Charles Sinclair

Charles Sinclair photo

Project Title: 

Integration of nutrient, stress and immunological signals during vaccination

Host Organisation: 

Emory Vaccine Center, Atlanta, USA

Short biography

Originating from Worthing, a popular tourist destination on the south coast of the UK, Charles obtained a BSc in biological sciences from the University of Warwick in 2007.

He went on to obtain a PhD and perform a short postdoctoral project with Dr. Ben Seddon at the MRC National Institute for Medical Research (London, UK). Here he studied a novel kinetic model of T-cell development, making significant contributions towards understanding the developmental control of T-cell homeostasis.

He joined the lab of Bali Pulendran at Emory Vaccine Center (Atlanta, USA) in 2013. Here he has been combining his experience with cellular homeostasis with models of inflammation, focusing around the mTOR nutrient-sensing pathway.

Charles completed his fellowship at the end of December 2015 to take up prestigious new post as a Senior Scientist in the new Immunooncology Department at Astra Zenaca in Cambridge, UK.

Brief description of research project

Vaccines are one of the most successful public health interventions of the last century, but many diseases are resistant to this method. It remains unclear how vaccines activate the immune system to induce effective immunity.

Evidence emerged in the last ~5 years suggesting that activity of the mTOR signalling pathway inhibits innate immune responses to immunological stimuli. It was proposed that this pathway could be suppressed in order to improve vaccine response. To directly test this concept, we studied mice that have genetic defects in mTOR within innate immune cells.

In contrast to our expectation, mTOR ablation had minimal effects on overall vaccine responses. Instead, mTOR controlled steady-state numbers of immune cells at discrete anatomical sites. This effect was most evident in the lung, where mTOR ablation led to an absence of innate cells, leading to profound immunodeficiency, enhanced asthmatic severity upon exposure to allergens, and accumulation of proteinaceous lung surfactant (a condition termed pulmonary alveolar proteinosis). These results specifically implicate the mTOR signalling pathway in lung-specific pathology for the first time.

This study represents a significant scientific advance in our understanding of innate programming of adaptive immunity in the lung. Moreover, the results are of great interest to clinicians, providing deeper mechanistic understanding of the potential side-effects of mTOR inhibitors, and identify alternative molecular targets that could be targeted to treat respiratory diseases.