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Nyazika, Tinashe (2020) Cellular immune responses against Streptococcus pneumoniae in the human lung, Thesis (Doctoral), Liverpool School of Tropical Medicine.
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Tinashe K. Nyazika full PhD Thesis final.pdf - Accepted Version Download (56MB) | Preview |
Abstract
Background
Streptococcus pneumoniae is the leading cause of community-acquired pneumonia in all ages, with the greatest incidence occurring in children, the elderly and HIV-infected individuals. HIV-infected adults are at least 25-fold at risk of bacterial pneumonia compared to age-matched HIV-uninfected individuals, but the immunological mechanisms for this risk are still unclear. Alveolar macrophages (AMs) are the major sentinel phagocytic population found in the airway responsible for the early clearance and control of respiratory pathogens. I hypothesise that HIV infection is associated with impaired airway alveolar phagocyte killing function, leading to survival and propagation of pneumococci.
Methods
Three groups of participants aged between 18 to 60 years were recruited, consisting of asymptomatic HIV-uninfected adults, HIV-infected adults on shortterm or long-term antiretroviral therapy (ART) residing in Blantyre, Malawi. Lower airway samples (bronchoalveolar lavage fluid) were collected from the participants and used to investigate airway mediated defence immunity against S. pneumoniae in an ex vivo model. The airway cells were infected with pneumococci (serotype 3 strain) and the number of alveolar phagocytes associated with bacteria were measured and phenotyped using flow cytometry. Intracellular and extracellular bacterial killing was measured using quantitative culture in a gentamicin protection assay (GPA) and bacterial outgrowth assay, respectively. Confocal microscopy was used to visualise pneumococci within AMs following infection.
Results
Alveolar macrophages were the principal phagocytic cells associated with IgGopsonised pneumococcal-ST3 following ex vivo infection, irrespective of HIV status. AM from HIV-infected adults did not exhibit impaired binding and internalisation of IgG-opsonised pneumococcal-ST3, irrespective of ART duration. Furthermore, airway cell-mediated control of extracellular S. pneumoniae outgrowth during early infection was also not impaired in HIV-infected adults on ART. However, HIV-infected adults on ART demonstrated reduced AMs-mediated intracellular killing capacity of S. pneumoniae during the late killing phase (24-hours post infection) with pneumococci persisting in CD206+AMs. The presence of extracellular S. pneumoniae 24-hours post infection in a bacterial outgrowth assay was propagated by intracellular bacterial persistence.
Conclusion
In summary, the data from this thesis demonstrates that AMs from HIV-infected adults on ART have impaired late bacterial killing capacity, leading to intracellular bacterial persistence and propagation of extracellular pneumococcal outgrowth. Persistence of the pneumococci within CD206+AMs could serve as a reservoir for pneumococcal infection in the lung, potentially contributing to increased susceptibility to pneumococcal pneumonia in HIV-infected individuals.
| Item Type: | Thesis (Doctoral) |
|---|---|
| Subjects: | QW Microbiology and Immunology > Reference Works. General Immunology > QW 520 Research (General) WC Communicable Diseases > Infection. Bacterial Infections > Bacterial Infections > WC 210 Streptococcal infections (General or not elsewhere classified) WF Respiratory System > Lungs > WF 600 Lungs |
| Faculty: Department: | Clinical Sciences & International Health > Clinical Sciences Department |
| Depositing User: | Lynn Roberts-Maloney |
| Date Deposited: | 16 Dec 2020 12:04 |
| Last Modified: | 28 Jul 2022 15:54 |
| URI: | https://archive.lstmed.ac.uk/id/eprint/16428 |
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