002). In addition to Cd and Zn, metallothioneins have the capacity of binding Cu, Hg, and As (Lu et al., 2001; Nordberg and Nordberg, 2000; Toyama et al., 2002).

Already in the 1970s it was shown that volunteers exposed to live attenuated Venezuelan equine encephalitis virus vaccine and monkeys infected with Salmonella typhimurium responded with an early fall in serum Fe and Zn concomitant with a rise in Cu (Pekarek et al., 1970; Pekarek et al., 1975). An increased Cu/Zn quotient in blood has been used to indicate infection already before the development of clinical illness (Ilback et al., 1983) and in vitro results of Salmonella enteritidis infected enterocytes indicate that infection decreases the gastrointestinal absorption of Fe (Foster et al., 2001). Thus, during infection, there is a flux in the body of both essential and non-essential trace elements between blood and tissues.


Almost all nutrients in the diet have been claimed to be crucial for an “optimal” immune response, but both deficiency and excessive amounts of nutrients can adversely influence host resistance to a variety of pathogens (Chaturvedi et al., 2004; Field et al., 2002). The feeding of poor-quality silage seems to predispose farm animals to listeriosis (Roberts and Wiedmann, 2003). Malnourished coxsackievirus-infected mice showed increased virus persistence in target organs of infection and increased mortality, but this decrease in host resistance was completely reversed after change to a normal diet (Woodruff, 1970; Woodruff and Kilbourne, 1970). In line with this observation influenza vaccinated subjects consuming an experimental nutritional formula containing antioxidants, Zn, Se, oligosaccharides, and triglycerides experienced enhanced immune function and fewer days of symptoms of upper respiratory tract infection (Langkamp-Henken et al., 2004).

It is not surprising that proteins are regarded as the most important nutrients. Amino acids are used by immune cells for cell proliferation, and antibody and cytokine production (Beisel, 1998; Field et al., 2002), for the synthesis of acute phase proteins (Beisel, 1998; Grimble, 1996), as well as for energy production by gluconeogenesis (Beisel, 1998; Beisel and Wannemacher, 1980).

Although protein-energy malnutrition is cited as the major global cause of immunodeficiency, vitamins, fatty acids, and essential trace elements (Fe, Zn, Cu, Se) are also important for immune function and host defense (Beisel, 1998; Field et al., 2002; Grimble, 1996). Fatty acids serve as precursors for eicosanoids (prostaglandins, prostacyclines, thromboxanes, lipoxines) that trigger many immune cell responses during infection and inflammation (Beisel, 1998) while hypercholesterolemia seems to decrease host resistance against coxsackievirus infection in the mouse, but not based on increased replication of viruses (Loria et al., 1976).

The normal balance of essential trace elements (e.g., Cu, Fe, Zn) is changed in target organs of infections and other inflammatory processes (Funseth et al., 2000b; Ilback et al., 2003b; 2007). Trace elements are important for the activity of certain enzymes involved in free radical scavenging, including Superoxide dismutase (Cu, Zn) and glutathione peroxidase (Se) (Shenkin, 1995). In addition, Zn plays a central role in enzymecatalyzed reactions of protein synthesis and both Cu and Fe are part of the cytochrome system.

Fe is an essential nutrient for many pathogens and the ability of the host to sequester Fe is a primary defense mechanism against several bacterial infections (McDermid and Prentice, 2006). In several intracellular infections (parasitic, bacterial, viral) the disease-aggravating potential of Fe seems to be related to loss of the macrophages’ ability to kill the pathogen by cytokine-dependent (mainly IFNgamma) effector pathways (Serafin-Lopez et al., 2004; Weinberg, 1999). This contrasts to the finding that Fe loading of macrophages in vitro results in enhanced capacity to kill or to prevent replication of the intracellular microorganisms Listeria monocytogenes and Brucella abortus (Bisti et al., 2000). Thus, Fe seems to be a double-edged sword in infection and host resistance. Trace elements are known to affect cell death in normal cells (Shen et al., 2001). Furthermore, a lack of Zn caused by chelation can trigger cell death in virus-transformed cells (Fernandez-Pol et al., 2001). However, data have been published showing that dengue virus type 2-induced cell death increases at high extra cellular Zn concentrations (Shafee and AbuBakar, 2002). Zinc is important in the functioning of the immune cells (Driessen et al., 1995) and Zn- deficient persons experience an increased susceptibility to a variety of pathogens (Shankar and Prasad, 1998). The macrophage, a pivotal cell in many immunologie functions, is known to be adversely affected by Zn deficiency, which can dysregulate intracellular killing, cytokine production, and phagocytosis (Shankar and Prasad, 1998). Zn supplementation has been found to reduce the disease burden of pneumonia and other respiratory infections in children (Bhandari et al., 2002; Bhaskaram, 2002) and to beneficially affect the course of the common cold (Prasad et al., 2000).

Most humans suffering from Chagas’ disease (Trypanosoma cruzi) have lower than normal levels of Se in the heart where the parasite is harbored (de Souza et al., 2003; Rivera et al., 2002). Accordingly, in experimental Trypanosoma cruzi infection Se deficiency increases parasitemia and the severity of inflammation (Gomez et al., 2002), whereas supplementation limits the replication of parasites (Davis et al., 1998) and protects the heart from inflammatory lesions that are caused by the parasite (de Souza et al., 2003). There is also a strong link between Se deficiency and viral infection as causative in the cardiomyopathy of Keshan disease (Beck and Levander, 2000). The oxidative stress of the host can have a profound influence on a viral pathogen (Beck and Levander, 2000) and the antioxidant properties of Se are important when macrophages and neutrophils release increased quantities of Superoxides and hydrogen peroxides during digestion of invading microorganisms (Davis et al., 1998). Mice deficient in Se or vitamin E, a nutritional antioxidant like Se, are more susceptible to the development of virus-induced inflammatory lesions in both influenza (Beck et al., 2001) and coxsackievirus infection (Beck et al., 1994). In experimental Candida albicans infection neutrophils in Se deficient cattle were less able to kill the fungi than were neutrophils from cattle with normal Se levels (Boyne and Arthur, 1979); analogous results were found for Staphylococcus aureus infected cows (Gyang et al., 1984). Further, Se-deficient rodents showed impaired ability of neutrophils to kill Candida albicans and Staphylococcus aureus (Boyne and Arthur, 1986; Boyne et al., 1986), a condition resulting in more microorganisms in target organs of infection.


Important adverse effects of potentially harmful xenobiotics present in the environment and in food have been shown to be directed against our immune system, which, in the long term, could affect our susceptibility to infections and autoimmune diseases (Burchiel, 1999; Lawrence, 1981; Thomas and Hinsdill, 1978; Van Loveren et al., 1998; Zelikoff et al., 1994).

Numerous studies using Ni, Hg, Pb, and Cd, as well as organohalogen compounds (e.g., PCB, TCDD) have shown that xenobiotics can adversely affect the host defense to a variety of microorganisms such as influenza virus, coxsackievirus, and herpes simplex virus (Clark et al., 1983; Ellermann-Eriksen et al., 1994; Funseth and Ilback, 1992; Gomez et al., 2002; Ilback, 1991; Ilback et al., 1994a; Ilback et al., 1994b; Ilback et al., 1996; Imanishi et al., 1980; Lee et al., 2002; Seth et al., 2003). However, it is important to distinguish between small and biologically unimportant changes in immune parameters presumed to be without health consequences and those changes that may jeopardize our host defense. In many studies an alteration in certain immune functions has been observed in the absence of a demonstrable change in host resistance (Kimber and Dearman, 2002).

A complex and finely tuned relationship appears to exist between the immune system and the neuroendocrine system, and some environmental pollutants (e.g., Cd, Pb, PCB, DDT) seem to act as both neurotoxicants and immunotoxicants (Friedman and Lawrence, 2002; Kaiser, 2000; Safe, 2003). Moreover, parasitic (Moniliformis moniliformis) infection and Cd exposure affect stress hormone (cortisol) levels in an additive manner (Klar and Sures, 2004). Estrogens are not only essential for reproduction but are also immunomodulating agents affecting host resistance and elimination of microorganisms (Kittas and Henry, 1980; Luster et al., 1984; Pung et al., 1984). Macrophages have even been reported to have classical cystosolic oestrogen receptors (Ma et al., 2003). Thus, at immune activation following infection oestrogen-weakening effects on immune function may likely add to the toxic effects of xenobiotics.

Diethylstilbestrol, a typical oestrogen-like chemical, has in mice been shown to induce immune suppression and reduce elimination of bacteria (Listeria monocytogenes) (Pung et al., 1984) and parasites (Trichinella spiralis) (Luebke et al., 1994), possibly because of reduced mobilization of phagocytizing macrophages (Pung et al., 1984). Similarly, in mice the endocrine disrupter bisphenol A reduced the elimination of Escherichia coli (Sugita-Konishi et al., 2003b). A reduced bacterial clearance of Staphylococcus aureus has been noted in both blood and spleen in As- and Pb-exposed rat (Bishayi and Sengupta, 2003). This reduction was associated with a reduced chemotactic migration of macrophages. The immune responses to any pathogen require a tightly controlled balance between the mechanisms bringing about the pathogen elimination and the mechanisms governing the repair of damaged tissue. Whereas controlled inflammation is beneficial, aberrant function of immune cells induced by xenobiotics may disturb this balance and result in enhanced tissue damage.


From cell culture studies, microorganisms are known to be highly sensitive to the environment they grow in. Metal ions are important components in several gene regulatory proteins, including virus proteins (Fernandez-Pol et al., 2001), and seem to play a pivotal role in the replication of rhino-, polio-, and influenza-viruses (Krenn et al., 2005). Essential viral and cellular Cu- and Zn- containing metal proteins are being studied intensively as central factors in the control and prevention of virus infection (Fernandez- Pol et al., 2001). From present data, however, it is often extremely difficult to evaluate whether an increased number of microorganisms are due to an immunotoxic effect or to an actual effect on the specific microorganism.

The Cu-containing ceruloplasmin is an important acute-phase reactant in generalized infections (Beisel, 1998). Moreover, the Cu level in plasma is known to increase in infections that are caused by various microorganisms (Beisel, 1998; Friman et al., 1982; Ilback et al., 2003b). Higher levels of blood Cu are correlated to the viral load in patients with chronic hepatitis C (Ko et al., 2005). However, Cu is inhibitory to the survival of Escherichia coli and several other microorganisms (Wilks et al., 2005) and the number of Trypanosoma lewisi parasites in blood was twice as high in Cu- deficient rats (Ongele et al., 2002). One study has even implicated a role of Cu in the pathogenesis of neuronal injury in Alzheimer’s disease and the prion-induced encephalopathies (Waggoner et al., 1999).

It is known that most microorganisms require Zn for basic cellular processes (Shankar and Prasad, 1998) and that chelation of Zn can reduce the growth of Candida albicans (Sohnle et al., 2001). Inhibition of DNA replication in Salmonella enteritidis after nitrogen oxide exposure is accompanied by Zn mobilization, implying that DNA-binding Zn metalloproteins are critical targets of antimicrobial activity (Schapiro et al., 2003). Zn influences gene expression in cytomegalovirus (Takekoshi et al., 1993) and replication of respiratory syncytical virus (Suara and Crowe, 2004). Moreover, electron microscopy studies on herpes simplex virus have demonstrated massive deposition of Zn onto virions, which interfered with glycoprotein-mediated fusion of the virus (Suara and Crowe, 2004). The lack of Zn, however, has been shown to increase the risk of Streptococcus pneumoniae infection to take a serious course (Strand et al., 2001) and to cause a four-fold increase of Trypanosoma musculi parasites in the blood in experimental infection (Ongele et al., 2002).

Many pathogens (fungi, protozoa, bacteria) must acquire Fe from their host to survive and increase in number (Weinberg, 1999; Weiss, 2002). Somewhat unexpectedly, the susceptibility to parasite infection with Leishmania major can be suppressed with Fe supplementation (Bisti et al., 2000). However, several experimental and epidemiological studies show that excess of Fe can worsen the outcome of infectious diseases (e.g., human listeriosis) (Roberts and Wiedmann, 2003), tuberculosis, HIV, and hepatitis C (Lounis et al., 2001; Weiss, 2002). Moreover, in human hepatitis C virus infection Fe accumulation in the liver is associated with both an impaired response to IFNa therapy and with faster progression of the disease (Weiss, 2002). Mycobacterium avis (Boelaert et al., 1996), Chlamydia pneumoniae (Al-Younes et al., 2001 ; Freidank et al., 2001), Staphylococcus aureus (Skaar et al., 2004), and Candida albicans (Knight et al., 2005) are dependent on Fe for their growth. Furthermore, a greater availability of Fe has been shown to increase the virulence of Salmonella enteritidis bacteria (Foster et al., 2001) and stimulate the growth of Mycobacterium tuberculosis (SerafinLopez et al., 2004). Elevated enterocyte Fe status in Salmonella enteritis infected Caco-2 cells seems to increase the susceptibility to infection and the mucosal inflammatory response (Foster et al., 2001). The amount of Fe in sclerotic cardiac valves in patients with Chlamydia pneumoniae in their valves shows a clear association with the degree of calcified, damaged tissue (Nystrom- Rosander et al., 2003).

Non-essential trace elements can also affect growth and virulence of microorganisms. Helicobacter pylori has welldeveloped metal ion homeostatic systems but these fail to regulate the level of Co within the bacteria, allowing toxic levels to be reached (Bruggraber et al., 2004). Pb exposure increases virus multiplication and disease development in mice infected with semliki forest virus (Gupta et al., 2002). In encephalomyocarditis virus infection Hg (Koller, 1975) and Co (Gainer, 1972) increased the mortality. In addition, in Coexposed mice the amount of virus and the concentration of Co in the spleen and heart increased. Although Cd disturbs the host’s defense system against intracellular Listeria monocytogenes (Thomas et al., 1985), encephalomyocarditis virus (Exon et al., 1979), cytomegalovirus (Daniels et al., 1987) and influenza virus (Chaumard et al., 1991; Thomas et al., 1985), organism titers do not seem to be influenced. However, Cd appears to dose-dependently increase the susceptibility to herpes simplex virus (Thomas et al., 1985) and to cause an earlier virus attack and more extensive pathological changes in the brain in encephalomyocarditis, semliki forest, and Venezuelan equine encephalitis virus infections (Seth et al., 2003). Higher levels of Trypanosoma lewisi parasites in blood and prolonged disease have been reported in rats exposed to Cd, Pb, and Hg (Hogan and Lee, 1988).

Arsenic has been shown to increase mortality in pseudorabies, encephalomyocarditis virus, and St. Louis encephalitis virus infection in mice (Gainer and Pry, 1972). It enhances HIV infectivity (Turelli et al., 2001), stimulates transcription, and accelerates the kinetics of spreading of HIV infection within the T helper cell pool and the number of T cells containing provirus (Berthoux et al., 2003). In vitro data suggest that As also enhances the pathogenicity of enteroviruses (Pass et al., 1979), but in coxsackievirus infection in mice As is decreased in the target organs of active viral replication (Benyamin et al., 2006). Accordingly, As has been shown to increase the stability of the replication protein compartments that need to be disrupted for successful replication and production of progeny herpes simplex virus (Burkham et al., 2001) and to be a potent inhibitor of hepatitis C virus replication, possibly by interfering with cellular factors necessary for replication (Hwang et al., 2004).

Certain trace elements possess antioxidant functions that can possibly alter the genomes of microorganisms, particularly of viruses (Bhaskaram, 2002). Ca increases infectivity of rotaviruses, which is not due to changed surface properties in host cells but rather to conformation changes of the virus particles (Pando et al., 2002). Se deficiency in mice produces genetic changes in replicating influenza virus and more serious lung injuries (Beck et al., 2001; Nelson et al., 2001). Concerning coxsackievirus, a lack of Se can result in increased virulence (Beck et al., 1994), whereas supplementation mitigates infection (Ilback et al., 1998; Ilback et al., 1989). Mn can change the virulence of retroviruses, including HIV (Vartanian et al., 1999) and genes inserted into the human cytomegalovirus genome can be expressed by such metals as Zn (Takekoshi et al., 1993). Cd has even been shown to reactivate herpes simplex virus in latent-infected mice (Fawl et al., 1996).

The mortality of ducks (Friend and Trainer, 1970) and mice (Imanishi et al., 1980) that were infected with the herpes simplex virus was increased after PCB exposure. Even with no signs of PCB intoxication, PCB-exposed mice challenged with Salmonella typhimurium showed higher mortality and increased numbers of viable organisms in the spleen, liver, and blood (Thomas and Hinsdill, 1978). Moreover, more larvae from parasites (Trichinella spiralis) in the small intestine have been shown to be released and recovered in muscle of TCDD exposed mice (Luebke et al., 1994). Because of the more complex genomic structure of parasites than of viruses, it seems unlikely that a specific genetic mutation is responsible for the increased parasite growth and virulence after TCDD exposure (Rivera et al., 2003).


Intestinal homeostasis relies on the equilibrium between absorption (nutrients, ions), secretion (ions, cytokines, IgA), and barrier capacity (to pathogens and chemical substances) of the digestive epithelium. The absorption of individual amino acids from the intestine may be depressed and delayed or increased depending on the infection studied (Beisel, 1998). Food components (such as lipids) in the gastrointestinal tract can markedly alter the bioavailability of chemical substances and possibly increase the absorption of lipid soluble xenobiotics (Ilback et al., 2004). For example, preclinical studies in human volunteers have shown that the bioavailability of the antipicornaviral drug PIeconaril is markedly enhanced together with food, with roughly a seven-fold difference in bioavailability between fed and fasting states (Abdel-Rahman and Kearns, 1998).

Enterocytes are able to synthesize and secrete a variety of immunomodulatory molecules (cytokines, chemokines, growth factors) (Foster et al., 2001). Convincing data exist indicating that proinflammatory cytokines (IFNgamma, IL-4, IL-10) can act synergistically to reduce colonie epithelial cell barrier function (Walsh et al., 2000). Host dependent zonulin secretion, a modulator of small intestinal tight junctions, caused an impairment of the barrier function after exposure of rabbit jejunum to Salmonella typhimurium and Escherichia coli (El Asmar et al., 2002). Vibrio cholerae toxin and other bacterial toxins increased the permeability of the small intestinal mucosa by affecting the structure of the intercellular tight junctions (Fasano et al., 1991). Zn seems to protect the intestinal lining from bacteria residing in the gut by inhibiting the adhesion and internalization of bacteria and consolidating tight junction permeability and modulating cytokine gene expression (Roselli et al., 2003).

This contrasts to the finding that parasites, even when administered parenterally, decrease the absorption of Cu from the gastrointestinal tract (Adogwa et al., 2005). Moreover, an early fall in plasma Fe occurs in many infections (Beisel, 1998). This may be explained by a decreased intestinal absorption of Fe in combination with an increased uptake by the liver. Accordingly, clinical studies in patients carrying Helicobacter pylori evidenced impaired Fe absorption (Ciacci et al., 2004). Notwithstanding, in gastrointestinal infection, including Salmonella enteritis infection, enterocytes accumulate Fe necessary for bacterial growth (Foster et al., 2001).

Coxsackievirus infection induces an increased and dosedependent uptake of Cd from the gastrointestinal tract (Fig. 4) (Glynn et al., 1998). Cd competes with Zn (Goyer, 1997) and Zn supplementation seems to reduce gastrointestinal absorption and accumulation of Cd, whereas Zn deficiency intensifies Cd accumulation and toxicity (Brzoska and Moniuszko-Jakoniuk, 2001). An increased exposure of Hg and Ni during coxsackievirus infection in mice increases tissue accumulation of these metals (Ilback et al., 1992a; Ilback et al., 1996). Supplementation of the diet with Se results in increased gastrointestinal uptake and improved Se status (Ilback et al., 1998), as well as reduced uptake of Hg (Glynn et al., 1993). Hg administered in food changes the trace element balance in the infected and inflamed heart, indicating changed gastrointestinal uptake during infection (Ilback et al., 2000). Consistent with these observations is the finding that harbor porpoises dying of infectious diseases that are caused by parasitic, bacterial, fungal, or viral pathogens had increased contents of Zn, Hg, and Se (Bennett et al., 2001). The porpoises also showed an increase in the Hg/Se molar ratio in the liver indicating a disturbed absorption and trace element balance. In addition, elevated hepatic concentrations of Cd have been found in sea otters that died from infections diseases (Kurunthachalam et al., 2006).

Figure 4 Dose-dependent Cd accumulation in selected organs in control and coxsackievirus-infected mice 24 hours after a single oral Cd dose (Glynn et al., 1998).


In several infections the accumulation of fat occurs in infected tissues, often accompanied by tissue necrosis: when arteries are the targets of the microorganisms, arteriosclerotic changes may ensue (Ilback et al., 1984e; Ilback et al., 1990; Nystrom-Rosander et al., 2003). Inflammatory fluid seems to accelerate the uptake of lipoproteins in resident macrophages (Raymond et al., 1985) and the increased uptake of lipids in the heart in coxsackievirus myocarditis is histologically localized to “macrophage dense” areas (Ilback et al., 1990). This infection is associated with a concomitant accumulation of the lipid soluble TCDD in the thymus, spleen, pancreas, brain, and liver (Funseth and Ilback, 1994). However, this organ distribution pattern of TCDD contrasts with the distribution of another lipid soluble compound, i.e. PBDE, which, in coxsackievirus infection, mainly accumulates in the liver but not in the pancreas, thymus, spleen, or brain (Darnerud et al., 2005). As a response to coxsackievirus infection in normally fed mice the normal balance of both essential and non-essential trace elements is changed in target organs of the infection (Funseth et al., 2000b; Ilback et al., 2003b). For example, Cu and Cd accumulate in the liver and kidneys to various extents (Ilback et al., 2004); Ca, Zn, Se, and Cu accumulate in the heart (Funseth et al., 2000b; Ilback et al., 2003b); and Ca, Cu, V, and Mg accumulate in the pancreas (Ilback et al., 2003a). In the brain there is a concomitant accumulation of Se and Hg (Ilback et al., 2005), as well as an increased content of Cu (Ilback et al., 2006). An increased Fe accumulation is known to occur in the liver in human hepatitis C viras infection (Weiss, 2002); in the brain of HIV-infected humans (Boelaert et al., 1996); in the brain of scrapie-infected mice (Kim et al., 2000); and in human sclerotic cardiac valves that harbor Chlamydia pneumoniae (Nystrom-Rosander et al., 2003).

During coxsackievirus infection, potentially toxic chemical substances to which the individual is being exposed will be distributed quantitatively differently in the body as compared with the distribution in a healthy individual (Figs. 5 and 6). For instance, Ni is accumulated in the pancreas and heart (Ilback et al., 1992a), Cd in the spleen and kidneys (Ilback et al., 1992b), TCDD in the brain and thymus (Funseth and Ilback, 1994), acrylamide in the blood and thymus (Abramsson-Zetterberg et al., 2005), and PBDE in the liver (Darnerud et al., 2005). When Hg or Ni (Ilback et al., 1994a; Ilback et al., 1996), but not Cd (Ilback et al., 1994b), is administered in food during coxsackievirus infection, inflammatory lesions and damage to the heart are increased. Moreover, viruses of Hg-exposed mice are more persistent than viruses of non-exposed mice (Ilback et al., 1996), and a changed balance of Zn and Ca in the inflammatory lesions in the heart exists only in Hg-exposed mice (Ilback et al., 2000). Cd exposure during ongoing infection affects the normal trace element homeostasis, resulting in increased Cu and Fe concentrations in the brain, with Fe accumulating in focal deposits (Ilback et al., 2006).


During early coxsackievirus infection the amount of metallothionein increases about five-fold in the liver and kidneys (Funseth et al., 2002a; Ilback et al., 2004). This induction of metallothionein, even at normal physiological levels of trace elements, results in redistribution of Cd and Cu from the liver to the kidneys (Ilback et al., 2004). Influenza infection has also been shown to induce gene expression of metallothionein in both the liver and the lungs (Ghoshal et al., 2001). Ni seems to remain for long periods in infected-inflamed tissues (e.g., pancreas and heart, Fig. 6), which is probably due to an accumulation in macrophages that are mobilized to the injured area to participate in the healing process (Ilback et al., 1994a; Ilback et al., 1990).

Figure 5 Whole-body autoradiogram of Cd distribution in a non- infected mouse (A) and a coxsackievirus-infected mouse (B) (Ilback et al., 1992b).

A negative consequence of the acute phase reaction, seen from a toxicological perspective, is that the synthesis of proteins involved in less acute life important functions, including enzymes in our detoxifying P450 system, has low priority and is down- regulated in virus (Darnerud et al., 2005; Funseth et al., 2002a; Selgrade et al., 1984), bacterial (Morgan, 1997), and parasitic infections (Luebke et al., 1994). However, the cytokine pattern varies in different infections: for example, T. spiralis stimulate the production of IL-1, IL-2, IL-5, and IFNgamma (Luebke et al., 1994); L. monocytogenes stimulate IL-1 andIL-6(Dyatlov and Lawrence, 2002); influenza simulate IL-2 and IFNgamma (Warren et al., 2000); and coxsackievirus stimulate TNF and IFNy (Ilback et al., 1993). Since cytokines modulate specific P450 enzymes differently and selectively (Morgan, 1997; Singh and Renton, 1981), this may result in different and infection-specific effects on the P450 system.

Besides degradation of proteins (Friman et al., 1984), there is also degradation of stored body fat, especially in more longlasting infections (Beisel, 1998), which may result in release of previously accumulated xenobiotics (e.g., TCDD) from fat tissue into the blood (Fig. 7) (Funseth et al., 200[degrees]c). An infectioninduced decrease in the detoxification capacity of xenobiotics may further increase a changed body burden in infected individuals (Funseth et al., 2002a) and explain earlier findings of a decreased elimination of TCDD in mice infected with the parasite T. spiralis (Luebke et al., 1994), as well as increased tissue contents of PCB and HCB in P. berghei-infected mice (Loose et al., 1978).


Several experimental studies with coxsackievirus infection have demonstrated that chemical substances (Cd, Ni, Hg, TCDD), even when occurring in small amounts as in food, can produce an aggravated disease, including complications (Funsethetal.,2002b;Ilbacketal., 1994a;Ilbacketal., 1994b;Ilback et al., 1996). In an early paper by Selye et al (Selye et al., 1966) it was shown that a normally well- tolerated dose of Pb increases the sensitivity to endotoxins of various gram-negative bacteria and that the adverse effect is greatest when the two compounds are given simultaneously. Moreover, infection-induced mortality resulting from western encephalitis virus was reduced when As was administered before virus inoculation, but when administered during ongoing infection As increased mortality (Gainer and Pry, 1972).

Earlier and higher levels of parasitemia in Trypanosoma lewisi infection have been detected in animals exposed to Cd, Pb, and Hg (Hogan and Lee, 1988). Similarly, aggravated disease has been reported with these metals in influenza, semliki forest, Venezuelan equine encephalitis, encephalomyocarditis, and herpes simplex virus infections (Burleson et al., 1996; EllermannEriksen et al., 1994; Gainer, 1972; Gupta et al., 2002; Seth et al., 2003). Moreover, mice exposed to subclinical doses of PCB (i.e. doses insufficient to produce overt clinical signs of intoxication) showed impaired ability to withstand challenge with Salmonella typhimurium and increased sensitivity to endotoxin (Thomas and Hinsdill, 1978). Similarly, in ducks challenged with duck hepatitis virus doses of PCB, dieldrin and DDT produced higher mortalities despite no apparent clinical intoxication (Friend and Trainer, 1970). Resistance to the parasite Trichinella spiralis has been shown to be decreased after exposure to benzo-a-pyrene (Dean et al., 1982). Prolonged low-dose exposure to bis (tri-nbutylin) oxide (TBTO), a biocide compound, caused no effects on general toxicologie or basal immunotoxicologic parameters, but decreased resistance to Trichinella spiralis as evidenced by increased numbers of muscle larvae and decreased IgE titers (Vos et al., 1984). Moreover, TBTO reduced the clearance of Listeria monocytogenes (Vos et al., 1990). In addition, PCB and HCB exposure not only increased the severity of malaria in mice but also the tissue deposits of the xenobiotics (Loose et al., 1978). Thus, even low-dose exposure to xenobiotics without any clinical signs of toxicity or significant immune effects when tested in vitro seems to have the capability to jeopardize the host defense in vivo to a variety of microorganisms. However, an aggravated disease may also indicate an increased toxicity of xenobiotics when exposure occurs during ongoing disease.

Figure 6 Whole-body autoradiogram of Ni distribution 10 min after administration in a non-infected mouse (A), at 10 min after administration in a coxsackievirusinfected mouse (B), and at 4 hours after administration in a coxsackievirus-infected mouse (C) (Ilback et al., 1992a).

Figure 7 Redistribution of TCDD over time in non-infected control mice (o) and coxsackievirus-infected mice (- ) in blood, brain and thymus at days O, 4, and 7 after inoculation of virus (Funseth et al., 2000e).

Trace elements are crucial for the host defense, resulting in redistribution of elements between body compartments involved by the infection (Beisel, 1998; Milanino et al., 1993; Pekarek and Engelhardt, 1981). However, all changes in trace elements may not be favorable to the host (Weiss, 2002). Two examples are the progressive increase of Fe in the brain during scrapie infection in mice (Kim et al., 2000) and in HIV infection in man (Boelaert et al., 1996). Furthermore, many bacteria need Fe for their growth and multiplication and excessive Fe in specific tissues has been shown to promote bacterial infection in those tissues (Al-Younes et al., 2001; Foster et al., 2001; Lounis et al., 2001; Weiss, 2002). Even some neoplasias, cardiomyopathies, and neurodegenerative disorders have been associated with increased levels of Fe (Ke and Qian, 2003; Nystrom-Rosander et al., 2003; Sullivan and Weinberg, 1999; Weinberg, 1999).

Figure 8 Hepatic CYP1A1 and CYP1A2 activities in control mice and in mice at 3 days after inoculation with coxsackievirus (Darnerud et al., 2005).

Cultured macrophages are prone to accumulate Hg, an event resulting in impaired migration, phagocytosis, and antiviral function (Christensen et al., 1996). Hg has also been shown to impair cytokine production and the respiratory burst of herpes simplex virus activated macrophages (Ellermann-Eriksen et al., 1994). In target organs of coxsackievirus infection and inflammation Hg exposure is associated with disturbed Zn balance (Ilback et al., 2000), as well as more persistent virus, increased inflammation, and increased cytokine levels (Ilback et al., 1996). Se can modify the gastrointestinal uptake and tissue distribution of Hg (Glynn et al., 1993) and potentially limit Hg-induced toxicity (Bennett et al., 2001 ; Lindh et al., 1996). The organohalogen compound TCDD is also known to change the trace element balance in infection (Funseth et al., 2002b). A diminished resistance to encephalomyocarditis virus (Gainer, 1977) and an increased amount of herpes simplex virus in the liver (Christensen et al., 1996) have been reported in Cd- exposed mice. Moreover, Cd apparently induces a dose-related increase in the susceptibility to herpes simplex virus (Thomas et al., 1985) and to accumulate dose-dependency in target organs of coxsackievirus infection and toxicity (Glynn et al., 1998). However, in cytomegalovirus infection there was no effect of Cd on mortality (Daniels et al., 1987), whereas Cd inhalation seems to decrease mortality in influenza-infected mice (Chaumard et al., 1991). This enhanced resistance to influenza infection in Cd-exposed mice was due to an enhanced mobilization of neutrophils and macrophages to the lungs (Chaumard et al., 1991).

In encephalomyocarditis, semliki forest, and Venezuelan equine encephalitis virus infections Cd causes an earlier virus attack and more extensive pathological changes in the brain (Seth et al., 2003). The brain is known to be occasionally a target organ in coxsackievirus-infection as well, resulting in meningoencephalitis (Gear, 1984; Ilback et al., 2007). Furthermore, Cd exposure results in increased Cu and Fe concentrations in the brain, where Fe was accumulated in focal deposits (Fig. 9) (Ilback et al., 2004). Fe accumulation in the brain is also known to occur in HIV patients (Boelaert et al., 1996) and in scrapieinfected animals (Kirn et al., 2000).

Figure 9 Iron distribution in the brain of a cadmium-exposed and coxsackievirus-infected mouse (Ilback et al” 2006).

Even sub-clinical doses of Pb may increase the mortality in Salmonella typhimurium-infected mice (Hemphill et al., 1971). Recently Pb exposure in semliki forest virus-infected mice was found to cause a dose-dependent increase in tissue lesions (Gupta et al., 2002). A striking difference, however, has been noted between Cd and Ni in their effects on host resistance to both cytomegalovirus and coxsackievirus infection. More specifically, Ni increased mortality but Cd did not (Ilback et al., 1994a; Ilback et al., 1994b; Seigrade et al., 1992). Moreover, in coxsackievirus infection the target organs of toxicity are not the same, i.e. Ni accumulates in the heart, pancreas, and lungs (Ilback et al., 1992a), whereas Cd dose- dependently accumulates in the liver and kidneys (Glynn et al., 1998), where it may cause adverse health effects (Lu et al., 2001; Nordberg and Nordberg, 2000). The rapid increase in metallothionein in the liver and kidneys during infection may explain an infection- induced flux of both essential (Cu and Zn) and non-essential (Cd) trace elements between organs (Ilback et al., 2004), and the previously reported difference in tissue accumulation of Ni and Cd (Glynn et al., 1998; Ilback et al., 1992a; Ilback et al., 1992b). Consequently, infections may well have an impact on the toxicity of metals, unfolding the possibility for detrimental effects even at exposure levels normally regarded as safe.

Competition between essential and non-essential trace elements can account for an unfavorable trace element balance in infected organs (Funseth et al., 2000b; Ilback et al., 2003a; Ilback et al., 2003b; Ilback et al., 2004). Thus, exposure to a potentially toxic trace element can result in an increased retention rate of the potentially toxic element during the course of the infection (Glynn et al., 1998; Ilback et al., 1992a; Ilback et al., 1992b), a disturbed balance of essential trace elements (Ilback et al., 2000, 2006), a reduced clearance of microorganisms (Christensen et al., 1996; Ilback et al., 1996; Koller, 1975), a changed virulence of microorganisms (Bhaskaram, 2002; Fawl et al., 1996; Thomas et al., 1985), more extensive pathological changes in target organs (Ilback et al., 1994a, 1996;Sethetal., 2003), and adverse effects on the healing of inflammatory lesions (Milanino et al., 1993).

In mice Se deficiency leads to higher mortality but similar parasitemia of Trypanosoma cruzi causing Chagas’ disease (de Souza et al., 2002). Se deficiency in humans is involved in the pathogenesis of Chagas’ disease (Rivera et al., 2003) and Keshan disease, the latter caused by a combination of Se deficiency and a viral infection (Peng et al., 2000). Both these diseases are associated with inflammatory heart lesions. Survival in SB- deficient rodents has been reported to be increased in Salmonella typhimurium, unchanged in Listeria monocytogenes and impaired in Staphylococcus aureus and Candida albicans infections (Ongele et al., 2002). Se deficiency increased resistance to S. typhimurium and Plasmodium berghei in rats and to Plasmodium berghei, Listeria monocytogenes, and pseudorabies virus infections in mice, but decreased resistance to Streptococcus pneumoniae infection in mice (Boyne et al., 1986). Moreover, Se deficiency increases the severity in both influenza (Beck et al., 2001) and coxsackievirus infection (Beck et al., 1994), with the latter having been shown to be associated with an increased virulence of the virus (Beck et al., 1994). Conversely, supplementation with Se increases the resistance to coxsackievirus infection, which seems to be associated with immune stimulatory effects (Ilback et al., 1998; Ilback et al., 1989) and reduced oxidative stress in the target organs of the infection (Beck and Levander, 2000). The major beneficial effect of Se may be in limiting tissue lesions that are caused by the infection and in limiting genetic mutations in replicating viruses.

TCDD reduces immune defense mechanisms against both endotoxin- producing (Salmonella typhimurium) and non-toxinproducing (Streptococcus pneumoniae) bacteria (Thigpen et al., 1975; Hinsdill et al., 1980), but the susceptibility to Listeria monocytogenes infection seems uninfluenced by TCDD (House et al., 1990) or even reduced for Streptococcus pneumoniae (Vorderstrasse and Lawrence, 2006). TCDD also appears to increase intestinal parasite expulsion of T. spiralis (Luebke et al., 1994). Accordingly, the adaptive immune response to influenza virus is generally suppressed by TCDD, whereas some parts of the innate immune response seem to be enhanced by TCDD (Funseth and Ilback, 1992; Mitchell and Lawrence, 2003; Warren et al., 2000; Vorderstrasse et al., 2003). Insufficient cytokine production (e.g., IL-2) in TCDD-exposed mice challenged with influenza virus has been suggested to contribute to a more severe disease (Mitchell and Lawrence, 2003).

It seems unlikely that increased mortality in influenza (Lawrence and Vorderstrasse, 2004; Vorderstrasse et al., 2003) and coxsackievirus infections (Funseth and Ilback, 1992; Funseth et al., 2002b; Ilback et al., 1989; Ilback et al., 1993) after TCDD exposure results from uncontrolled viral replication because virus titers are not increased and the ability to clear the virus not affected. However, it seems that TC-DD-induced aryl hydrocarbon receptor (AhR) activation impairs the priming but not the recall of influenza virus- specific CD8 cells in the mouse lung (Lawrence et al., 2006). Constituents in bronchoalveolar lavage (Luebke et al., 2002) and pulmonary neutrophilia (Teske et al., 2005) have indicated pulmonary inflammation to be the cause of the increased lethality in TCDD- exposed, influenzainfected mice (Nohara et al., 2002; Vorderstrasse et al., 2003). However, a recent study in influenza-infected mice revealed no correlation between increased mortality and the severity of lung injury (Bohn et al., 2005).

The increased lethality that is caused by TCDD in influenza (Burleson et al., 1996; House et al., 1990; Lawrence et al., 2000; Warren et al., 2000) and coxsackievirus infection (Funseth et al., 2002b), as well as lethality induced by PCB and HCB in parasitic infection (Loose et al., 1978; Luebke et al., 1994), may be associated with tissue accumulation of the xenobiotic. Halogenated aromatic hydrocarbons are able to bind to the specifie aryl hydrocarbon receptor (AhR) and thereby act as an inducer of the detoxifying P450 system (Kerkvliet, 2002; Morgan, 1997). Cytokines produced during infection are important for the regulation of the P450 system (Morgan, 1997; Singh and Renton, 1981). However, the specific forms of P450 enzymes can be selectively modulated by different cytokines (Morgan, 1997) because infections have different cytokine responses (Dyatlov and Lawrence, 2002; Ilback et al., 1993; Luebke et al., 1994; Warren et al., 2000) they have the potential to affect the detoxification of various xenobiotics differently (Fig. 8). Accordingly, even in the same coxsackievirus infection, TCDD (Funseth and Ilback, 1994; Funseth et al., 2002a), PBDE (Darnerud et al., 2005) and acrylamide (Abramsson-Zetterberg et al., 2005), that are detoxified by P450 enzymes, each exhibit its own specific target organ distribution.


The ability of a pathogen, virus, bacterium, or parasite, to cause infection depends on a successful invasion of the host, which, in turn, requires that the host’s various defense mechanisms are overcome. For the host, an infectious assault is a highly complex situation to deal with, even when the immune system is not disturbed by xenobiotics or in a state of deficiency of essential nutrients. Although impairment in a single immune function can be potentially deleterious, it does not necessarily mean that the host resistance to all microorganisms is insufficient. During the incubation period, a xenobiotic that disturbs the balance of essential trace elements and/or the initial cytokine production has the potential to impair immune activation and cause an early change in the progression of the disease that will become more severe and where the target organs of the infection may be changed. After the end of the incubation period, i.e. in the acute phase of the disease, the same xenobiotic may have changed its effects; for example, it may now compete with other essential trace elements, influence other arms of the immune defense, and, moreover, disturb the production of metal-binding proteins, often resulting in a more severe course of the disease. This could lead to increased tissue uptake of xenobiotics, toxicity to the tissues and to interactions where microorganisms, and toxicants “cooperate,” all of which results in increased damage. Finally, in the recovery phase the same chemical may in situ disturb those immune cells and trace elements that are involved in the clearing of microorganisms and the healing of lesions in the target organs of the infection. Consequently, xenobiotics may affect the course of an infectious disease differently depending on in which phase of the disease the exposure occurs.

It is well-recognized from clinical studies that an impaired metabolism in infection can modulate the P450 system, causing drug toxicity as a result (Morgan, 1997). Hepatitis B virus infection and aflatoxins are risk factors for hepatocellular carcinoma. One hypothesis to explain this interaction is that carcinogen metabolism is altered in the presence of virus and associated liver cell injury (Chemin et al., 1999; Chen and Nirunsuksiri, 1999; Chomarat et al., 1998). Cytokines are important for the regulation of the P450 system and viral, parasitic, and bacterial infections evoke different cytokine patterns (Dyatlov and Lawrence, 2002; Luebke et al., 1994; Warren et al., 2000). It is also clear that the activities or expression of individual P450s may be affected differently by different cytokines (Morgan, 1997). Furthermore, because they are differently expressed in different organs, even the activities of specific P450s may depend on the site of the infection. Thus, the tissue accumulation, the target organ of toxicity, and detoxification may all depend on the type of microorganism and the cytokine pattern it evokes.

Infections, wherever they are seated, may influence the gastrointestinal tract via systemic cytokine responses. This may lead to a more permeable intestine that permits the passage of macromolecules and antigens that cause immune-mediated pathologic changes in the host. A more severe encephalomyocarditis virus infection has been noted in mice pre-treated with pesticide mixtures (DDT, fenitrothion) (Cracker et al., 1974). However, studies on encephalomyocarditis and influenza in mice indicate that emulsifiers, acting as surfactants for chemicals ordinarily not water soluble, used in pesticide preparations may enhance virus induced lethality (Crocker et al., 1986). Surfactants have also been shown to enhance infectivity of a wide variety of viruses in various mammalian cell lines (Rozee et al., 1978; Schmidt, 1983).

Many bacteria are dependent on Fe for their multiplication and numerous diseases are associated with Fe overload. Accordingly, an excess of Fe has been shown to worsen the outcome of a variety of infectious diseases (Lounis et al., 2001; SerafinLopez et al., 2004; Weinberg, 1999; Weiss, 2002). Whether the Fe accumulation in target organs of opportunistic infections in HIV and AIDS is the initial event that causes the complications or if it is a consequence of the disease processes, including the host responses associated with the infection, is not known.

In a host of experimental studies several essential trace elements (Ca, Cu, Fe, Mn, Se, Zn) at levels in the physiological range and non-essential trace elements (As, Cd, Hg, Pb) at exposure levels normally found in food, have been shown to influence growth and virulence of microorganisms, as well as the clinical course and complications of viral, bacterial, and parasitic infections. However, different microorganisms have varying requirements of trace elements. The most frightening discoveries regarding changes in virulence are the in vivo studies of both coxsackievirus and influenza virus showing that dietary Se deficiency can cause relatively harmless viruses to mutate into virulent forms (Beck et al., 1994; Beck et al., 2001). This warrants further study to determine whether and to what extent it is relevant to humans, other microorganisms, and other nutrients/xenobiotics. If so, it may be shown that certain populations exposed to certain xenobiotics are at increased risk, such as, at the outbreaks of new epidemics expected to appear in the future (Bhaskaram, 2002).

Because of their ability to migrate and phagocytize, as well as to present antigens to T-helper cells, macrophages play an important role against viral, parasitic, and bacterial infections, and in the healing of associated tissue lesions (Bishayi and Sengupta, 2003; Ilback et al., 1989; Van Loveren, 1995; Vos et al., 1990). In the heart of coxsackievirus-infected mice, the number of macrophages is correlated to the size of the inflammatory and necrotic lesions (Ilback et al., 1989; Ilback et al., 1990). A changed cytokine response to infection in individuals exposed to environmental chemicals may, in addition to an altered immune activation, reflect changes in the release of Superoxides and peroxides from macrophages during digestion of microorganisms (Bishayi and Sengupta, 2003; Christensen et al., 1996; Davis et al., 1998). Hg impairs the respiratory burst of herpes simplex virus-activated macrophages (Ellermann-Eriksen et al., 1994) and Pb efficiently blocks murine splenic macrophage nitric oxide production (Tian and Lawrence, 1995). Nitric oxide is highly microbicidal and parasiticidal (Beisel, 1998) and is thus likely to contribute to phagocytosis and intracellular killing of invading microorga