We all know how hackers deploy malware, or malicious software, to gain unauthorised access to the victim’s computer system to disrupt or damage it. Fascinatingly, cybercriminals aren’t the only ones that make use of this technique: some bacteria employ a similar hacking approach during infection.
For example, Mycobacterium tuberculosis, the bacteria that causes tuberculosis (TB), sidesteps the immune system by gaining access to the host’s DNA and meddling with immune cell genes, much like microscopic malware. The bacteria’s evasive tactics made it the 13th leading cause of death worldwide in 2021, and the second highest cause of death by infectious disease in the same year, superseded only by COVID-19.
“For many years, we have been working on understanding the host-pathogen interaction of TB to decipher its immune evasive mechanisms,” said Amit Singhal, Senior Principal Investigator at A*STAR Infectious Diseases Labs (ID Labs). Singhal and colleagues suspected that the TB-causing bacteria’s modus operandi may lie in a chemical modification of host cell DNA: specifically, a biochemical process known as histone acetylation that unravels DNA, making it vulnerable to modifications that disrupt proper immune cell function.
Recent breakthrough studies describing a new high-throughput genomic technology called histone acetylome-wide association studies (HAWAS) offered a way to finally crack the code behind TB infections, says Shyam Prabhakar, Senior Group Leader at A*STAR’s Genome Institute of Singapore (GIS). Though HAWAS was previously used to study genomic alterations in Alzheimer’s and heart disease, in this study, A*STAR scientists pioneered its application in infectious diseases.
The scientists obtained blood samples from TB patients and healthy donors based in Singapore and with the help of international collaborators, also obtained matching samples from a South African cohort. They then looked for signature changes in histone acetylation in the samples from TB patients across all groups using HAWAS.
In their study published in Nature Microbiology, the team described changes to over 2,000 immune cell genes resulting from Mycobacterium tuberculosis infections. Of these, one stood out: a gene called KCNJ15 that encodes for a channel that lets potassium in and out of immune cells. Mycobacterium tuberculosis infection seemed to significantly elevate levels of histone acetylation in KCNJ15.
Singhal said the discovery, which to his knowledge has not previously been reported, spotlights KCNJ15 as a protective shield that is deployed in TB disease. “It regulates the levels of potassium inside the immune cell, which then causes the cell to commit suicide through a process called apoptosis,” Singhal explained. “This reduces the ability of Mycobacterium tuberculosis to reproduce inside the cell.”
The good news is KCNJ15 is a potentially druggable target. “We envision developing drugs targeting these potassium modulators to add to the antibiotics we currently use against infectious diseases,” Singhal concluded, adding that such strategies to combat antibiotic resistance are urgently needed to reduce TB’s impact on global mortality.
The A*STAR-affiliated researchers contributing to this research are from Genome Institute of Singapore (GIS), Singapore Immunology Network (SIgN) and A*STAR Infectious Diseases Lab (ID Labs).
