Iron and Tuberculosis pathogenesis

Cowie, Danielle (2014-04)

Thesis (MSc)--Stellenbosch University, 2014.

Thesis

ENGLISH ABSTRACT: Iron is an essential element that plays a role in the process of respiration, oxygen transport and as a principle cofactor to several enzymes. Iron homeostasis is a finely regulated process since excess levels become toxic to healthy cells via the production of reactive oxygen species. A plethora of genes that control several key points throughout this regulatory process have been identified. Research focusing on changes in expression levels and downstream functional effects of these genes has become increasingly important over the past decade. One area of particular interest has emerged since a link between iron status and host response to Mycobacterium tuberculosis infection was discovered. Although the prevalence of Tuberculosis has decreased across the globe with the exception of Africa and parts of Europe, the mortality rate remains high. Therefore, research that focuses on understanding an individual’s predetermined susceptibility to TB infection at the genetic level could provide health care practitioners with the tools required to identify and educate at-risk individuals prior to TB infection. RT-qPCR was utilised to determine expression profiles for eight iron genes (CP, CYBRD1, FTH, FTL, LTF, HFE, HMOX1, and SCL40A1) normalised to three reference genes (ACTB, GUSB, and RPL37A1). Up-regulation is demonstrated in the TB group for transcript levels recorded for CYBRD1, HFE, HMOX1, and SLC40A1. Several measured serum parameters including conjugated, unconjugated, total bilirubin, and total protein were increased in the TB group while albumin was significantly lower in this group. Correlation analysis demonstrated that a positive correlation exists between transferrin saturation and iron and a negative correlation exists between transferrin and ferritin levels. Individuals categorised with low serum iron levels demonstrated lower CP/GUSB levels and higher HMOX1/GUSB levels. Individuals categorised with low transferrin saturation levels demonstrated higher FTL/GUSB and SLC40A1/GUSB levels and lower CP/GUSB. Results from this study provide further evidence for the relationship between iron status and TB infection rates, although protein studies are required to confirm these results. The data obtained illustrate the important role that these profiles and iron parameters may play in the clinical field when identifying at-risk individuals. Further investigation that focuses on which gene profile and parameter combinations show the most distinctive utility in the clinical setting is warranted.

AFRIKAANSE OPSOMMING: Yster is ‘n noodsaaklike element wat ‘n rol speel in die proses van respirasie en die vervoer van suurstof en ook ‘n belangrike ko-faktor vir verskeie ensieme is. Yster homeostase is op ‘n fyn manier gereguleer omdat oormatige vlakke toksies kan wees vir gesonde selle wanneer reaktiewe suurstofspesies geproduseer word. ‘n Magdom gene wat verskeie sleutelpunte in hierdie proses kontroleer is voorheen identifiseer. Navorsing wat fokus op die veranderinge in geenuitdrukkingsvlakke en die funksionele gevolge daarvan het oor die afgelope dekade toenemend belangrik geword. Een gebied van spesifieke belang het na vore gekom nadat ‘n verband tussen ystervlakke en die manier waarop die immuunstelsel reageer op Mycobacterium tuberculosis infeksie, ontdek is. Alhoewel die voorkoms van Tuberkulose wêreldwyd, behalwe in Afrika en sekere dele van Europa, afgeneem het, bly die sterftesyfer hoog. Daarom kan navorsing wat daarop fokus om ‘n individu se voorafbepaalde vatbaarheid vir TB-infeksie op die genetiese vlak te verstaan dalk aan gesondheidswerkers die regte instrumente verskaf om hoë-risiko individue te identifiseer en op te voed voordat hulle TB ontwikkel. RT-qPKR is gebruik om die geenuitdrukkingsvlakke van agt ystergene, wat met drie verwysings-gene (ACTB, GUSB, en RPL37A1) genormaliseer is, te bepaal. ‘n Toename in die uitdrukkingsvlakke van CYBRD1, HFE, HMOX1, en SLC40A1 is in die TB-groep waargeneem. Die bloedvlakke van verskeie parameters insluitend gekonjugeerde, ongekonjugeerde, totale bilirubin, en totale proteïen was hoër in die TB-groep, terwyl albuminvlakke laer was in hierdie groep. Korrelasie-analise het ‘n positiewe korrelasie tussen transferrin-versadiging en yster getoon, terwyl daar ‘n negatiewe korrelasie tussen transferrin- en ferritinvlakke gevind is. Individue met lae ystervlakke het laer CP/GUSB-vlakke en hoër HMOX1/GUSB-vlakke getoon. Individue met lae transferrin-versadiging het hoër FTL/GUSB- en SLC40A1/GUSB-vlakke en laer CP/GUSB-vlakke getoon. Resultate uit hierdie studie verskaf verdere getuienis dat daar ‘n verwantskap tussen ystervlakke en TB-infeksiekoerse bestaan, alhoewel proteïenstudies nodig is om hierdie resultate te bevestig. Die data dui op die belangrike rol wat hierdie profiele en ystervlakke in die kliniese veld mag speel in die identifisering van hoë-risiko individue. Verdere ondersoek, gefokus op watter geenprofiel en parameterkombinasies die grootste nut in die kliniese omgewing bied, is geregverdig.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/86566
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