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Neutrophils as effector cells in resistance to infection by mycobacterium tuberculosis in HIV-infected individuals
Thesis (PhD)--Stellenbosch University, 2022.
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| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2022
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| _version_ | 1867613984046186496 |
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| access_status_str | Open Access |
| author | Kroon, Elouise Elizabeth |
| author2 | Hoal, Eileen |
| author_browse | Hoal, Eileen Kroon, Elouise Elizabeth |
| author_facet | Hoal, Eileen Kroon, Elouise Elizabeth |
| author_sort | Kroon, Elouise Elizabeth |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2022. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/125166 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:44:49.127Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2022 |
| publishDateRange | 2022 |
| publishDateSort | 2022 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/125166 Neutrophils as effector cells in resistance to infection by mycobacterium tuberculosis in HIV-infected individuals Kroon, Elouise Elizabeth Hoal, Eileen Moller, Marlo Tromp, Gerard Schurr, Erwin Wilkinson, Robert J. Coussens, Anna Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics. Mycobacterium tuberculosis -- Epidemiology Neutrophils -- Immunology HIV-positive persons UCTD Thesis (PhD)--Stellenbosch University, 2022. ENGLISH ABSTRACT: Epidemiological studies have highlighted persons who, despite exposure to Mycobacterium tuberculosis (Mtb), the causative organism of tuberculosis (TB), do not show immune conversion to tests used to infer Mtb infection. Current immunological tests used to infer latent Mtb infection, the tuberculin skin test (TST) and interferon gamma release assay (IGRA) do not capture the full spectrum of T-cell responses to Mtb. Persons defined as Mtb infection resisters show Mtb specific antibodies and interferon gamma (IFN-γ)-independent T-cell responses. This has highlighted a range of responses to Mtb, with an interplay between innate and adaptive immune cells in host resistance to TB. The study of host resistance to TB within the context of persons living with HIV (HIV+), was until recently still limited. HIV+ persons have an increased risk for TB. Identifying persons who despite previously low CD4+ counts and prolonged and persistent TB exposure, do not develop TB, pointed to remarkable underlying host protection mechanisms. In this thesis we classified and identified 48/286 (17%) HIV+ persons, aged 35-60 years old, who prior to ART initiation had low CD4+ counts, are now immune reconstituted on ART, and despite prolonged and persistent exposure to TB, remained consistently TST and IGRA negative over an average period of 206±154 days. Age was used as a proxy for prolonged exposure and exposure intensity was reflected by the persons living in Cape Town, South Africa, a high TB prevalence environment. None of these persons have a history of current or previous TB. This phenotype has been defined as HIV-1-positive persistently TB, tuberculin and IGRA negative (HITTIN). In addition, we identified a group of persons, following similar criteria, but with repeated TST and IGRA positive results. This group was defined as HIV-1-positive IGRA positive tuberculin positive (HIT). Next, we investigated the role of the innate immune system in host resistance to Mtb by examining the role of neutrophils. Neutrophils are among the first innate cells to make contact with Mtb after infection. The dichotomous role of neutrophils in TB is well researched, with disease severity in some linked to neutrophil driven type 1 IFN responses. Neutrophils in mice exert their beneficial role early in the infection process though controlled apoptosis. Here the role of human neutrophils in host resistance to Mtb was explored by comparing neutrophil gene responses to Mtb infection between HITTIN and HIT. Neutrophils from HITTIN (PMNHITTIN) had 1068 more upregulated and 1217 more downregulated genes compared to neutrophils from HIT (PMNHIT), after 6 hours of infection with Mtb. Key pathways and genes controlling cell death and inflammation were highlighted. This research highlights a unique phenotype of neutrophils showing an altered gene expression profile, with key mechanisms of innate host resistance to TB which require further investigation. This can contribute to identifying novel TB prevention and treatment strategies. AFRIKAANSE OPSOMMING: Epidemiologiese studies het mense uitgelig wat ten spyte van blootstelling aan Mycobacterium tuberculosis (Mtb), die organisme wat tuberkulose (TB) veroorsaak, geen immuniteitomkering wys in die toetse wat gebruik word om Mtb infeksie af te lei nie. Die immunologiese toetse wat tans gebruik word om latente Mtb infeksie af te lei, naamlik die tuberkulien vel toets (TST) en interferon gamma-vrystellingstoets (IGRA), kan nie die volle spektrum van T-selreaksies vasvang nie. Persone gedefinieer as Mtb-infeksie weerstandig het Mtb spesifieke teenliggaampies en interferon-gamma (IFN-γ)-onafhanklike T-sel reaksies. Hierdie fenotipe beklemtoon die wye reeks van reaksies teen Mtb, asook die samespel tussen aangebore en aanpasbare immuunrespons van selle in mense wat weerstandig is teen TB. Navorsing in gasheerweerstandigheid teen TB in mense wat met MIV leef (MIV+) was tot onlangs toe nog beperk. MIV+ persone het ‘n verhoogde risiko vir TB. Persone met ‘n geskiedenis van baie lae CD4+ tellings en wat ten spyte van aanhoudende en gedurende blootstelling aan TB, nie TB ontwikkel nie, verwys na unieke onderliggende gasheerweerstandigheid meganismes. In hierdie tesis het ons 48/286 (17%) MIV+ persone geïdentifiseer en geklassifiseer wat tussen die ouderdom van 35-60 jaar oud was, met vorige lae CD4+ tellings voordat hulle op antiretrovirale terapie (ART) geplaas is en hulle immuniteit herstel het, en wat ten spyte van aanhoudende en gedurende blootstelling aan TB, herhaaldelik TST en IGRA negatief toets oor ‘n tydperk van 206±154 dae. Ouderdom verteenwoordig voortdurende blootstelling en die intensiteit van blootstelling was weerspieël deur die feit dat deelnemers afkomstig is van ʼn area met ʼn hoë TB voorkomsyfer, Kaapstad, Suid-Afrika. Nie een van die persone het huidige of vorige TB gehad nie. Hierdie fenotipe staan bekend as MIV+, aanhoudelik TB, tuberkulien en IGRA negatief (HITTIN). Daarteenoor het ons mense met herhaaldelike TST en IGRA positiewe resultate geklassifiseer as MIV+, IGRA en tuberkulien positief (HIT). Volgende het ons die rol van die aangebore immuunsisteem bestudeer deur die rol van neutrofiele in die konteks van gasheerweerstandigheid teen Mtb te ondersoek. Neutrofiele is een van die eerste selle in die aangebore immuunsisteem wat kontak maak met Mtb na infeksie. Die tweeledige rol van TB is al goed nagevors, met erns van siekte in sommige mense wat gekoppel word aan neutrofiel gedrewe tipe 1 IFN reaksies. Neutrofiele van muise wys ‘n beskermende rol vroeg in die infeksie proses deur gekontroleerde apoptose. Hier het ons die rol van menslike neutrofiele in gasweerstandigheid teen Mtb bestudeer deur die neutrofiel geen reaksie met Mtb infeksie te vergelyk in HITTIN en HIT. Neutrofiele van HITTIN (PMNHITTIN) het 1068 op- en 1217 afgereguleerde gene teenoor neutrofiele van HIT (PMNHIT), na 6 ure van infeksie met Mtb gewys. Belangrike biologiese bane en gene wat seldood en inflammasie beheer was uitgelig. Hierdie navorsing sit die klem op neutrofiele met ‘n unieke fenotipe en veranderde geen-uitdrukkingsprofiel wat gekoppel is aan belangrike meganismes van aangebore gasheerweerstandigheid teen TB. Verdere navorsing kan bydra tot die ontdekking van nuwe TB beskerming en behandelingstrategieë. Doctorate 2022-01-18T09:07:10Z 2022-04-29T12:56:56Z 2023-01-24T03:00:11Z 2022-03 Thesis http://hdl.handle.net/10019.1/125166 en_ZA Stellenbosch University v, 157 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Mycobacterium tuberculosis -- Epidemiology Neutrophils -- Immunology HIV-positive persons UCTD Kroon, Elouise Elizabeth Neutrophils as effector cells in resistance to infection by mycobacterium tuberculosis in HIV-infected individuals |
| title | Neutrophils as effector cells in resistance to infection by mycobacterium tuberculosis in HIV-infected individuals |
| title_full | Neutrophils as effector cells in resistance to infection by mycobacterium tuberculosis in HIV-infected individuals |
| title_fullStr | Neutrophils as effector cells in resistance to infection by mycobacterium tuberculosis in HIV-infected individuals |
| title_full_unstemmed | Neutrophils as effector cells in resistance to infection by mycobacterium tuberculosis in HIV-infected individuals |
| title_short | Neutrophils as effector cells in resistance to infection by mycobacterium tuberculosis in HIV-infected individuals |
| title_sort | neutrophils as effector cells in resistance to infection by mycobacterium tuberculosis in hiv infected individuals |
| topic | Mycobacterium tuberculosis -- Epidemiology Neutrophils -- Immunology HIV-positive persons UCTD |
| url | http://hdl.handle.net/10019.1/125166 |
| work_keys_str_mv | AT kroonelouiseelizabeth neutrophilsaseffectorcellsinresistancetoinfectionbymycobacteriumtuberculosisinhivinfectedindividuals |