A team of scientists from the University of Cape Town (UCT), UCT’s Institute for Infectious Disease and Molecular Medicine and the Council for Scientific and Industrial Research (CSIR) have detailed – for the first time – the mechanism of how the immune system remembers prior exposures to, for example, pathogens to then trigger the right response to reinfection.

In the study, which was published in Nature Genetics on 10 December 2018, the first author and CSIR Senior Researcher, Dr Stephanie Fanucchi, explained how 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.

She added that 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, resulting in accelerated responses by the immune system to re-exposure to the infection or pathogen or even chronic diseases like cancer. 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 the study, the scientists, with international collaborators from China, Germany, Italy, Singapore and the US, have now 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, Prof Musa Mhlanga from UCT/IDM and colleagues characterise 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 TB, chronic obstructive pulmonary disease, ischaemic heart disease, cystic fibrosis and autoimmune 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. Alternatively, this knowledge may be useful to boost the training of the immune system, to enable individuals with weakened immune systems to clear infections,” said Dr Fanucchi.

Prof Mhlanga added that their 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,” said Prof Mhlanga.

Second author Ezio Fok, a PhD student at UCT and the CSIR, who, under the supervision of Prof Mhlanga, 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 TB 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,” said Fok.

The study is the product of numerous 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. 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,” concluded Prof Mhlanga.

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