2026-27 Project (Bengoechea & Reljic)

Dissecting immune checkpoint PD-L1-mediated immune evasion in Klebsiella pneumoniae

SUPERVISORY TEAM

Supervisor

Professor Jose Bengoechea at LSHTM
Faculty of Infectious & Tropical Diseases, Department of Infection Biology
Email: jose.bengoechea@lshtm.ac.uk

Co-Supervisor

Professor Rajko Reljic at City St George’s
School of Health & Medical Sciences, Department of Medicine
Email: rreljic@citystgeorges.ac.uk

PROJECT SUMMARY

Project Summary

Klebsiella pneumoniae (KP) is a global health threat due to its resistance to antibiotics. While most individuals successfully fend off KP infections through natural immune responses, the precise mechanisms of protection remain poorly understood, representing a major barrier to developing immune-based therapies. This PhD project will investigate a novel immune evasion strategy employed by KP: the manipulation of the immune checkpoint molecule PD-L1. Widely known for its role in cancer immune suppression, PD-L1 may also be exploited by KP to dampen host immune defenses and facilitate infection. Through cutting-edge molecular and cellular immunology techniques, this project will uncover how KP manipulates PD-L1 to subvert immune responses. The findings shall lay the foundation for therapeutic strategies blocking PD-L1 to antagonize KP infection. This project offers a unique opportunity to work at the intersection of infectious disease, immunology, and translational medicine, contributing to the development of next-generation therapeutics against antibiotic-resistant pathogens.

Project Key Words

Klebsiella, immune checkpoint, anti-immunology

MRC LID Themes

Infectious Disease
Global Health
Translational and Implementation Research

Skills

MRC Core Skills

Interdisciplinary skills
Whole organism physiology

Skills we expect a student to develop/acquire whilst pursuing this project:

Technical skills: broad experience in tissue culture including siRNA and CRISPR-Cas9 knock-outs; high-throughput cellular-based screens; molecular and cellular microbiology -construction of mutants and assessing gene expression (macrophage, and bacteria) in infected cells, extensive knowledge on cell intrinsic innate immunity.

Soft skills: scientific presentation, write scientific reports, critical thinking.

Education skills: training visiting students and Msc/Mres students, contribution to postgraduate teaching (short course).

Routes

Which route/s are available with this project?

1+4 = Yes
+4 = Yes

Possible Master’s programme options identified by supervisory team for 1+4 applicants:

City St Georges – MRes Biomedical Science – Infection and Immunity
City St Georges – MSc Applied Biomedical Science
LSHTM – MSc Control of Infectious Diseases
LSHTM – MSc Immunology of Infectious Diseases
LSHTM – MSc Medical Microbiology

Full-time/Part-time Study

Is this project available for full-time study? Yes
Is this project available for part-time study? No

Location & Travel

Students funded through MRC LID are expected to work on site at their primary institution. At a minimum, all students must meet the institutional research degree regulations and expectations about onsite working and under this scheme they may be expected to work onsite (in-person) more frequently. Students may also be required to travel for conferences (up to 3 over the duration of the studentship), and for any required training for research degree study and training. Other travel expectations and opportunities highlighted by the supervisory team are noted below.

Day-to-day work (primary location) for the duration of this research degree project will be at: LSHTM – Bloomsbury, London

Travel requirements for this project: None

Eligibility/Requirements

Particular prior educational requirements for a student undertaking this project

Minimum standard institutional eligibility criteria for doctoral study at LSHTM
Undergradute on Biomedical Science, Human biology, Biology, or similar discipline that will include notions of biology, physiology, microbiology, and immunology
MSc/MRes on infectious diseases, microbiology, immunology, microbial pathogenesis, cellular biology, cancer

Other useful information

Potential Industrial CASE (iCASE) conversion? = No

PROJECT IN MORE DETAIL

Scientific description of this research project

Klebsiella pneumoniae (KP) is at the forefront of the global antibiotic resistance crisis, causing over 100,000 deaths each year. Particularly alarming are strains resistant to carbapenems and third-generation cephalosporins, which leave clinicians with limited treatment options. Recognising this, the World Health Organisation has singled out KP as a priority pathogen for which urgent therapeutics are needed.

Despite significant advances in understanding KP’s population structure, resistance mechanisms and transmission patterns, a critical gap remains: how does KP persist in the human host while evading immune clearance? Pathogens such as KP represent a paradigm of host-adapted microbes because they have evolved to flourish in our tissues despite the attack of the immune system. The outcome of a KP infection can be conceptualized as a dynamic equilibrium between immunological control and bacterial persistence in which KP evades and exploits immune responses. A detailed molecular understanding of KP infection cycle offers the opportunity to develop innovative therapeutics based on targeting host factors crucial in the infection biology of the pathogen, boosting innate protective responses.

To gain an integrated in vivo perspective on the host-KP interaction, we recently generated a lung immune cell atlas across the infection timeline using a novel technology we developed, Bac-CyTOF1. Our data revealed a striking, time-dependent accumulation of PD-L1-expressing immune cells, particularly neutrophils and monocytes/macrophages, which KP preferentially infects.1 High surface levels of PD-L1 is a hallmark of tumour microenvironment, resulting in inhibition of innate immune cell function. While we have detected membrane PD-L1 (mPD-L1) in KP-infected cells in vivo and in vitro, our preliminary data reveal two additional unprecedented PD-L1 pools in bacterial infected cells: vacuolar PD-L1 (vPD-L1), localised to the Klebsiella containing vacuole (KCV), a compartment in which KP evades lysosomal degradation in mouse and human macrophages, and nuclear PD-L1 (nPD-L1). Importantly, absence of PD-L1 results in a decrease in KP intracellular survival, and an increase in inflammation. We propose that PD-L1 is not merely a passive surface marker in bacterial infection but an active regulator of cell-intrinsic defence pathways, redefining PD-L1 as a dynamic host factor exploited by bacteria for niche protection.

Together, these findings support a previously unrecognised notion: KP co-opts the PD-L1 immune checkpoint to suppress host immunity and promote its own survival. By integrating advanced single-cell technologies with biochemical, cellular microbiology, we will dissect the contribution of PD-L1 to KP immune evasion. We will provide mechanistic insights to the following fundamental questions:

How does KP manipulate PD-L1 spatial localization in macrophages?
What molecular mechanisms does KP exploit to hijack PD-L1 and suppress cell-intrinsic immunity?

This project introduces the concept of immune checkpoint as a microbial immune evasion strategy, redefining PD-L1 biology beyond oncology. By positioning PD-L1 as a central player in KP’s immune evasion strategies, this work shall be the foundation of pre-clinical research targeting PD-L1 by leveraging the existing portfolio of PD-L1 inhibitors currently being used in oncology. This pathway to impact offers an accelerated path from bench to bedside.

Additional information from the supervisory team

The supervisory team has provided a recording for prospective applicants who are interested in their project. This recording should be watched before any discussions begin with the supervisory team.

Bengoechea & Reljic Recording

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