Abstract
Cadmium (Cd) is a toxic heavy metal that is considered an environmental contaminant. Several sources of human exposure to Cd, including employment in primary metal industries, production of certain batteries, foods, soil and cigarette smoke, are known. Its inhalation has been related to different respiratory diseases and toxic effects, among which alterations of the physiological redox state in individuals exposed to the metal have been described. Host-cell redox changes characteristic of oxidative stress facilitate the progression of viral infection through different mechanisms. In this paper, we have demonstrated that pre-treatment with CdCl2 of MDCK cells increased influenza virus replication in a dose-dependent manner. This phenomenon was related to increased viral protein expression (about 40% compared with untreated cells). The concentration of CdCl2, able to raise the virus titer, also induced oxidative stress. The addition of two antioxidants, a glutathione (GSH) derivative or the GSH precursor, N-acetyl-l-cysteine, to Cd pre-treated and infected cells restored the intracellular redox state and significantly inhibited viral replication. In conclusion, our data demonstrate that Cd-induced oxidative stress directly increases the ability of influenza virus to replicate in the host-cell, thus suggesting that exposure to heavy metals, such as this, could be a risk factor for individuals exposed to a greater extent to the contaminant, resulting in increased severity of virus-induced respiratory diseases.
Highlights
Cadmium (Cd) is a toxic heavy metal and, as a byproduct of smelters, is a prevalent environmental contaminant
Cells treated with 75 μM CdCl2 appeared rounded and lost intercellular contact, and most of the cells were detached at concentrations of 100 and 500 μM, indicating a high rate of cell death
The 24 h post-infection (p.i.) viral yields are expressed as the ratio between hemagglutinin units (HAU) values obtained from Cd-treated cells versus those recorded for control cells
Summary
Cadmium (Cd) is a toxic heavy metal and, as a byproduct of smelters, is a prevalent environmental contaminant. The molecular mechanisms, which cause the toxic effects of Cd, involve interference with antioxidant enzymes, alteration in thiol proteins, inhibition of energy metabolism, alteration in DNA structure and modification of some enzyme activities [3]. It induces depletion of reduced glutathione (GSH) and protein-bound sulfhydryl groups, resulting in enhanced production of reactive oxygen species (ROS) [4,5,6]. A decrease in GSH levels and general oxidative stress has been demonstrated during influenza virus infection in both in vitro and in vivo experimental models [16,17,18,19,20]. We have demonstrated that pre-treatment with CdCl2 of Madin Darby Canine Kidney (MDCK) cells induced: (i) an imbalance in the redox state versus an oxidized state; (ii) an increase in viral protein synthesis and, as a consequence, an increase in virus release from infected cells; and (iii) the addition of two antioxidants, a GSH derivative (GSH-C4) or the GSH precursor, N-acetyl-L-cysteine (NAC), to Cd-treated and infected cells significantly inhibited viral replication
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