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Viral
Infection
bacteria viruses
• Viruses
• Decreased T cell response due to methylation cycle
mutations.
• Impaired DNA synthesis that is needed for T cell clonal
expansion.
• Impaired B cell response due to lack of T helper cells,
and T regulatory cells.
• Increased IDO, impact on self versus non self
• Further Induction of IDO by interferon gamma
• Interferon gamma increases in intestinal permeability
and blood-brain permeability
• Decreased vaccine efficiency, increased viral load
• Nature of retroviruses themselves.
• Reduced viral silencing due to methylation cycle
mutations.
Viruses as Parasites
• Induction of Metallothionein proteins
by viral infection
• Trapping of heavy metals by virus
“Viruses use a “Trojan horse” strategy in
which the victim assists the intruder. To
extract assistance from the host cell,
viruses use the detailed “inside
information” that they have acquired
during million of years of coevolution with
their hosts.”
Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, Spiegelman D, Ascherio A.
CONTEXT: Infection with Epstein-Barr virus (EBV) has been associated with an increased risk of multiple sclerosis
(MS), but the temporal relationship remains unclear. OBJECTIVE: To determine whether antibodies to EBV are
elevated before the onset of MS. DESIGN, SETTING, AND POPULATION: Nested case-control study conducted
among more than 3 million US military personnel with blood samples collected between 1988 and 2000 and stored in
the Department of Defense Serum Repository. Cases were identified as individuals granted temporary or permanent
disability because of MS. For each case (n = 83), 2 controls matched by age, sex, race/ethnicity, and dates of blood
sample collection were selected. MAIN OUTCOME MEASURES: Antibodies including IgA against EBV viral capsid
antigen (VCA) and IgG against VCA, nuclear antigens (EBNA complex, EBNA-1, and EBNA-2), diffuse and restricted
early antigens, and cytomegalovirus. RESULTS: The average time between blood collection and MS onset was 4
years. The strongest predictors of MS were serum levels of IgG antibodies to VCA or EBNA complex. The risk of MS
increased monotonically with these antibody titers; relative risk (RR) in persons in the highest category of VCA (> or
=2560) compared with those in the lowest (< or =160) was 19.7 (95% confidence interval [CI], 2.2-174; P for trend
=.004). For EBNA complex titers, the RR for those in the highest category (> or =1280) was 33.9 (95% CI, 4.1-283; P
for trend <.001) vs those in the lowest category (< or =40). Similarly strong positive associations between EBV
antibodies and risk of MS were already present in samples collected 5 or more years before MS onset. No
association was found between cytomegalovirus antibodies and MS. CONCLUSION: These results suggest
a relationship between EBV infection and development of MS.
Viral Infection and MS
Association of human herpes virus 6 (HHV-6) with multiple sclerosis: increased IgM response to HHV-6 early
antigen and detection of serum HHV-6 DNA.
Soldan SS, Berti R, Salem N, Secchiero P, Flamand L, Calabresi PA, Brennan MB, Maloni HW, McFarland HF,
Lin HC, Patnaik M, Jacobson S.
Viruses have long been suggested to be involved in the etiology of multiple sclerosis (MS). This suggestion is based on (1)
epidemiological evidence of childhood exposure to infectious agents and increase in disease exacerbations with viral
infection; (2) geographic association of disease susceptibility with evidence of MS clustering; (3) evidence that migration to
and from high-risk areas influences the likelihood of developing MS; (4) abnormal immune responses to a variety of
viruses; and (5) analogy with animal models and other human diseases in which viruses can cause diseases with long
incubation periods, a relapsing-remitting course, and demyelination. Many of these studies involve the demonstration of
increased antibody titers to a particular virus, whereas some describe isolation of virus from MS material. However, no virus
to date has been definitively associated with this disease. Recently, human herpesvirus 6 (HHV-6), a newly described beta-
herpes virus that shares homology with cytomegalovirus (CMV), has been reported to be present in active MS plaques. In
order to extend these observations, we have demonstrated increased IgM serum antibody responses to HHV-6 early
antigen (p41/38) in patients with relapsing-remitting MS (RRMS), compared with patients with chronic progressive MS
(CPMS), patients with other neurologic disease (OND), patients with other autoimmune disease (OID), and normal controls.
Given the ubiquitous nature of this virus and the challenging precedent of correlating antiviral antibodies with disease
association, these antibody studies have been supported by the detection of HHV-6 DNA from samples of MS serum as a
marker of active viral infection.
Viral Infection and CFS
Methylation status affects viral load and hence metal accumulation.
Since metal toxicity has been associated with CFS this has direct
relevance for CFS.
Thimerosal, micromercurialism and chronic fatigue syndrome.
Miller R.
PMID: 15780514 [PubMed - indexed for MEDLINE]
Kalpana Ghoshal,1 Sarmila Majumder,1 Qin Zhu,1 John Hunzeker,2 Jharna Datta,1
Manisha Shah,3 John F. Sheridan,2 and Samson T. Jacob1
Copyright © 2001, American Society for Microbiology
Mol Cell Biol. 2001 December; 21 (24): 8301–8317
DOI: 10.1128/MCB.21.24.8301-8317.2001
Purpose:To measure the concentration of toxic heavy metals in the fluids and tissues of human
eyes.
Methods: Thirty autopsy eyes of 16 subjects were dissected to obtain the aqueous, vitreous, lens,
ciliary body, retina, and retinal pigment epithelium/choroid. Concentrations of lead, cadmium,
mercury, and thallium in ocular tissues, ocular fluids, and blood were determined using an
inductively coupled plasma-mass spectrometer and expressed as ng/g. Heavy metal concentrations
in ocular tissues were compared using a paired t test.
Results: Lead and cadmium were found in all of the pigmented ocular tissues
studied, concentrating to the greatest extent in the retinal pigment epithelium/choroid (mean, 432
± 485 ng/g and 2,358 ± 1,522 ng/g). Cadmium was found in the retina in all eyes (mean, 1,072 ±
489 ng/g) whereas lead was found in the retina in 9 (30%) of 30 eyes (mean, 53 ± 54 ng/g). Trace
concentrations of lead and cadmium were detected in the vitreous (mean, 0.5 ± 1.0 ng/dl and 19 ±
29 ng/dl), lens (mean, 13 ± 18 ng/g and 20 ± 18 ng/g), and blood (mean, 0.5 ± 1.2 μg/dl and 3.1 ±
4.1 μg/l) but were not detected in the aqueous. Mercury and thallium were not detected in any
ocular tissues or fluids or in the blood.
Conclusions: Lead and cadmium accumulate in human ocular tissues, particularly in the
retinal pigment epithelium and choroid. The potential ocular toxicity of these heavy metals and their
possible role in eye disease requires further study.
Relationship between Virus and Metals
Beltsville Human Nutrition Research Center, US Department of Agriculture, Agricultural Research Service, Maryland 20705-
2350, USA.
An amyocarditic strain of coxsackievirus B3 (CVB3/0) induces heart damage when inoculated into selenium
(Se)-deficient mice. Mercury (Hg), an Se antagonist, is known to aggravate viral infections. The experiments
reported here assessed the effect of prior Hg treatment in mice subsequently inoculated with an
amyocarditic strain of coxsackievirus. A pilot study showed that under our conditions the maximum tolerated
dose of HgCl2 in uninfected mice was 6 mg HgCl2/kg body weight. In the main study, doses of 0, 3 or 6 mg
HgCl2/kg body weight were administered intraperitoneally (ip) to 7-wk-old male mice fed a standard chow
diet. Two hours later, half the mice were inoculated ip with CVB3/0. Ten days postinoculation, no mortality
was observed in mice given only virus. In mice not given virus, 10% injected with 6 mg HgCl2/kg body
weight died. On the other hand, 64% of the mice given both virus and 6 mg HgCl2/kg body weight died.
Fifteen percent of the hearts from virus-infected mice given 3 mg HgCl2/kg body weight and 33% of the
hearts from virus-infected mice given 6 mg HgCl2/kg body weight exhibited a higher incidence of lesions
than hearts from mice-given virus alone. Moreover, viral heart titers were elevated in infected mice injected
with 6 mg HgCl2/kg body weight compared to infected mice receiving no Hg. Thus, an amyocarditic
coxsackievirus given to mice after a nonlethal subacute dose of Hg results in mortality, increased incidence
of heart lesions, and elevated viral heart titers. These results demonstrate the important role of toxic
elements in determining the severity of viral infections.
Relationship between Virus and Metals
Toxicol Lett. 1996 Dec;89(1):19-28
A myocarditic coxsackievirus B3 (CB3) infection in Balb/c mice was used to investigate the effects of 12
weeks of methyl mercury (MeHg) exposure (3.69 mg/g diet) on inflammatory heart lesions, virus in the heart,
the cytokine response, i.e. cachectin/TNF-alpha and gamma-interferon (IFN-gamma) levels in plasma, and
on disease complications and mortality. This dose of MeHg did not influence mortality in this infection model.
The inflammatory and necrotic lesions in the ventricular myocardium 7 days after the inoculation covered
2.2% of the tissue section area in infected control mice. This damage was increased (n.s.) by 50% (to 3.3%
of the tissue section area) in MeHg-treated mice. The response pattern of lymphocyte subsets in situ in
myocardial inflammatory lesions was corroborated using an immune histological technique. MeHg treatment
tended to increase (2.2-fold, n.s.) the number of Mac 2+ cells (macrophages) in the heart muscle in this
infection. Plasma levels of both TNF-alpha and IFN-gamma increased on day 3 of the infection in MeHg-
treated as well as in non-MeHg-treated mice, but the mean IFN-gamma response was more pronounced in
the MeHg-treated mice. On day 7 of the infection, when most animals still showed clinical signs of disease,
cytokine levels were back to normal. MeHg-exposure in non-infected mice did not affect cytokine levels. In
situ hybridization of virus RNA in myocardial tissue showed remaining virus in those mice who had the
lowest plasma IFN-gamma levels. A 20% increased (P < 0.05) lymphoproliferative response to the T cell
mitogen Con A was observed as a result of the MeHg treatment. Even heart tissue lesions and virus
persistence tended to be influenced by MeHg in a direction compatible with the development of chronic
disease.
Relationship between Virus and Metals
Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Sweden.
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.
Relationship between Virus and Metals
During most infections plasma, concentrations of trace elements change, but it is unclear if this reflects
changes in infected target tissues. In coxsackievirus B3 (CB3) infection, the myocardium is a target in both
humans and mice. The concentrations of 12 trace elements were analyzed by inductively coupled plasma-
mass spectrometry (ICP-MS) in the myocardium of sham-inoculated controls and infected A/J mice 4 and 7 d
postinoculation. The size of the inflammatory lesion was positively correlated to the virus content of the heart,
as estimated by histopathology and in situ hybridization, respectively. Iron, cobalt, vanadium, and selenium
showed transient changes, whereas for the other elements, tendencies on d 4 were manifest on d 7. A three-
fold increase in calcium on d 7 suggests prestages of calcification, whereas increases in zinc, selenium, and
copper may be the result of the accumulation of immune cells. The magnesium decrease may contribute to
the increased sensitivity to cardiac arrhythmias in myocarditis.
Relationship between Virus and Metals
The effects of 10 wk of selenium (Se) supplementation (5 ppm) in drinking water on immune responses and
resistance to a myocarditic Coxsackie virus B3 (CB3) infection were studied in female Balb/c mice. Se
supplementation reduced CB3-induced mortality: at day 14 postinoculation, survival was 58% in the Se-treated
group as compared to 25% in the untreated group. Whole-blood glutathione peroxidase (GSH-Px) activity was
elevated by 68% (p < 0.001) and Se content in the liver by 24% (p < 0.001). Red (RBC) and white blood cell
(WBC) counts, as well as the number of cells in the spleen and thymus, were unaffected. The cellular counts
of T-lymphocytes (CD4+, CD8+) and natural killer (NK+) cells in the blood were not affected. However, the
CD4+/CD8+ ratio (5.2) tended to increase after Se supplementation (5.9). The spleen lymphoproliferative
response to T- and B-cell mitogens were increased by 9 and 43%, respectively (ns), in the Se-supplemented
group. The total NK cell activity in blood and spleen showed minor increases, but when the activity in the blood
was expressed per cell, the increase amounted to 35% (ns) with Se supplementation. The inflammatory and
necrotic lesions in the ventricular myocardium at 7 and 14 d postinoculation were not significantly reduced by
Se treatment, probably owing to the increased survival with Se even of mice with the most pronounced heart
damage; comparable untreated mice were estimated to have died at day 14. Results indicate that modest
doses of Se can improve immune function, which may increase the general resistance to this viral infection.
Relationship between Virus and Metals
The magnitude of inflammatory lesions in the hearts of coxsackie B3 (CB3)-virus infected mice can be
affected by the potentially toxic heavy metals cadmium (Cd), nickel (Ni) and methyl mercury (MeHg). The
infection is associated with a changed distribution, such as Cd accumulation in the spleen and kidneys. New
target organs for Ni during the infection were the heart, pancreas and lungs in which inflammatory lesions
were present. This increased uptake was correlated with the disturbed function of immune cells and an
increased inflammatory reaction. Ni and MeHg appeared to have a direct effect on immune cells that resulted
in changed natural killer cell activity and decreased mobilization of macrophages, CD4+ and CD8+ cells into
the inflammatory lesions. Although MeHg increased spleen T cell activity and gamma-interferon (IFN-gamma)
levels, the inflammatory lesions in the heart increased. Another detrimental effect of MeHg treatment was
evident by an increased calcium and decreased zinc content in the inflamed heart, which may partly explain
the more severe inflammatory lesion. The host's response, CB3 infection, changed the distribution of each
metal in a specific way, a fact which may subsequently result in altered target organ toxicity and resistance to
the infection.
Relationship between Virus and Metals
The autoradiographic distribution of the toxic heavy metal nickel (Ni) was studied at 4 and 7 days post-
coxsackievirus B3 (CB3) infection in Balb/c mice. The distribution of the iv injected 63Ni was studied 10 min,
4 hr, and 24 hr after administration. Results clearly show that the site of 63Ni accumulation is greatly
changed during this viral infection. This newly discovered distribution was mainly visible as a greatly
increased accumulation in the pancreas and the wall of the ventricular myocardium. Healthy animals
showed almost no 63Ni accumulation in these tissues. These results for the first time show that an invading
microorganism can change the distribution of an environmental pollutant
Relationship between Virus and Metals
This report presents evidence that a micro-organism common in our environment, coxsackievirus B3 (CB3)
and the host responses it causes, can change the body distribution of heavy metals and lipids. The present
results show that the distributions of intravenously injected 109Cd, 63Ni and 14C-Cholesterol are changed
during infection, in a way that is specific for each of the studied compounds. Increased accumulation of
109Cd in the spleen and kidneys, 63Ni in the pancreas and ventricular myocardium, and 14C-Cholesterol in
the heart and pancreas was observed during CB3 infection. This may affect the development of inflammatory
lesions and subsequently result in altered and/or increased target organ toxicity as well as lipid accumulation.
Thus, risk assessment in exposed populations may have to be evaluated depending on individual nutritional
and exposure status.
Relationship between Virus and Metals
The effects of 10 weeks of treatment with cadmium (Cd) on the immune function and resistance to
coxsackievirus B3 (CB3)-induced myocarditis in female Balb/c mice were investigated. A 2mM dose of Cd in
the drinking water did not influence mortality due to the CB3 infection. The inflammatory and necrotic
lesions in the ventricular myocardium seven days after inoculation (2.94% of tissue section area) were not
increased by Cd (2.82% of tissue section area). The response pattern of lymphocyte subsets in situ in
myocardial inflammatory lesions was elucidated by an immune histochemical staining technique. With Cd
treatment the number of cytotoxic T cells and B cells in these lesions decreased by 22% (n.s.) and 21% (p <
0.05), respectively. Spleen weight and the lymphoproliferative response to the B-lymphocyte mitogen
increased by 19% (p < 0.05) and 23% (n.s.), respectively. The titers of neutralizing antibodies increased by
22% (n.s.) with Cd treatment. However, the activity of spleen T lymphocytes and spontaneous cell-mediated
cytotoxicity (NK-cell) was unchanged. Thymus weight and WBC count in peripheral blood tended to
decrease. Thus, Cd exposure seems to result in a decreased maturation and mobilization of T and B
lymphocytes, but increased humoral immune host responses.
Relationship between Virus and Metals
Toxicology. 1992;71(3):193-202
The distribution of the toxic heavy metal cadmium (Cd) was studied in Coxsackie virus B3 (CB3)-infected
Balb/c mice by whole-body autoradiography and gamma-counting. The distribution of 109Cd was studied 4
days post CB3-inoculation and 10 min after intravenous injection of 0.21 microgram of Cd/kg body weight.
Whole-body autoradiography results showed that the distribution of 109Cd is greatly changed during this
viral infection. This newly discovered distribution was mainly visible as a greatly increased accumulation in
the renal and adrenal cortices. After impulse counting of selected organs it was found that the normal
accumulation of 109Cd in the kidneys (184,354 +/- 30,961 c.p.m.) was increased by 47% (P less than
0.05) during CB3 infection (270,503 +/- 54,780 c.p.m.). In contrast to healthy animals, some infected mice
showed accumulation of 109Cd in the spleen. These results show for the first time that an invading micro-
organism can change the distribution of an environmental pollutant.
Relationship between Virus and Metals
Biol Trace Elem Res. 2000 Winter;78(1-3):131-47
Methyl mercury (MeHg) has been shown to change Coxsackie virus type B3 (CB3) myocarditis in a direction
compatible with the development of chronic disease. Murine models of CB3 myocarditis closely mimic the
pathogenesis in humans. There are also indications that metals, such as mercury, and trace elements may
interact and adversely affect viral replication and development of inflammatory lesions. The effects of low-dose
MeHg exposure on myocardial trace element distribution, as determined by means of nuclear microscopy, was
studied in CB3 myocarditis. Balb/c mice were fed a MeHg-containing diet (3.9 mg/kg diet) for 12 wk prior to
infection. Areas of inflammatory lesions in the myocardium were identified by traditional histologic examination,
and serial tissue sections in these selected areas were used for immune histology (macrophages), in situ
hybridization of virus genomes, and nuclear microscopy of tissue trace element distribution. Areas with no
inflammation or virus were compared with areas of ongoing inflammation and viral replication. In the
inflammatory lesions of MeHg-exposed mice as compared to nonexposed mice, the myocardial contents of
calcium (Ca), manganese (Mn), and iron (Fe) were significantly increased, whereas the zinc (Zn) content was
decreased. The increased Ca and decreased Zn contents in the inflamed heart may partly explain a more
severe disease in MeHg-exposed individuals. Although not significant in the present study, with a limited
number of mice, the inflammatory and necrotic lesions in the ventricular myocardium on d 7 of the infection was
increased by 50% (from 2.2% to 3.3% of the tissue section area) in MeHg-exposed mice and, also, there was a
tendency of increased persistence of virus with MeHg exposure. No increased MeHg uptake, either in the
inflammatory lesions or in the areas of noninflamed heart tissue in infected mice, could be detected. The
present results indicate that a "competition" exists between potentially toxic heavy metals from the
environment/diet and important trace elements in the body and that a disturbed trace element balance
adversely influences the development of pathophysiologic changes in inflammatory heart disease.
Relationship between Virus and Metals
The trigger for some cases of juvenile diabetes has been suggested to be an interaction between a virus and
various trace elements. Infection with human coxsackievirus B3 (CB3) in the murine model results in viral
replication and inflammation in the pancreas. AIM: To determine how infection affects the trace element
balance in the pancreas. METHODOLOGY: Concentrations of the following trace elements were measured
in the serum and pancreas during the early phase (days 1 and 3) of CB3 infection in female Balb/c mice:
aluminium, arsenic, cadmium (Cd), calcium (Ca), cobalt (Co), copper (Cu), iron (Fe), lead (Pb), magnesium
(Mg), manganese (Mn), mercury (Hg), selenium, silver, vanadium (V), and zinc (Zn). The trace element
concentrations were measured through inductively coupled plasma mass spectrometry. The histopathology
was established by hematoxylin-eosin techniques and immunohistochemical staining of both CD4 and CD8
cells of the pancreas. RESULTS: Infected mice developed expected clinical signs of disease. The only
changes at day 1 occurred in the serum, with a pronounced decrease in the Zn concentration and a small
increase in the V concentration. At day 3, concentrations of several trace elements, including Cu, Zn, Fe,
Ca, V, and Mn, showed pronounced changes in both the serum and the pancreas. Ca, Cu, Mg, Mn, and V,
but none of the potentially toxic elements, accumulated in the pancreas. Cu and V concentrations increased
in the serum as well. CONCLUSION: Several trace element changes, preceding the development of
pancreatitis, occurred in the pancreas in this viral infection, the exact pathogenic interpretation of which
warrants further studies.
Relationship between Virus and Metals
During most infections the plasma levels of trace elements change, but it is not clear if this reflects changes
in the infected tissues. Coxsackievirus B3 (CB3) infection may result in viral replication, subsequent
inflammation and changed trace element levels in the myocardium. In the present study, the trace element
levels in the plasma and heart of adult male A/J mice were determined during the pre-inflammatory stage
(day 4) of CB3 myocarditis for the following trace elements: aluminium (Al), arsenic (As), calcium (Ca),
cobalt (Co), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), selenium (Se), silver (Ag),
vanadium (V) and zinc (Zn). The severity of the infection was assessed through clinical signs of disease
and trace element levels were measured through inductively-coupled plasma mass-spectrometry (ICP-MS).
In the heart, the levels decreased for V (59%; p < 0.01), Co (38%; p < 0.01), Al (81%; p < 0.01), As (66%; p
< 0.01) and Se (16%; p < 0.01). Increased levels were detected for Mn (13%; p < 0.05), Fe (48%; p < 0.01),
Cu (34%; p < 0.01) and Ag (46%; p < 0.01). In the plasma, decreases were detected in the level of Zn
(32%; p < 0.05), whereas increases were seen in Mn (362%; p < 0.05), Fe (272%; p < 0.01), Co (71%; p <
0.05), Cu (25%; n.s.) and Mg (43%; p < 0.01) levels. A correlation was found between the levels in plasma
and myocardium for Co (r(s) = -0.636; p < 0.05), Fe (r(s) = 0.764; p < 0.05), Mn (r(s) = 0.682; p < 0.05) and
Mg (r(s) = -0.791; p < 0.05). Thus, determination of some of these trace elements in the plasma may be
useful to indicate target tissue involvement in the early pre- inflammatory stage of an infectious disease.
Some of these elements are important nutrients for the immune system, while others may be associated
with the development of disease complications, such as cardiac arrhythmias.
Relationship between Virus and Metals
Murine intestinal absorption, tissue accumulation and redistribution of 109Cd during infection were
studied using the common human virus Coxsackie virus B3 (CB3) adapted to the mouse. Female Balb/c
mice were infected with CB3 and, on day 4 of the infection, dosed orally with 0.3 or 750 microgram Cd/kg
body weight, with 109Cd as a tracer, in order to study intestinal absorption and tissue distribution of Cd
during infection (Experiment 1). Other mice were dosed with 0.3 microgram Cd/kg body weight 3 days
before being infected and, on day 4 of the infection, Cd redistribution was studied (Experiment 2). In both
experiments non-infected control animals received the same treatment as infected animals. Results
showed that the infected animals had a higher gastrointestinal absorption of Cd than noninfected animals
when Cd was administered during infection. In the infected animals the absorption at the low Cd dosage
was increased by 70% and was tripled at the high dosage. The increased absorption enhanced the
accumulation of Cd in all organs studied. Moreover, the infection caused a Cd dose-dependent change in
the organ distribution of Cd, when Cd was administered during the infection. However, no redistribution of
previously accumulated Cd occurred during ongoing disease, indicating that Cd was not mobilised from
body stores by the infection. These results show, for the first time, that an invading micro-organism can
increase the intestinal absorption and concomitantly alter the tissue distribution of an environmental
pollutant (Cd) if exposure occurs during the course of viral infection.
Virus Induced Metallothionein Synthesis
Toxicology Division, Swedish National Food Administration, P.O. Box 622, Uppsala S-751 26, Sweden. nils-
gunnar.ilback@slv.se
In experimental studies on the common human coxsackievirus B type 3 (CB3) infection, administered
cadmium (Cd) is known to accumulate in the liver and kidneys. CB3 adapted to Balb/c mice was used to
study whether infection affects the Cd-binding protein, metallothionein (MT) and if this alters the normal
physiological trace element balance in the liver, kidney, spleen and brain. On day 3 of infection, degradation
of liver proteins (44%, P<0.01) occurred, whereas in the spleen, protein increased (63%, P<0.05). The
infection increased MT five-fold (P<0.01) in liver and kidneys, and in spleen by 34% (P<0.05). A
redistribution of Cd and copper (Cu) from the liver to the kidney was associated with this increase in MT,
resulting in an increased (P<0.01) kidney/liver ratio for both elements. The infection increased the zinc (Zn)
concentration more in the kidney than in the liver, but the kidney/liver ratio was not significantly affected.
Results show that MT is increased in several organs during the early phase of infection and is associated
with redistribution of both essential and non-essential trace elements. This may be a normal response in
common infections that could adversely influence the pathogenesis when the host is concomitantly exposed
to potentially toxic trace elements, even at levels in the physiological range.
Virus Induced Metallothionein Synthesis
Sci Total Environ. 2002 Feb 4;284(1-3):37-47
Effects of coxsackievirus B3 infection on the acute-phase protein metallothionein
and on cytochrome P-4501A1 involved in the detoxification processes of TCDD in
the mouse.
Funseth E, Pahlman M, Eloranta ML, Friman G, Ilback NG.
During acute infections, the synthesis of acute-phase proteins and other proteins participating in the host
defence are stimulated in the liver and kidney. In previous studies of coxsackievirus B3 (CB3) infection in
mice, we found that cadmium (Cd) accumulates in the kidney, whereas 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD) accumulates in the liver. To study if CB3 infection affects the synthesis of the Cd-binding protein
metallothionein (MT) and the TCDD-binding/detoxifying cytochrome P-450 (CYP-450) isozyme CYP1A1,
the basal and TCDD-induced levels of serum MT and liver CYP1A1 isozyme were determined in healthy
and CB3-infected A/J mice. Furthermore, because interferons affect CYP450 activity, the serum levels of
the interferons alpha (IFN-alpha) and -beta (IFN-beta) were measured in CB3-infected mice and in mice
treated with the interferon-inducer polyinosinic/polycytidylic acid (poly I/C). Virus or poly I/C was
administered intraperitoneally (i.p.) on day 0 and 500 ng TCDD/kg bodyweight on day 1. On day 4, CB3
infection had induced MT approximately 10-fold, regardless of TCDD treatment (P < 0.01 in infected mice
and P < 0.001 in infected, TCDD-treated mice). TCDD alone induced a 10-fold increase in CYP1A1 activity
(P < 0.001), whereas infection alone suppressed the normal CYP1A1 activity by 75% (P < 0.001). Infection
also suppressed the TCDD-induced CYP1A1 activity by approximately 30% (n.s.). Poly I/C suppressed
CYP1A1 by 20-25% (n.s.) at both basal and TCDD-induced levels. Serum IFN-alpha and IFN-beta levels
were undetectable in controls, in TCDD-treated and in the poly I/C-treated groups on day 4, probably
because the short IFN peak is detectable only hours after injection. Conversely, on day 4 of the infection,
IFN-alpha and IFN-beta were consistently raised in the TCDD-treated infected mice, whereas increased
IFNs as a result of infection alone could be detected in only one individual. These results suggest that the
normal host responses during acute infections down-regulate detoxifying processes in favour of acute-
phase protein synthesis. This may explain the observed changed pattern of accumulation, excretion and
toxicity of the environmental pollutants cadmium and TCDD during this common virus infection.
Virus Induced Metallothionein Synthesis
Mol Cell Biol. 2001 Dec;21(24):8301-17
Influenza virus infection induces metallothionein gene expression in the
mouse liver and lung by overlapping but distinct molecular mechanisms.
Ghoshal K, Majumder S, Zhu Q, Hunzeker J, Datta J, Shah M, Sheridan JF, Jacob ST.
Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, 333 Hamilton Hall, 1645
Neil Ave., Columbus, OH 43210, USA.
Metallothionein I (MT-I) and MT-II have been implicated in the protection of cells against reactive oxygen
species (ROS), heavy metals, and a variety of pathological and environmental stressors. Here, we show a
robust increase in MT-I/MT-II mRNA level and MT proteins in the livers and lungs of C57BL/6 mice exposed
to the influenza A/PR8 virus that infects the upper respiratory tract and lungs. Interleukin-6 (IL-6) had a
pronounced effect on the induction of these genes in the liver but not the lung. Treatment of the animals with
RU-486, a glucocorticoid receptor antagonist, inhibited induction of MT-I/MT-II in both liver and lung,
revealing a direct role of glucocorticoid that is increased upon infection in this induction process. In vivo
genomic footprinting (IVGF) analysis demonstrated involvement of almost all metal response elements,
major late transcription factor/antioxidant response element (MLTF/ARE), the STAT3 binding site on the MT-
I upstream promoter, and the glucocorticoid responsive element (GRE1), located upstream of the MT-II
gene, in the induction process in the liver and lung. In the lung, inducible footprinting was also identified at a
unique gamma interferon (IFN-gamma) response element (gamma-IRE) and at Sp1 sites. The mobility shift
analysis showed activation of STAT3 and the glucocorticoid receptor in the liver and lung nuclear extracts,
which was consistent with the IVGF data. Analysis of the newly synthesized mRNA for cytokines in the
infected lung by real-time PCR showed a robust increase in the levels of IL-10 and IFN-gamma mRNA that
can activate STAT3 and STAT1, respectively. A STAT1-containing complex that binds to the gamma-IRE in
vitro was activated in the infected lung. No major change in MLTF/ARE DNA binding activity in the liver and
lung occurred after infection. These results have demonstrated that MT-I and MT-II can be induced robustly
in the liver and lung following experimental influenza virus infection by overlapping but distinct molecular
mechanisms.
Virus Induced Metallothionein Synthesis
Influenza virus, the causative agent of the common flu, is a worldwide health problem with significant
economic consequences. Studies of influenza virus biology have revealed elaborate mechanisms by which
the virus interacts with its host cell as it inhibits the synthesis of cellular proteins, evades the innate antiviral
response, and facilitates production of viral RNAs and proteins. With the advent of DNA array technology it
is now possible to obtain a large-scale view of how viruses alter the environment within the host cell. In this
study, the cellular response to influenza virus infection was examined by monitoring the steady-state mRNA
levels for over 4,600 cellular genes. Infections with active and inactivated influenza viruses identified
changes in cellular gene expression that were dependent on or independent of viral replication, respectively.
Viral replication resulted in the downregulation of many cellular mRNAs, and the effect was enhanced with
time postinfection. Interestingly, several genes involved in protein synthesis, transcriptional regulation, and
cytokine signaling were induced by influenza virus replication, suggesting that some may play essential or
accessory roles in the viral life cycle or the host cell's stress response. The gene expression pattern induced
by inactivated viruses revealed induction of the cellular metallothionein genes that may represent a
protective response to virus-induced oxidative stress. Genome-scale analyses of virus infections will help us
to understand the complexities of virus-host interactions and may lead to the discovery of novel drug targets
or antiviral therapies.
Virus Induced Metallothionein Synthesis
Department of Microbiology and Immunology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555-
0133, USA.
Data suggesting that the hepatitis C virus (HCV) core protein influences normal cellular processes remain
controversial. To determine the effects of core on cellular gene expression in hepatocytes, we developed
a human hepatoma (Huh7)-derived cell line with tightly regulated core expression under the control of a
tetracycline-regulated promoter. Cells expressing core did not have impaired proliferative abilities.
Changes in gene expression profiles in response to core expression were determined using commercial
oligonucleotide microarrays (Affymetrix GeneChip). Significant increases were observed in the
abundance of mRNA-encoding members of the metallothionein (MT) family, as well as nicotinamide N-
methyltransferase (NNMT) and glutathione peroxidase-like protein (GPLP). These changes did not result
from removal of tetracycline from growth media, and were confirmed in reverse-transcription polymerase
chain reaction (RT-PCR) assays. They suggest that core protein expression leads to intracellular
oxidative stress, and that vital cellular functions are, in turn, protected by up-regulation of cellular
antioxidant defense mechanisms. In conclusion, these findings can explain many potentially conflicting
prior observations concerning the effects of core on cellular physiology, and are of relevance to the role of
core protein in the pathogenesis of HCV-related fibrosis and hepatocellular carcinoma.
Measles Mumps
Rubella
Nutrigenomics
Support methylation cycle mutations
Metals 1,2,3
Nutrigenomics
Support methylation cycle mutations
Nutrigenomics
Support methylation cycle mutations
glutathione/taurine
http://heartfixer.com/AMRI-Nutrigenomics.htm
James C. Roberts MD FACC
CBS
So, we can look at
the levels of
taurine and
glutathione as a
way to assess
methylation cycle
balance
Treatment Study of Methylation Cycle Support in
Patients with Chronic Fatigue Syndrome and
Fibromyalgia
by
Neil Nathan, M.D.
and
Richard A. Van Konynenburg, Ph.D
0 3 6
global methylation
assay
Principle & Procedure
The Methylamp™ Global DNA Methylation
Quantification Kit contains all reagents required
for quantification of global DNA methylation. In
this assay, DNA is immobilized to the strip well
specifically treated to have high affinity to the
DNA. The methylated fraction of DNA can be
recognized by 5-methylcytosine antibody and
quantified through an ELISA-like reaction. The
amount of methylated DNA is proportional to
the OD intensity.
SCHEMATIC PROCEDURE:
Now, where we get into the catch 22...the editing function relies on
methylation. The way that the editing works is to add methyl groups to the
DNA to turn on and off certain areas. SO...while mutations in other areas
would be less of an issue, the mutations that we look at, in the methylation
cycle are of such central importance as they affect the actual DNA
sequence, as well as the editing function. While the actual mutations will not
change with methylation cycle support, the editing function should be able to
change over time.
1 2
6/02
10/04
MUMPS Virus
5/06
5/07
How do we evaluate
progress?
•Methylation cycle progress
glutathione/taurine
global methylation assay
•Viral titers
•Metal excretion
Metal
excretion
http://micro.magnet.fsu.edu/micro/gallery.html
Molecular Expressions
Photo Gallery contains
thousands of full color
photomicrographs
(photographs taken through
a microscope).
The Nucleotide Collection: Adenosine Triphosphate
The Nucleotide Collection: Cytidine
The Nucleotide Collection: Guanosine
The Nucleotide Collection: Thymidine
The Nucleotide Collection: Uridine
Acetylcholine
Epinephrine
Norepinephrine
Serotonin
Dopamine