Table showing the human TB blood transcriptional signature as a modular signature by RNA-Sequencing analyses, compared to that of resistant (C57BL/6J) and susceptible mice (C3HeB/FeJ) infected with the laboratory strain of M. tuberculosis, H37Rv, or a clinical isolate HN878 and at a low and high dose of infection. The human signature is preserved in blood of the susceptible mice infected with the clinical M. tuberculosis isolate (modular red dots show over-abundance of genes; modular blue dots show under-abundance of genes).
Researchers at the Crick have optimised a mouse model which exhibits the same blood immune response to Mycobacterium tuberculosis infection as humans at the peak of disease, allowing further research.
Each year over 1.5 million people around the world die from tuberculosis (TB). However, only 10% of people who catch the disease become ill. The rest either fight off the disease or have ‘latent’ TB (LTBI), meaning that they have responded to the infection, but their immune system keeps the infection under control and they do not have symptoms.
Some people with latent TB can go on to develop ‘active’ TB. This group is known as ‘LTBI-progressors’. However, there is a lack of understanding around why their immune systems eventually fail to control the disease. This has in part been due to the lack of an animal model which resembles the human disease.
In this Nature Immunology study, researchers optimised a susceptible mouse TB model that has the same unique transcriptional blood gene signature, dominated by type I interferon-inducible genes, as is seen in the blood of people with active TB and people in the LTBI-progressor group. This signature shows which genes are either more or less active in the blood, representing the body’s response to the infection. The genes were assayed using data from RNA-Sequencing of samples generated from the experimental TB models with the help of the Advanced Sequencing Facility at the Crick.
The similarities between the blood signature in this strain of mice infected with a clinical isolate of the pathogen Mycobacterium tuberculosis and that in the blood of people with active TB and people in the LTBI-progressor group, provide a valuable model for further research into TB. The similarities were uncovered through a collaboration with a group led by Margarida Saraiva at the 3is Institute, in Porto, who helped the Immunoregulation and Infection Laboratory at the Crick advance the study.
“Researchers often use mice to study how diseases progress. To make sure their work supports future development of medicines, it’s important that the mouse model used for any disease mirrors how the disease behaves in humans. We’ve shown here that this susceptible mouse model for TB accurately reflects the disease in humans and we have all the tools that researchers need to use it now to test targets and mechanisms to uncover new therapies,” says Anne O’Garra, co-author and group leader of the Immunoregulation and Infection Laboratory at the Crick.
In the blood of the mice which are susceptible to TB, researchers detected an additional new finding that genes associated with a type of white blood cell, called granulocytes, were more active. The researchers found that this is also the case in the blood of people with active TB, proving that the mouse model can help lead to new findings about the disease in humans.
The use of an experimental mouse model allows the study of the local immune response to infection, which is prohibitive in humans. Meanwhile, in the lungs of mice that are resistant to TB, the researchers found that genes associated with other white blood cells, B cells making Immunoglobulins (antibodies), T cells and natural killer cells, were more active. This was verified by immunohistochemistry in collaboration with pathologists and the Experimental Histopathology team at the Crick. These cells could therefore be playing a role in helping to control the disease.
“Examining what is going on in the lungs in cases of TB is really important as this is the site of infection. This is difficult to study in patients however, so having a susceptible mouse model that closely resembles the disease in humans, and another that is more resistant to the infection will be invaluable for future research into the lung immune response in TB”, explains Lúcia Moreira-Teixeira, co-lead author and postdoc in the Crick’s Immunoregulation and Infection Laboratory.
The research also found that the blood gene signature is the same in the blood of LTBI-progressors and people with active TB. This builds on a proof-of-principle study by the researchers in 2018, in collaboration with clinicians at the University of Leicester, which linked the presence of the TB blood signature and the onset of early TB, before the patient has symptoms. This understanding could help develop new diagnostics and provide clues as to how individuals exposed or infected with M. tuberculosis can progress to active TB disease, or on the other hand keep the infection under control.
“Our research found that the gene signature of people who become ill after a period of latency is the same as that for people who already have active TB. This means this signature could be used to predict whether a person with latent TB could become ill. It also suggests that there may be genes within this signature itself, that dictate how the immune system is responding to the infection and contributing to progression of the disease,” says Olivier Tabone, co-lead author and Bioinformatics postdoc in the Crick’s Immunoregulation and Infection Laboratory.
The researchers have also developed an interactive open access app that others can use to search for genes of interest and examine changes in the blood and lungs from the different mouse TB models as well as from the blood of human TB cohorts.