Hwa, Shi-Hsia;
(2021)
Inhibition of respiratory pathogens Mycobacterium tuberculosis and SARS-CoV-2 by human serum and monoclonal antibodies.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Antibodies are a key host immune response against pathogens. Yet the effects of antibodies on Mycobacterium tuberculosis (Mtb) at the cellular level are incompletely understood, as is the effect of HIV co-infection on antibody-mediated immunity to SARS-CoV-2. By investigating these questions at the epicenter of the HIV/TB co-epidemic in KwaZulu-Natal, South Africa, I have: 1) Cloned immunoglobulins from B cells of Mtb-exposed donors and investigated the effect of Mtb-specific polyclonal and monoclonal antibodies on infection of macrophages; 2) Characterised antibody responses in viraemic, virologically suppressed, and HIV-negative Covid-19 patients to determine whether HIV status and viraemia influence neutralization of SARS-CoV-2. Sera from TB-exposed individuals on average increased host cell survival and inhibited intracellular bacterial growth compared to non-specific control serum, although there was a wide range of individual variation. I cloned several Mtb-specific antibodies from South African donors including one which significantly inhibited intracellular bacterial growth in THP-1 monocytes and primary macrophages. I developed a live virus neutralisation assay for SARS-CoV-2 to circumvent the problem of a lentiviral pseudovirus neutralization assay being incompatible with samples containing antiretrovirals for HIV. Among Covid-19 patients, the kinetics of RBD-binding and neutralising antibodies differed little between HIV-uninfected and virologically suppressed people living with HIV (PLWH), whereas viraemic PLWH had a much lower and delayed response. In addition, I observed that plasma from individuals either previously infected with earlier variants of SARS-CoV-2 or vaccinated with AstraZeneca’s AZD1222 recombinant adenovirus vaccine showed decreases in neutralisation against newer variants of concern. Taken together, these results demonstrate that antibody-mediated immunity is relevant to the control of TB but is highly heterogeneous. Similarly, there is individual heterogeneity in the neutralisation response to SARS-CoV-2, with the latter partially determined by HIV status and suppression state.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Inhibition of respiratory pathogens Mycobacterium tuberculosis and SARS-CoV-2 by human serum and monoclonal antibodies |
| Event: | UCL |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| Keywords: | tuberculosis, covid-19, antibodies, immunology, mycobacteria, coronavirus |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10139827 |
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