Macrophages in the Liver Capture Fungi, Limiting Dissemination

Dissemination of fungi, including Cryptococcus neoformans and Candida albicans, is limited by liver macrophages, according to a new study from the University of Maryland.

The liver plays an important role in preventing invasive fungal infections, according to new research that could inform future treatment options.

The study, published in the journal Nature Communications, found that liver macrophages called Kupffer cells (KCs) capture fungi in the bloodstream.

“The liver is the largest solid organ in the body,” Meiqing Shi, DVM, PhD, associate professor with the University of Maryland Department of Veterinary Medicine, told Contagion®. “There is a large amount of blood going through the liver. Now we discover that the liver plays a prominent role in filtering disseminating fungi from the blood through liver resident macrophages. Thus, we have identified a previously undescribed mechanism to limit fungal dissemination.”

Using intravital microscopy, investigators examined mouse models infected with Cryptococcus neoformans and Candida albicans and observed the liver KCs capturing fungal cells.

“The target organs for invasive Cryptococcus and Candida are the brain and kidney, respectively,” Shi told Contagion®. “The liver is not the target organ of fungi. Thus, very few studies focus on the liver during fungal infections. However, recent clinical data suggest that patients with liver disease are more susceptible to Cryptococcosis. The reason was not clear. With this question in mind, we decided to study the liver during fungal infection. We surprisingly discovered that the liver plays an important role in filtering the disseminating fungi out of circulation.”

Yeast cells injected into mice appeared to move at the same speed as blood before stopping in the liver. Investigators examined the role of KCs in the capture of fungi by using clodronate liposomes (CLL) to deplete KCs and comparing the response to that of a control group.

Invasive fungal infections affect 1.2 billion people worldwide each year and kill 1.5 million people each year. The fungi examined in the study are pervasive and difficult to treat if they get into the bloodstream. Cryptococcus is the main cause of meningitis, which kills about 60% of those who contract the disease. A recent study found that cryptococcal meningitis is a leading cause of death among adults living with HIV in Africa.

“We would like to take a look at whether enhancing the function of liver macrophages ameliorates the disease,” Shi said.

Health care practitioners should be aware of the increased risk of fatal fungal infections for patients with liver disease.

Investigators have been searching for new treatments for invasive fungal infections. A recent study suggested that chloroquine and primaquine diphosphate may be good candidates for slowing the growth of Cryptococcus.

The whole-system approach of the University of Maryland study shows promise for reducing the need for such treatments by preventing the spread of fungi and associated invasive infections.

“Stopping the dissemination process throughout the body is so important, because once you get dissemination, you get the disease,” Shi said in a news release. “These findings suggest therapeutic strategies for preventing dissemination, and this could be applied across many types of fungal infections, since they work in similar ways.”