VIDI’s newest assistant member, Dr. Tobias Hohl, is trying to track down the cells and molecules used by human immune system to battle invasive fungal infections, in an effort to improve care for immunocompromised patients who contract fungal diseases. Hohl’s field of choice is a challenge for clinicians and researchers because, compared to bacterial and viral pathogens, fungal diseases are understudied and difficult to diagnose and treat.
Hohl studies the invasive fungus Aspergillus fumigatus, an opportunistic mold that is ubiquitous in nature. Invasive Aspergillus infections occur in severely immunocompromised patients, such as transplant patients or those with certain types of cancer, said Hohl, who recently moved to the Center following a fellowship in infectious disease at Memorial Sloan-Kettering Cancer Center in New York. The infection can be devastating when it sets in, and is frequently fatal in certain high-risk patient groups.
Ironically, humans are not a natural host for Aspergillus. The fungus “normally wants to hang out in a compost pile– as that’s its natural habitat,” Hohl said. During its lifecycle, the fungus forms airborne spores called conidia that disperse in the air. Humans breathe in the spores on a daily basis. When inhaled, the spores try to germinate in the lung, a process that, if left unchecked, results in harmful fungal filaments that bore into tissues. A healthy immune system recognizes germinating spores and clears them quickly. Invasive fungal infections are more common now than 20 years ago, Hohl said. “This is a disease that we’ve really enabled to flourish because of advances in medical technology,” he said. Medical improvements that allow cancer and transplant patients to live longer in immune-suppressed states also give opportunistic pathogens such as Aspergillus the chance to take hold.
To help improve care for immunocompromised patients, scientists must first understand how the healthy immune system effectively clears Aspergillus on its own. During his fellowship, Hohl found that the receptor protein Dectin-1, which binds the sugar β-glucan, is important for host recognition of Aspergillus. Airborne spores do not have β-glucan on their surface, but when spores germinate, β-glucan is produced on the surface of the fungus, and the mammalian immune system uses this difference to detect the threat posed by germinating spores and filaments.
In a follow-up study, Hohl looked at the mechanism of how a specific class of antifungal drugs, echinocandins, kills Aspergillus. Echinocandin drugs target the synthesis of fungal b-glucan. Surprisingly, these drugs don’t kill Aspergillus particularly well in a petri dish, Hohl said, but are effective at treating infections in live animals. Hohl found that echinocandin drugs stimulate cells of the immune system to mount heightened inflammatory responses to Aspergillus. This occurs because echinocandin drugs cause b-glucan to accumulate on the surface of Aspergillus filaments, thus enabling the drug-treated filaments to be more easily recognized by macrophages and neutrophils.
“This is a really novel mechanism of drug action,” Hohl said. It is unusual to find a drug that kills pathogens effectively in the body but does not kill them well in a petri dish within the lab setting. This finding also demonstrates the importance of studying antibiotics in the context of the immune system to avoid missing useful effects that cannot be discovered by direct microbial killing assays.
In his newly founded lab at the Center, Hohl will continue work to elucidate how the immune system battles Aspergillus, and how that knowledge might be applied to treatments for immunocompromised patients. There is evidence that other signaling proteins, for example members of Toll-like receptor family, may contribute to immune responses against Aspergillus. To identify the immune cells involved in recognizing Aspergillus, Hohl has developed a transgenic mouse line to examine the role of monocytes, white blood cells that circulate and give rise to certain types of immune cells in the lung, in initiating immune responses against Aspergillus.
Hohl is also excited at the prospect of forming collaborations with established VIDI members to focus on identifying genetic factors that influence the risk of contracting an invasive Aspergillus infection in highly vulnerable patient groups, thus enabling clinicians to better predict which patients may benefit from prophylactic drugs.
In an effort to look for molecules that bind to Aspergillus and prevent its germination or growth, Hohl has formed a collaboration with Dr. Sean Gray of the Seattle Biomedical Research Institute to engineer large libraries of antibody-like molecules that bind to Aspergillus. Ideally, screening large combinatorial libraries could yield molecules that inhibit fungal germination or growth and could be used to help prevent or treat invasive infections in immunocompromised patients by augmenting the host immune defense during vulnerable periods, Hohl said.
Hohl joined the Center on May 1st, and was honored July 22 with a young investigator award from the American Society for Microbiology. The award will be presented in September at the Interscience Conference on Antimicrobial Agents and Chemotherapy.