A Fumigatus Recruits Actin to Help Cross Key Barrier

New research posits a new method by which the fungal pathogen Aspergillus fumigatus is able to cross the first major barrier in its quest to infect a human host.

A team of French researchers wanted to understand how A. fumigatus is able to get past the airway epithelium, the first hurdle the spores face after being inhaled. First author Julien Fernandes, PhD, of the Pasteur Institute, and colleagues, used 2 approaches to study the question. They infected both primary human reconstituted pseudo-stratified epithelium cultured in an air-liquid interface and bronchial epithelial cell monolayers with A. fumigatus conidia.

Under observation in the lab, the fungus appeared to use the protein actin to create a tunnel through which the fungus’ hyphae could enter the human cell without disrupting its integrity. The findings represent a new, previously unknown method of infection by the pathogen.

“Our study describes a novel mechanism by which A. fumigatus gains entry into [human bronchial epithelial cells] by direct penetration of germ tubes without altering cell viability, by a mechanism requiring a complete reorganization of the host actin exoskeleton,” the authors wrote.

The study is important because A. fumigatus is known to be both ubiquitous and opportunistic, but the full effects of its opportunism haven’t been described. The fungus can lead to aspergillosis, but the condition usually only occurs in immunocompromised patients, such as patients with HIV or patients who have recently undergone an organ transplant.

A. fumigatus conidia are tiny—just 2 to 3 micrometers in diameter—which makes it possible for the spores to get as far as the lung alveoli. However, the authors note, ciliary beating is able to remove most of the spores from the lungs in an immunocompetent patient. Alveolar macrophages are able to destroy other spores.

However, evidence in previous research seemed to indicate that there was more to the story.

“Histopathological surveys of experimental animal infections suggested that penetration into the lung epithelium is not restricted to the deeper alveolar level, but that A. fumigatus germ tubes can also cross the epithelium of the upper respiratory tract,” the authors wrote.

Precisely how that happens hadn’t been closely investigated until now. Previous studies have posited that A. fumigatus conidia can be “internalized” by epithelial cells, where it theoretically germinates and then causes infection. But that research had been done using cell lines, rather than human reconstituted respiratory epithelia.

A. fumigatus isn’t alone in recruiting actin to assist in infection, according to the researchers. Many pathogens either recruit or interact with the protein.

“In the case of A. fumigatus, sensing of the cell wall molecules may trigger the formation of actin tunnels in the host epithelial cells,” the authors noted.

The researchers suggest that there are three steps to the actin-assisted infection process: adherence to the epithelial cell surface followed by an exertion of intracellular fungal osmotic pressure on the cells. The recognition of that pressure triggers the actin, which then sets in motion the tunneling mechanism.

Brian W. Christman, MD, a professor at Vanderbilt Medicine and a national spokesman for the American Lung Association, said Aspergillus fungi are all over the place—in the air and soil—but in the vast majority of cases, the body's defenses protect against it. He said this paper offers important insights into how such a potentially dangerous disease manages to take hold.

Dr Christman said a number of new drugs are currently in development that aim to affect the cell cytoskeleton, and it's possible such research could lead to a new way to stop the actin-tunneling mechanism of A. fumigatus. He said the research could also lead to new ways to treat invasive aspergillosis, or perhaps even to preventative measures that could be administered to all patients undergoing an organ transplant.

"If we can prevent them from getting in with a broad agent that prevents this actin tube formation, maybe we can prevent it," he told Contagion^®.

However, Dr Christman said a lot of research would be needed to develop and ensure the safety of any such treatment.

"There’s all kind of potential downsides and we have a lot to learn," he said.

Feature Picture Source: CDC's Public Health Image Library. Caption: This photomicrograph reveals a conidiophore that has branched from the hypha of an Aspergillus fumigatus fungal organism. The conidiophore gave rise to a cluster of phialoconidia, which are strands, or chains of conidia, or spores, that grow outward from each phialide. Note that there were also a number of scattered conidia, which had broken away from the conidial cluster.