74 research outputs found
An Observational Cohort Study of the Kynurenine to Tryptophan Ratio in Sepsis: Association with Impaired Immune and Microvascular Function
Both endothelial and immune dysfunction contribute to the high mortality rate in human sepsis, but the underlying mechanisms are unclear. In response to infection, interferon-Ξ³ activates indoleamine 2,3-dioxygenase (IDO) which metabolizes the essential amino acid tryptophan to the toxic metabolite kynurenine. IDO can be expressed in endothelial cells, hepatocytes and mononuclear leukocytes, all of which contribute to sepsis pathophysiology. Increased IDO activity (measured by the kynurenine to tryptophan [KT] ratio in plasma) causes T-cell apoptosis, vasodilation and nitric oxide synthase inhibition. We hypothesized that IDO activity in sepsis would be related to plasma interferon-Ξ³, interleukin-10, T cell lymphopenia and impairment of microvascular reactivity, a measure of endothelial nitric oxide bioavailability. In an observational cohort study of 80 sepsis patients (50 severe and 30 non-severe) and 40 hospital controls, we determined the relationship between IDO activity (plasma KT ratio) and selected plasma cytokines, sepsis severity, nitric oxide-dependent microvascular reactivity and lymphocyte subsets in sepsis. Plasma amino acids were measured by high performance liquid chromatography and microvascular reactivity by peripheral arterial tonometry. The plasma KT ratio was increased in sepsis (median 141 [IQR 64β235]) compared to controls (36 [28β52]); p<0.0001), and correlated with plasma interferon-Ξ³ and interleukin-10, and inversely with total lymphocyte count, CD8+ and CD4+ T-lymphocytes, systolic blood pressure and microvascular reactivity. In response to treatment of severe sepsis, the median KT ratio decreased from 162 [IQR 100β286] on day 0 to 89 [65β139] by day 7; pβ=β0.0006) and this decrease in KT ratio correlated with a decrease in the Sequential Organ Failure Assessment score (p<0.0001). IDO-mediated tryptophan catabolism is associated with dysregulated immune responses and impaired microvascular reactivity in sepsis and may link these two fundamental processes in sepsis pathophysiology
The kynurenine pathway activities in a sub-Saharan HIV/AIDS population
BACKGROUND : Tryptophan is an essential amino acid for the synthesis of proteins and important metabolites such as
serotonin, melatonin, tryptamine and niacin. After protein synthesis, more than 90 % of tryptophan catabolism
occurs along the kynurenine pathway. The inflammation-inducible enzyme indoleamine 2,3 dioxygenase (IDO) is
responsible for the first rate-limiting step in the kynurenine pathway, i.e., oxidation of tryptophan to kynurenine.
Excessive IDO activity in conditions such as HIV/AIDS may lead to tryptophan depletion and accumulation of
metabolites downstream from kynurenine. Little is known about the kynurenine pathway of HIV/AIDS patients in
sub-Saharan regions. This study, in a low income sub-Saharan HIV/AIDS population, examined the effects of
activities in the kynurenine pathway on plasma levels of tryptophan, kynurenine and the neurotoxin quinolinic acid,
and on de novo synthesis of nicotinamide.
METHODS : Plasma samples were obtained from a cohort of 105 HIV patients and 60 controls. Kynurenine pathway
metabolites were analysed using gas chromatography β mass spectrometry. ELISA and flow cytometry were used
to assess plasma inflammatory markers.
RESULTS : IDO activity, depletion of tryptophan, as well as accumulation of kynurenine and the neurotoxin quinolinic
acid, were not only significantly greater in the patients than in the controls, but also markedly greater than in
HIV/AIDS patients from developed countries. Tryptophan levels were 12.3 % higher, kynurenine levels 16.2 % lower,
quinolinic acid levels 43.2 % lower and nicotinamide levels 27,2 % lower in patients on antiretroviral treatment than
in antiretroviral-naΓ―ve patients. Patientsβ kynurenine pathway metabolites correlated with the levels of inflammatory
markers, including that of the major IDO-inducer, interferon-gamma. Indications are that the rate of de novo
synthesis of nicotinamide in the kynurenine pathway correlates with increases in quinolinic acid levels up to a point
where saturation of the enzyme quinolinate phosphoribosyl transferase occurs.
CONCLUSIONS : Higher levels of inflammatory activity in this low income sub-Saharan HIV/AIDS population than in
patients from developed countries lead to greater tryptophan depletion and greater accumulation of metabolites
downstream from tryptophan with quinolinic acid levels often reaching levels associated with the development of
HIV/AIDS-associated neurocognitive dysfunction. De novo synthesis of nicotinamide from quinolinic acid contributes
to the maintenance of nicotinamide, and by implication NAD levels, in HIV/AIDS patients from low income
populations. Antiretroviral treatment partially corrects disturbances in the kynurenine pathway.Medical Research Council of South Africa and the South African Sugar Association (SASA Project 213).http://www.biomedcentral.com/bmcinfectdis/hb201
Influenza vaccination for immunocompromised patients: systematic review and meta-analysis from a public health policy perspective.
Immunocompromised patients are vulnerable to severe or complicated influenza infection. Vaccination is widely recommended for this group. This systematic review and meta-analysis assesses influenza vaccination for immunocompromised patients in terms of preventing influenza-like illness and laboratory confirmed influenza, serological response and adverse events
Tryptophan depletion in context of the inflammatory and general nutritional status of a low-income South African HIV-infected population
MV was the project leader. PB developed and validated the GC-MS method for
the analysis of tryptophan and performed the biochemical and immunological
analyses. MV and PB were responsible for the project design, analyses of the
results and writing of the manuscript. PL was involved in the sourcing of
patients and the clinical examination of all patients.The authors wish to thank the participants and staff of the Immunology
Clinic at Kalafong Hospital and the South African National Blood Service at
the Pretoria West satellite site.BACKGROUND : The essential amino acid tryptophan cannot be synthesised in the body and must be acquired
through dietary intake. Oxidation of tryptophan, due to immune induction of the enzyme indoleamine 2,3-
dioxygenase (IDO), is considered to be the main cause of tryptophan depletion in HIV infection and AIDS.
We examined plasma tryptophan levels in a low-income sub-Saharan HIV-infected population and compared it to
that of developed countries. Tryptophan levels were further examined in context of the general nutritional and
inflammatory status.
METHODS : This cross-sectional study included 105 HIV-positive patients recruited from the Kalafong Hospital in
Pretoria, South Africa, and 60 HIV-negative controls.
RESULTS : Patient tryptophan levels were in general markedly lower than those reported for developed countries. In
contrast to reports from developed countries that showed tryptophan levels on average to be 18.8 % lower than
their control values, tryptophan levels in our study were 44.1 % lower than our controls (24.4 Β± 4.1 vs. 43.6 Β±
11.9 ΞΌmol/l; p < 0.001). Tryptophan levels correlated with both CD4 counts (r = 0.341; p = 0.004) and with proinflammatory
activity as indicated by neopterin levels (r = β0.399; p = 0.0001). Nutritional indicators such as albumin
and haemoglobin correlated positively with tryptophan and negatively with the pro-inflammatory indicators
neopterin, interleukin 6 and C-reactive protein. The most probable causes of the lower tryptophan levels seen in
our population are food insecurity and higher levels of inflammatory activity.
CONCLUSIONS : We contend that inflammation-induced tryptophan depletion forms part of a much wider effect of
pro-inflammatory activity on the nutritional profile of HIV-infected patients.This research was supported by grant funding
received from the Medical Research Council of South Africa and the South
African Sugar Association (SASA Project 213).http://www.jhpn.net/index.php/jhpnam2016Internal MedicinePhysiologyPsychiatr
Current topics in HIV-1 pathogenesis: The emergence of deregulated immuno-metabolism in HIV-infected subjects
Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection
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