23 September 2020
Combining forces against lethal fungal infection
Published online 13 June 2019
A combination therapy shows promise in targeting the fungus responsible for a severe blood infection.
Cases of mucormycosis, a rare fungal infection that primarily attacks the lungs and brains, are increasing around the world. Now, a promising immunotherapy may boost survival rates when used in tandem with existing anti-fungal drugs.
“Mucormycosis is a devasting infection, with a 50 to 100 per cent mortality rate,” explains Ashraf Ibrahim from the University of California in Los Angeles, who has been studying the disease for more than 20 years. “Existing drugs targeting the fungal pathogens are limited and doctors must often resort to disfiguring surgery, leaving surviving patients with a very poor quality of life. We’ve been exploring mechanisms of infection to identify likely therapeutic targets.”
Mucormycosis is caused by several fungal pathogens, the most common of which is Rhizopus. The infection is particularly serious in people who have suppressed immune systems, for example, those who have recently received stem cell therapy or organ transplants. People with blood cancer, poorly controlled diabetes, or severe trauma such as blast or motor accident injuries are also at risk.
Ibrahim and co-workers recently found that the fungal protein, CotH3, binds directly to host cells lining blood vessels to promote infection. CotH3 is widely conserved across many mucormycosis-inducing fungi, including Rhizopus. In their latest study, the researchers generated antibodies against the peptide regions of CotH3 responsible for host-fungal binding. Sameh Soliman, now based at the University of Sharjah, UAE, developed a CotH3 clone that enabled the team to test the antibodies’ reactivity. They then trialed the therapy very successfully on mice.
“I was cautiously excited when I first saw the results. I asked my team to keep repeating the experiments to make sure,” says Ibrahim. “It appears the antibodies have two modes of action. Firstly, they prevent invasion of the host tissue by Rhizopus. This halted infection progression quickly, even with quite a low dose. Secondly, the antibodies enhance the ability of white blood cells to recognize the fungus and kill it.”
The team found that using the antibodies alongside anti-fungal drugs gave the mice almost complete protection, and cleared them of infection even when administered in the late stages of the disease. The therapy worked well against other fungi harboring CotH3.
“We’re currently humanizing the antibody so we can evaluate its efficacy and determine its toxicity,” says Ibrahim. “We will then establish a commercially viable cell line to take into human clinical trials.”
Gebremariam, T. et al. Anti-CotH3 antibodies protect mice from mucormycosis by prevention of invasion and augmenting opsonophagocytosis. Sci. Adv. 5, eaaw1327 (2019).