Dr. Sharee Basdeo

Title

COVID-19 vaccines enhance innate immune function to drive protective immune responses

Summary

The development of pathogen-specific immune memory relies not only upon antigen recognition by adaptive lymphocytes (B and T-cells to drive antibody production and cellular responses, respectively), but also upon stimulation of the innate immune system, including myeloid cells like DC dendritic cells DC)"s and macrophages to drive inflammation and antigen-presentation. Recently, memory-like properties have been ascribed to innate immune cells through a process termed "Trained Immunity" " the extent of its effector functions and its durability however, are still under investigation. Early recognised drivers of this pathway in myeloid cells were the TB-specific vaccine BCG and fungal cell-wall components, beta-glucans. However, it is likely that other adjuvants or combinations of adjuvants trigger similar responses. While this area of investigation has received interest for how it could be harnessed to drive heterologous responses by priming for later re-stimulation/activation in areas like infection resistance and cancer, how these effects on innate immune cell reprogramming including metabolic and epigenetic reprogramming, contribute to the normal activation of adaptive immune cells and the development of immune memory is less well described. In particular, how the various components of COVID-19 vaccines can enhance innate immune function, aside from immediate inflammatory activation but over the longer course of the immunization schedule has not been examined. Preliminary data from the Basdeo Group has examined monocytes derived from individuals vaccinated with the adenoviral vector-based Astra-Zeneca vaccine and found a long-term, durable increased expression of molecules associated with antigen-presentation and co-stimulation which was maintained up to 3-months post-vaccination. Unbiased screening for Trained Immunity-sensitive genes in macrophages taken from beta-glucan-treated animals in the Sheedy Lab also highlighted increased basal expression of a subset of genes associated with MHC processing and antigen presentation. We therefore propose that specific activation of innate immune cells can be employed not just to enhance innate responses to infection, but to optimally drive vaccine responses and the generation of specific-immune memory, through epigenetically reprogramming and imprinting myeloid cells leading to increased expression of genes associated with antigen processing and improved APC- function. This is particularly relevant during the current COVID-19 crisis as more vaccine candidates come on line and face problems with availability and suitability and as we move toward an era of heterologous vaccination in response to the imminent threat of vaccine-resistant viral variants.

Funding Agency

SFI-AIB COVID-19 SPP

Date From

September 2020

Date To

August 2023

Title

Defining the role of Th17 lineage cells in human pulmonary health and disease.

Summary

The immune responses in the lung tread a tightrope between mounting defensive inflammation against pathogens and maintaining the integrity of the delicate mucosal barrier. T cells play a crucial role in balancing appropriate and inappropriate inflammation and can exhibit a range of distinct behaviours in the lung. Therefore, the immune responses of T cells that live long term in the lung are thought to be important to the outcome of a pulmonary infection. Research largely focuses on the aberrant behaviour of immune cells in disease settings; however, it is becoming increasingly evident that there is paucity of information around what constitutes a healthy immune response in the lung. This project will focus on a population of T cells called Th17 cells which display extensive diversity and adaptability by exhibiting a spectrum of behaviours depending on the context of the immune response and the signals in the microenvironment. These cells have been implicated in lung pathologies including autoimmunity and infection leading to chronic inflammation. However, discreet members of this lineage are also known to be protective at mucosal sites. We hypothesise that Th17 lineage cells in healthy lungs maintain the integrity of the mucosal barrier and strike a balance in the immune response they generate and propagate through the complex cellular network of the lung tissue. However, these cells also have the ability to switch into more proinflammatory effector cells that cause damage and propagate intractable inflammation. This project aims to understand the behaviours of Th17 lineage cells that balance appropriate inflammation with maintaining barrier integrity in healthy lungs. We will examine the effects of the lung environment on human Th17 lineage cells using established in vitro models. In addition, we will determine the effects of Th17 lineage cell subpopulations on the lung environment, including their differential ability to propagate inflammation versus promoting resolution. Finally, this project will reuse existing data sets generated from human lung samples to determine a role for Th17 lineage subpopulations in mounting effective versus pathological immune responses in the lung. This project has the potential to create actionable knowledge in diverse contexts of respiratory diseases. Furthermore, it may contribute valuable understanding of how Th17 lineage cells behave in the lung and the signals promoting them to establish long term tissue resident memory cells that can mediate appropriate protection against infections. These data may therefore help to inform the design of inhaled vaccines for respiratory infectious diseases.

Funding Agency

TCD

Date From

September 2021

Date To

August 2025

Title

Defining the consequences of innate immune training on protective versus pathogenic T cell responses in patients with tuberculosis.

Summary

Tuberculosis (TB) ranks alongside HIV as the world's most deadly infectious disease, killing 1.5 million people every year. It is caused by the bacteria Mycobacterium tuberculosis (Mtb), which primarily infects people's lungs. Treating this disease is becoming more difficult due to antibiotic-resistant Mtb, therefore, scientists are developing ways to boost the immune system to kill Mtb more effectively. Two immune cells that play a prominent role in our ability to fight Mtb are alveolar macrophages (AM) and T cells. AM are the guardians of the lungs and encounter the bacteria first. They try to contain infection by eating and killing the bacteria, and then switching on T cells. However, Mtb can manipulate the AM and live inside it, causing TB disease. T cells are the generals of the immune system, helping to coordinate long term defence. However, in TB, these cells can be a double-edged sword; sometimes they can help clear the infection, but they can also cause collateral damage to the lungs. It was recently discovered that AM can be "trained" to increase their functions (similar to the way training improves an athlete's performance). This improves the AM's ability to kill bacteria. In addition, we have evidence to suggest this training will give clearer signals to the T cells, which will balance the immune response towards clearing the infection, rather than damaging the lungs. This project will compare different training regimens to see which best promotes the killing of Mtb and what affect the training has on T cell responses. By studying the different types of T cells that are activated during Mtb infection, we will determine which response may be harmful to the patient. By better understanding the human immune response during Mtb infection, we will be able to adjust it to help the patient recover from TB.

Funding Agency

Health Research Board

Date From

01 March 2020

Date To

28 February 2025

Title

Defining prolonged innate immune alterations in people post-acute infection to develop a high-risk, high-gain proposal for an ERC Starting Grant application.

Summary

Funding Agency

TCD

Date From

01 Oct 2022

Date To

30 Sept 2023

Title

Defining how innate immune function is impacted long term in people who have had active Tuberculosis.

Summary

The Problem Tuberculosis (TB) is a complex disease caused by a bacteria called Mycobacterium tuberculosis (Mtb) and claims the lives of 1.4 million people annually. When a person is exposed to Mtb, their immune response may clear the infection asymptomatically, contain it in a dormant state (called latent TB) or it can grow and replicate inside the macrophage causing active TB disease. The gap in our knowledge TB doesn't play by the rules of the immunity to infection. If you have previously had active TB you are more likely to get sick again with TB than someone who has never had it before and we don't know why. Our proposed solution Our research team study the innate immune response to Mtb and have established ways to therapeutically boost a patient's own immune system to fight off the bug. We think that Mtb may alter the function of the innate immune response long term in people who have previously had TB. This altered function is a bit like a scar that is left after an injury and we propose that this may be the reason why people who have had TB are more vulnerable to getting TB again. We want to define the status of innate immune cells in people who have had TB compared with healthy people in order to determine if their innate immune responses are reprogrammed by the infection. This will enable us to design a therapy aimed at protecting these vulnerable people from contracting TB again.

Funding Agency

Health Research Board

Date From

September 2022

Date To

March 2025

Title

Vorinostat as a host-directed therapy for Tuberculosis; manipulating epigenetics to boost macrophage function and promote polyfunctional T cell responses.

Summary

According to the WHO, tuberculosis (TB) ranks alongside HIV as the world"s most deadly infectious disease. The rapidly increasing incidences of multiple and extreme drug resistant cases are making TB very hard to treat and difficult to contain in society. Therefore, emerging strategies to treat TB by promoting the patient"s own immune system are currently under investigation. These host-directed therapies will be effective against antibiotic-resistant strains. Alveolar macrophages (AM) are the sentinels of the lungs, thus, are the first cells to encounter mycobacterium tuberculosis (Mtb). Upon infection, the AM becomes activated and switches on its effector functions to ingest and kill the bacteria. Mtb, however, is very effective at shutting off these effector functions so it can live and replicate inside the AM, causing active TB disease. The adaptive immune response plays a key role in clearing infections that overwhelm the initial innate immune response driven by the AM and other infiltrating macrophages. Moreover, the adaptive response produces immune memory which can recognise previously encountered bacteria and respond quickly against them if reinfection occurs. It is these memory responses that are required to produce effective vaccination and to stimulate the clearance of bacteria in infected patients. Preliminary data from our lab indicates that vorinostat, an FDA approved drug for cancer, may prove to be useful in boosting macrophage function and subsequent adaptive T cell function during Mtb infection. This project aims to determine the effects of treating human macrophages with vorinostat and to produce better, prolonged immune responses to Mtb. The ultimate goal of this research is to generate proof-of-concept data for the use of vorinostat as a host-directed therapy to treat antibiotic-resistant TB.

Funding Agency

Irish Research Council

Date From

1 Oct 2017

Date To

31 March 2020

Title

Reprogramming systemic and tissue resident innate immunity post infection to inhibit autoinflammatory events and disease

Summary

Funding Agency

Enterprise Ireland

Date From

March 2023

Date To

February 2024