MRes Infectious & Tropical Diseases - Immunity and Immune Modulation

ID	Title	Overview
IM1	Rural–urban residence and parasitic infections in yellow fever vaccine waning in Ugandan adolescents. (Uganda)	Yellow fever vaccination is recommended as a single lifetime dose; however, emerging evidence suggests that vaccine-induced immunity may wane more rapidly in some settings. Chronic exposure to malaria may modulate immune function and influence the durability of vaccine responses. This study will investigate the long-term persistence of yellow fever vaccine–induced neutralising antibody responses among Ugandan adolescents, comparing participants from rural and urban settings. Participants previously enrolled in these trials will be traced for follow-up. Archived and newly collected samples will be analysed to characterise antibody trajectories over time. Neutralising antibody titres, measured by plaque reduction neutralisation tests (PRNT), will serve as the primary outcome, with ELISA-measured IgG as the secondary outcome. We hypothesise that adolescents in rural settings with higher parasitic exposure will exhibit faster waning of vaccine-induced antibody responses.
IM2	Multi-pathogen sero-surveillance in a Ugandan cohort. (London)	Most research is focused on single pathogens, yet individuals are exposed to multiple pathogens during their lifetimes. There are several examples of dual pathogen interaction (malaria and COVID, tetanus and malaria) but multiple pathogen interactions have not been well explored. Recent technological advances allow measurement of antibody responses to multiple antigenic/pathogen targets simultaneously in a very small blood volume. This project will apply this assay to very well characterised cohorts of children from 3 areas in Uganda with different levels of malaria transmission. The overall aim is to characterise how exposure to multiple pathogens develops in Ugandan children. Specific objectives will be to describe individual pathogen antibody kinetics, examine how select epidemiological factors influence these antibody kinetics and investigate interactions between antibodies to different pathogen classes.
IM3	Investigating inflammatory biomarkers in female genital schistosomiasis. (London)	Female genital schistosomiasis (FGS) is a parasitic gynaecological disease caused by Schistosoma haematobium. The systemic inflammatory response associated with FGS remains incompletely characterised. This project will investigate whether serum/cervicovaginal lavage from an ongoing study (Schista study in Zambia) concentrations of eosinophil cationic protein (ECP), a marker of eosinophil activation, and C-reactive protein (CRP), a marker of systemic inflammation, differ between women with and without FGS. Using stored serum samples and approved linked clinical data, the student will quantify both biomarkers using ELISA, compare concentrations between groups and explore associations with relevant clinical characteristics where data permit. the study will generate preliminary evidence on systemic inflammation associated with FGS and assess the feasibility of these biomarkers for further investigation. Neither biomarker will be assumed to be specific to FGS or suitable for diagnosis.
IM4	Unmasking the role of immune checkpoint PD-L1 in Klebsiella pneumoniae immune evasion. (London)	Klebsiella pneumoniae (KP) is among the leading global causes of AMR-caused mortality. A critical gap remains: how does KP persist in the human host while evading immune clearance? We recently generated a lung immune cell atlas across the infection timeline. Our data revealed a time-dependent accumulation of PD-L1–expressing immune cells. High surface levels of PD-L1 is a hallmark of tumour microenvironment, resulting in inhibition of innate immune cell function. These findings support KP co-opts the PD-L1 immune checkpoint to suppress host immunity and promote its own survival. By leveraging single-cell systems immunology, transcriptomics (RNA-seq) and cellular microbiology, and ex vivo precision cut-lung slices this project will determine how KP hijacks PD-L1 to counteract cell-intrinsic immune defences. Because medicines that target PD-L1 are already used, our findings could accelerate a transition from the pre-clinical stage to clinical development.
IM5	Dissecting the role of the T6SS to manipulate lung immunity. (London)	Our previous work has shown that the Type VI Secretion System (T6SS) of Klebsiella pneumoniae acts as a contractile nanoweapon that controls the interaction with myeloid cells (2024 Calderon-Gonzalez et al Plos Pathogens). This project will define how Klebsiella assembles and regulates T6SS architecture to manipulate lung immunity. We will determine how T6SS deployment remodels lung immunity using ex vivo precision cut-lung slices with reconstituted myeloid and lymphoid populations. Particularly, we will define the effect on macrophage engulfment, and inflammatory responses. Targeted single and combinatorial mutants will be generated using a high-throughput CRISPR–Cas9 platform to identify the T6SS effector(s) crucial to counteract tissue immunity. Using single-cell approaches, we will detect effector delivery ex vivo and assess which cell populations are the primary target. This project will redefine the role of the T6SS in immune evasion.
IM6	Disarming macrophages: how KivA hijacks innate immune signalling. (London)	IL-17 and IFN-γ are critical components of pulmonary immunity against Klebsiella pneumoniae, but their effects are mediated through distinct and potentially interacting cellular pathways. Our group established that IFN-γ promotes the antibacterial activity of alveolar macrophages, while other studies demonstrated that IL-17 enhances the microbicidal activity of recruited inflammatory monocytes. Whether these cytokines cooperate within individual phagocytes during Klebsiella infection, and whether bacterial immune-evasion proteins disrupt this cooperation, remains unresolved. This project will analyse whether KivA (a Klebsiella immune evasin) interacts with TIR-containing innate immune adaptors, disrupting signals that support IFN-γ-dependent macrophage defence. This work will combine infection assays and immune pathway analysis to determine a new mechanism of innate immune subversion in Klebsiella.

Title

Overview

IM1

Rural–urban residence and parasitic infections in yellow fever vaccine waning in Ugandan adolescents.

(Uganda)

Yellow fever vaccination is recommended as a single lifetime dose; however, emerging evidence suggests that vaccine-induced immunity may wane more rapidly in some settings. Chronic exposure to malaria may modulate immune function and influence the durability of vaccine responses.

This study will investigate the long-term persistence of yellow fever vaccine–induced neutralising antibody responses among Ugandan adolescents, comparing participants from rural and urban settings. Participants previously enrolled in these trials will be traced for follow-up. Archived and newly collected samples will be analysed to characterise antibody trajectories over time. Neutralising antibody titres, measured by plaque reduction neutralisation tests (PRNT), will serve as the primary outcome, with ELISA-measured IgG as the secondary outcome. We hypothesise that adolescents in rural settings with higher parasitic exposure will exhibit faster waning of vaccine-induced antibody responses.

IM2

Multi-pathogen sero-surveillance in a Ugandan cohort.

(London)

Most research is focused on single pathogens, yet individuals are exposed to multiple pathogens during their lifetimes. There are several examples of dual pathogen interaction (malaria and COVID, tetanus and malaria) but multiple pathogen interactions have not been well explored. Recent technological advances allow measurement of antibody responses to multiple antigenic/pathogen targets simultaneously in a very small blood volume.

This project will apply this assay to very well characterised cohorts of children from 3 areas in Uganda with different levels of malaria transmission. The overall aim is to characterise how exposure to multiple pathogens develops in Ugandan children. Specific objectives will be to describe individual pathogen antibody kinetics, examine how select epidemiological factors influence these antibody kinetics and investigate interactions between antibodies to different pathogen classes.

IM3

Investigating inflammatory biomarkers in female genital schistosomiasis.

(London)

Female genital schistosomiasis (FGS) is a parasitic gynaecological disease caused by Schistosoma haematobium. The systemic inflammatory response associated with FGS remains incompletely characterised.

This project will investigate whether serum/cervicovaginal lavage from an ongoing study (Schista study in Zambia) concentrations of eosinophil cationic protein (ECP), a marker of eosinophil activation, and C-reactive protein (CRP), a marker of systemic inflammation, differ between women with and without FGS.

Using stored serum samples and approved linked clinical data, the student will quantify both biomarkers using ELISA, compare concentrations between groups and explore associations with relevant clinical characteristics where data permit. the study will generate preliminary evidence on systemic inflammation associated with FGS and assess the feasibility of these biomarkers for further investigation. Neither biomarker will be assumed to be specific to FGS or suitable for diagnosis.

IM4

Unmasking the role of immune checkpoint PD-L1 in Klebsiella pneumoniae immune evasion.

(London)

Klebsiella pneumoniae (KP) is among the leading global causes of AMR-caused mortality. A critical gap remains: how does KP persist in the human host while evading immune clearance?

We recently generated a lung immune cell atlas across the infection timeline. Our data revealed a time-dependent accumulation of PD-L1–expressing immune cells. High surface levels of PD-L1 is a hallmark of tumour microenvironment, resulting in inhibition of innate immune cell function. These findings support KP co-opts the PD-L1 immune checkpoint to suppress host immunity and promote its own survival.

By leveraging single-cell systems immunology, transcriptomics (RNA-seq) and cellular microbiology, and ex vivo precision cut-lung slices this project will determine how KP hijacks PD-L1 to counteract cell-intrinsic immune defences. Because medicines that target PD-L1 are already used, our findings could accelerate a transition from the pre-clinical stage to clinical development.

IM5

Dissecting the role of the T6SS to manipulate lung immunity.

(London)

Our previous work has shown that the Type VI Secretion System (T6SS) of Klebsiella pneumoniae acts as a contractile nanoweapon that controls the interaction with myeloid cells (2024 Calderon-Gonzalez et al Plos Pathogens).

This project will define how Klebsiella assembles and regulates T6SS architecture to manipulate lung immunity. We will determine how T6SS deployment remodels lung immunity using ex vivo precision cut-lung slices with reconstituted myeloid and lymphoid populations. Particularly, we will define the effect on macrophage engulfment, and inflammatory responses. Targeted single and combinatorial mutants will be generated using a high-throughput CRISPR–Cas9 platform to identify the T6SS effector(s) crucial to counteract tissue immunity.

Using single-cell approaches, we will detect effector delivery ex vivo and assess which cell populations are the primary target. This project will redefine the role of the T6SS in immune evasion.

IM6

Disarming macrophages: how KivA hijacks innate immune signalling.

(London)

IL-17 and IFN-γ are critical components of pulmonary immunity against Klebsiella pneumoniae, but their effects are mediated through distinct and potentially interacting cellular pathways. Our group established that IFN-γ promotes the antibacterial activity of alveolar macrophages, while other studies demonstrated that IL-17 enhances the microbicidal activity of recruited inflammatory monocytes. Whether these cytokines cooperate within individual phagocytes during Klebsiella infection, and whether bacterial immune-evasion proteins disrupt this cooperation, remains unresolved.

This project will analyse whether KivA (a Klebsiella immune evasin) interacts with TIR-containing innate immune adaptors, disrupting signals that support IFN-γ-dependent macrophage defence. This work will combine infection assays and immune pathway analysis to determine a new mechanism of innate immune subversion in Klebsiella.