Pilot study to develop a novel model to investigate the mechanisms and consequences of foetal immune programming on immune fitness through life

How the immune system develops in early life is critical for defining immune fitness throughout adult life. The immune challenges which we are exposed to in early life play an important role in training the immune system, teaching it what to respond to, and how strongly to respond. Getting this balance right is critical for health in adult life, with dysregulated immunity leading to disease, such as allergies, autoimmunity, mental illnesses, and obesity.

Foetal development during gestation is a critical period of immune development, and the immune challenges faced by the mother influence how the baby's immune system develops. Infections in the mother alter foetal immune development, and can change the way the offspring responds in adult life to infections and allergies. Our group studies immunity to parasitic worms, which are a huge worldwide human health burden, and large economic burden for the livestock industry. They are very good at evading or suppressing immune responses, allowing them to survive for decades in their host. Maternal helminth infections are known to influence foetal immune development, and can suppress offspring immunity resulting in a lower level of immune responsiveness in later life. This can make them more susceptible to future infections, and can also impair their ability to respond to vaccination. However, it can also have beneficial effects, and can make them less susceptible to allergies. However, the mechanisms by which this occurs are unknown.

Unfortunately, it is very difficult to perform mechanistic work in humans, and there is a lack of experimental animal models. The goal of this proposal is to develop a new mouse model that will allow us investigate how helminth infection during pregnancy influences the development of the baby's immune system, and how this impacts their immune balance and health during adulthood. This will help identify why some immune challenges during pregnancy turn off the baby's immune responses, increasing infection susceptibility and lowering vaccine responsiveness and the risk of developing diseases, whilst other immune challenges activate the baby's immune system increasing their risk of diseases in later life. This will increase our fundamental knowledge, and this knowledge can be used to identify early-life disease associated risk markers allowing us to predict health in later life. It can also be used to suggest strategies to manipulate immune development during early life to prevent individuals subsequently developing disease. Identifying how maternal helminth infections inhibit the ability of offspring to respond to vaccinations is important for the development of vaccine strategies for helminth and non-helminth infections in both livestock and humans.

Early-life immune exposures prominently shape adult immunity; setting an individual's homeostatic balance between immune inflammation and tolerance. This balance defines health throughout adulthood. Gestation is a critical period of immune development, with foetal immunity being programmed in utero based on the mother's exposures. However, the mechanisms by which foetal immunity is sensitised towards inflammation or programmed towards tolerance, and how these direct an individual's immune homeostasis and health throughout life, are not well defined.

Maternal infections are an important determinant of foetal immune programming, impacting offspring responsiveness to vaccines, and susceptibility to infection, allergy, and mental illness. Human maternal filarial nematode infection results in two distinct immune outcomes in children, sensitisation or tolerance, so provides an ideal platform to elucidate the mechanisms of how in utero priming leads to these distinct outcomes. The goal of this pilot study is to use the filarial nematode Litomosoides sigmodontis to create a new model to study how maternal filariasis programs foetal immunity, the long-term impacts that in utero sensitisation versus tolerance have on immune homeostasis, and how this defines health throughout life. Alongside model development, we will determine whether maternal filariasis primes regulatory (tolerised Th2/Treg responses) and/or effector Th2 responses within offspring, and how this influences infection susceptibility. IL-4gfp and IL-4cre fate reporter mice will be used to functionally assess in utero primed Th2 cells.

This model will provide a unique new tool to study the mechanisms of foetal immune programming, and their long-term consequences on immune system development and homeostasis through life. Elucidating these mechanisms is important as the knowledge can be used to help predict and therapeutically tailor how individuals, such as humans or livestock, will respond in adult life.

The major outputs of this pilot proposal will be: (1) the development of a new murine model that can be used to study in utero programming of foetal immune responses during maternal infection, (2) fundamental knowledge on the in utero priming of foetal Th2 and Treg responses and how this impacts susceptibility to infection.

The major impact from this pilot study will be the future research stimulated by the development of a new research model. Thus, the benefits discussed below will mostly stem from future research based upon the new model (2 years onwards), and it will be important to engage the wider academic community to realize the full potential of future impacts.

Defining the factors and mechanisms that lead to in utero programming of foetal tolerance versus sensitisation will help identify, and mitigate against, risk factors associated with offspring susceptibility to infection, allergies, autoimmunity, mental illness, metabolic diseases and obesity (5-20 years). It will suggest new approaches for prophylactic therapies that program foetal immunity towards a tolerised or regulatory phenotype during early life to prevent these conditions during adult life (10-30 years). Identifying potential biomarkers, and novel therapies, will provide new directions for commercial exploitation for the prediction of individuals who are at higher risk of developing allergies, autoimmunity, mental illness and/or obesity, and the prophylactic treatment of these conditions. This has the potential to lead to spin-out companies to develop immunological therapies, and could also benefit biotech and pharmaceutical companies, as well as charities with active biomedical research programs. This will lead to increased investment in Research and Development (2-10 years), and in the long-term could lead to the development of commercially exploitable treatments (10-30 years). Defining pregnancy-linked risk factors associated with the development of non-communicable diseases, would help develop advice for pregnant women on life-style behaviours that minimise future risk for their children (10-20 years).

Helminth infections represent a huge economic burden for livestock management, and are responsible for worldwide human morbidity. Defining whether and how maternal infection impairs the offspring's immune responses to anti-helminth and non-helminth vaccinations will aid the design of anti-helminth vaccines for livestock and humans (5-20 yrs). It will also instruct policies for the timing and use of non-helminth vaccinations in livestock and humans, and whether vaccine efficacy may be improved by helminth treatment during or pre-pregnancy (5-10 yrs). Defining whether and how maternal helminth infection is a risk factor for offspring infection susceptibility will instruct whether livestock should be given anti-helminth drugs during pregnancy (5-10 yrs).