Sequential Changes in Fe, Cu, and Zn in Target Organs during Early Coxsackievirus B3 Infection in Mice

Abstract

In Coxsackievirus B3 (CB3) infection, the heart and pancreas are major target organs and, as a general host response, an associated immune activation and acute phase reaction develops. Although iron (Fe), copper (Cu), and zinc (Zn) are involved in these responses, sequential trace element changes in different target organs of infection have not been studied to date. In the present study, Fe, Cu, and Zn were measured through inductively coupled plasma mass spectrometry (ICP-MS) in the plasma, liver, spleen, heart, and pancreas during the early phase (d 1 and 3) of CB3 infection in female Balb/c mice. The severity of the infection was assessed through clinical signs of disease and histopathology of the heart and pancreas, including staining of CD4 and CD8 cells in the pancreas. During infection, the concentrations of Fe, Cu, and Zn changed in the plasma, liver, and pancreas, but not in the spleen and heart. The changes in plasma Cu, Zn, and Fe seemed to be biphasic with a decrease at d 1 that turned into increased levels by d 3. Cu showed similar biphasic changes in the liver, spleen, and pancreas, whereas, for Zn and Fe, this pattern was only evident in the liver. In the pancreas, the reverse response occurred with pronounced decreases in Fe (23%, p < 0.05) and Zn (64%, p < 0.01) at d 3. Although the pathophysiological interpretation of these findings requires further research, the sequential determination of these elements may be of clinical value in enterovirus infections in deciding the stage of disease development.

Interactions between Infections, Nutrients and Xenobiotics

“…Several trace elements are essential micronutrients required for various body functions and the well-being of the immune system, but also in preventing viral mutations which could change pathogenicity (Chaturvedi et al, 2004). 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;Pekarek and Engelhardt, 1981). However, plasma changes in Mn, Mg, Co, Cr, I, and Gal have been described (Funseth et al, 2000a;Pekarek and Engelhardt, 1981).…”

“…The host defence mobilisation is normally referred to as the "acute phase reaction" and is initiated during the early incubation period and peaks during fever. Host responses are similar in animals 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;Funseth et al, 2000a;Grimble, 1996;Ilback et al, 1984a;Ilback et al, 2003b).…”

“…Already in the 1970s it was shown that volunteers exposed to live attenuated Venezuelan equine encephalitis virus vaccine, as well as monkeys infected with S. typhimurium, responded with an early fall in serum Fe and Zn concomitant to 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 (Beisel, 1998;Ilback et al, 1983;Ilback et al, 2003b), and in vitro results of S. enteritidis infected enterocytes indicate that infection decreases absorption of Fe (Foster et al, 2001). Even at normal dietary trace element levels, the early infection induced MT elevation is associated with redistribution of essential as well as non-essential trace elements (e.g., a redistribution of Cd and Cu from the liver to the kidneys) (Ilback et al, 2004a).…”

“…The normal trace element balance of, for example, Cu and Zn is changed in target organs of infections and other inflammatory processes (Beisel, 1998;Funseth et al, 2000b;Ilback et al, 2003b). This flux of trace elements is mediated by metal transporting proteins, such as MT (Zn, Cu), ceruloplasmin (Cu) and ferritin (Fe).…”

“…The Cu-containing ceruloplasmin is an important acute-phase reactant in generalised infections (Beisel, 1998) and 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). Data on effects of Cu on virulence and growth of microorganisms in the host are limited, however.…”