UCT team in immune system breakthrough

Scientists have detailed for the first time how the immune system remembers prior exposures to pathogens (micro-organisms like bacteria that cause infection), for example, so that it triggers the right response to reinfection.

The study was published in Nature Genetics on 10 December 2018 by a team of scientists from UCT, the Institute for Infectious Disease and Molecular Medicine – based at UCT’s Faculty of Health Sciences – and the Council for Scientific and Industrial Research (CSIR), and led by UCT Professor Musa Mhlanga.

Dr Stephanie Fanucchi, first author and CSIR senior researcher, contextualised the research: “The immune system sits at the apex of our protection against all diseases, ranging from infectious diseases to chronic diseases, such as cancer and diabetes.”

Within the immune system reside two important actors: the innate and adaptive immune systems. The adaptive system is made up of lymphoid cells (T-cells and B-cells), which retain a memory of prior exposures to pathogens, infections and diseases. This memory can be ‘written’ to lymphoid cells by vaccines, for example. This results in accelerated responses by the immune system to re-exposure to the infection or pathogen, or even chronic diseases like cancer.
 

“Our study provides the first mechanistic explanation for how trained immunity works...”

The innate immune system is made up of myeloid cells (monocytes and macrophages), which historically have been thought to possess no such memory of prior exposures to pathogens, infections or disease.

In recent years, a phenomenon termed ‘trained immunity’ has been discovered and described by the laboratory of Professor Mihai Netea in The Netherlands.

Netea and others have observed that myeloid cells also retain a memory of prior exposures, though the mechanism was unknown. This memory appeared to be ‘written’ in chemical changes at the level of proteins associated with DNA encoding individual genes regulating the immune system in myeloid cells.

In the current study, the scientists – with international collaborators from China, Germany, Italy, Singapore and the United States – have unraveled and clarified the mechanism. Using the tools of genomics, bioinformatics, single-molecule imaging and gene editing, the authors demonstrated that another recently discovered group of biological molecules, called long non-coding RNAs (lncRNA), regulate the epigenetic acquisition of memory at immune genes that occurs during trained immune responses.

In their study, Mhlanga and colleagues characterised an example of one lncRNA called UMLILO, aptly named after the Zulu word for ‘fire’, which regulates how inflammatory genes retain a memory of prior exposures. These genes regulate inflammatory responses implicated in several major diseases including tuberculosis, chronic obstructive pulmonary disease, ischaemic heart disease, cystic fibrosis and autoimmune disease.
 

The innate immune system is made up of myeloid cells (monocytes and macrophages), which historically have been thought to possess no such memory of prior exposures to pathogens, infections or disease.

“This groundbreaking discovery of these lncRNAs can now be exploited therapeutically to discretely alter the immune response to treat a plethora of inflammatory-based diseases such as cancer and inflammatory bowel disease,” says Fanucchi. “Alternatively, this knowledge may be useful to boost the training of the immune system, to enable individuals with weakened immune systems to clear infections.”

Mhlanga adds: “Our study provides the first mechanistic explanation for how trained immunity works and exposes it to highly targeted intervention in immunomodulation, one of the largest therapeutic areas in the pharmaceutical industry. Broadly, it contributes to our fundamental understanding of immunology and gene regulation in general by indicating how gene expression can be influenced and maintain a persistent and heritable memory of environmental exposures. This memory can be ‘written’ and ‘erased’ continuously via environmental exposures over the lifetime of an individual.”

Second author Ezio Fok, a PhD student at UCT and the CSIR, who under the supervision of Mhlanga significantly contributed to the study, sees the very immediate practical result pertinent to South Africa from the study.

“Recent studies have, for example, implicated trained immunity in the mechanism by which yellow fever vaccine and BCG (a tuberculosis vaccine) work. This indicates that measuring specific lncRNA levels may be a useful biomarker for assessing effective innate immune activation (for example, BCG-induced vaccination). This could be of major importance in public health today in assessing vaccine efficacy.”

The study is the product of numerous fruitful international collaborations, as well as the continued financial support from the South African Department of Science and Technology, the South African Medical Research Council and the CSIR.

“We are very grateful for the support for this kind of fundamental research in South Africa,” Mhlanga adds. “Our goal is that scientists in Africa should not simply be consumers of fundamental scientific discoveries; rather they should be active contributors and producers to this body of basic scientific knowledge.

“We would like to train the next generation of scientists in Africa to become excellent scientists who routinely produce ground-breaking work.”