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Analysis of the effect of Mycobacterium tuberculosis (M.tb) on HIV infection in the presence of iron overload

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dc.contributor.advisor Dr. D. Meyer and Prof. L. Bornman en_US
dc.contributor.author Traoré, Hafsatou Ndama
dc.date.accessioned 2012-09-05T12:13:37Z
dc.date.available 2012-09-05T12:13:37Z
dc.date.issued 2012-09-05
dc.date.submitted 2004
dc.identifier.uri http://hdl.handle.net/10210/7028
dc.description Ph.D. en_US
dc.description.abstract Background: AIDS is characterized by a number of opportunistic infections and the immune depletion caused by HIV infection is the strongest risk factor for both reactivation of tuberculosis (TB) and progression of Mycobacterium tuberculosis (Mtb) infection to disease. Numerous studies have shown that concurrent infection of the same host cell by HIV,and M.tb stimulates replication of both pathogens. The interaction between the two is lethal. A synergistic relationship exists between Mtb and HIV. While HIV spurs the spread of TB, mycobacterial infection results in acceleration of HIV disease progression. The requirement for iron as a crucial factor for cellular processes has long been demonstrated. Excess iron leads to infections with harmful consequences such as cell death and function impairment. During infection, iron is required by both the host cell and the pathogens. Iron chelation is believed to modulate some of these effects. Objectives: Mtb, HIV and Fe-overload are common in sub-Saharan Africa and iron plays a major role in determining the outcome of several infections. In view of this, we wanted to (1) investigate the effect of excess iron on host cell defences during co-infection with the mentioned microorganisms, (2) evaluate the differences in both host and pathogen responses during acute and chronic infection in the presence of iron overload and (3) Determine the efficacy of iron chelation (with DFO) as a means of counteracting conditions associated with iron overload. Hypotheses: The combination of Fe-overload and co-infection of host cells with HIV and Mtb in an in vitro model should stimulate replication of the pathogens, which would ultimately result in host cell stress manifesting as lower viability or cell death and impaired immune defence functions. Also the detrimental effects of excess iron on host cell viability could be counteracted through the use of iron chelators. Methods: We analyzed the in vitro effect of Mtb in bothchronically and acutely HI V-infected cells (PBMC's and monocytes), exposed to 500 uM FeSO 4 and/or DFO for 4 days. Host cell viability, survival and death were assessed through viability assays (MIT and Alamar Blue) and flow cytometric analyses of apoptosis/necrosis (using Annexin V and propidium iodide). Secretion of IL- 6 and TNF-a and production of total nitrate were monitored as host immune/defence responses using specialized ELISAs. HIV replication was investigated by looking at core protein (p24) contents and reverse transcriptase (RT) activity. Mtb replication and growth was monitored using the microplate Alamar Blue assay (MABA) and quantitative culturing.Results: Co-infection caused a reduction of host cell viability (± 20% and 45% inhibition during chronic and acute infection respectively;, as measured by MTT), increases in the numbers of viral particles (2.3 times and 20% increases for chronic and acute infections respectively) and stimulation of both bacterial viability (36%) and host defence responses (30% increase in TNF-ct secretion). Excess iron further decreased viability with a marked increase in necrosis of cells and was found to enhance pathogen replication and growth (26% for HIV and 47% for Mtb). Chelation of iron with DFO abrogated the enhanced replication of the pathogens with a marginal restoration of host viability. Conclusion: The results obtained demonstrate the deleterious effect of excess iron during concurrent infection with both pathogens as well as its stimulating/enhancing properties on pathogens. On the other hand, DFO inhibited pathogen replication and host viability. en_US
dc.language.iso en en_US
dc.subject Mycobacterium tuberculosis en_US
dc.subject HIV infections en_US
dc.subject Iron en_US
dc.subject Immune response en_US
dc.title Analysis of the effect of Mycobacterium tuberculosis (M.tb) on HIV infection in the presence of iron overload en_US
dc.type Thesis en_US


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