#FEMSmicroBlog: A fungal pathogen escaping macrophages


Cryptococcus neoformans is a pathogenic fungus which is facultative intracellular and can cause life-threatening diseases in humans with weakened immune systems. While in healthy individuals macrophages eat and control the growth of pathogens, the fungus developed an unusual strategy to avoid immune killing. The study “Cryptococcus neoformans releases proteins during intracellular residence that affect the outcome of the fungal-macrophage interaction” in microLife characterized different proteins that might be involved in this escape mechanism. Carolina Coelho and Arturo Casadevall explain for the #FEMSmicroBlog, how studying the released proteins from this pathogen helps better understand the interactions between C. neoformans and macrophages. #FascinatingMicrobes


Cryptococcus neoformans grows or persists

The fungus C. neoformans can persist in trees or bird dung, meaning that humans regularly inhale airborne particles from this pathogen. Within our airways, the immune cells, particularly macrophages, use their antimicrobial arsenal to prevent fungal growth and kill the fungus.

However, C. neoformans has evolved sophisticated mechanisms to withstand macrophage attacks and can remain dormant in the human body for years. This is a life-threatening situation for immuno-compromised people, for example AIDS patients.

Due to the immune defects caused by AIDS, macrophages in AIDS patients can no longer prevent fungal growth. Now this previously sleeping microbe can cause pneumonia and meningitis so that each year cryptococcal disease kills about 180,000 HIV+ individuals.

Whether a person develops cryptococcal disease or not depends on whether C. neoformans persists or grows within macrophages. Yet, the molecular mechanisms behind this determining event are still unclear. So, if we want to prevent the deadly cryptococcal disease, we need to deepen our understanding of the interactions between fungus and macrophages.


Cryptococcus neoformans resists our immune system

Phagocytosis is one of the most effective antimicrobial strategies of our immune system, during which macrophages eat and digest microbial invaders. Successful pathogens like Cryptococcus evolved to withstand this process in very sophisticated manners. After ingestion, the fungus can kill the macrophage and escape or it can exit the macrophage cell in a process in which the host cell survives.

This complex cell-cell interaction is called cryptococcal non-lytic exocytosis. During the process, the fungus releases molecules that manipulate the phagocytic and antimicrobial machinery of the macrophage.

The study Cryptococcus neoformans releases proteins during intracellular residence that affect the outcome of the fungal-macrophage interaction” in microLife described factors that are involved in Cryptococcus escape process. By using mass spectroscopy, the work showed that C. neoformans releases at least 127 proteins during intracellular residency into the macrophage cells. These proteins include several virulence factors as well as a protein from the ATP-binding cassette transporter family known as Yeast-Oligomycin Resistance protein 1 (Yor1).

Since there is little knowledge on how Yor1 contributes to fungal survival during infection, the study focused on this protein transporter. Yor1 likely interacts with macrophages as previous studies found that C. neoformans loads Yor1 into its extracellular vesicles.

Deleting Yor1 led to reduced non-lytic exocytosis and attenuated C. neoformans capacity to kill wax moth larvae. Although the precise mechanism by which Yor1 affects non-lytic exocytosis remains elusive, this new virulence factor could be involved in the transport of molecules across fungal surfaces; many of those are likely required for non-lytic exocytosis.

The protein transporter Yor1 helps Cryptococcus neoformans escape macrophages and cause disease.
Yor1 in Cryptococcus neoformans. From Jung et al. (2022).


Understanding Cryptococcus neoformans mechanisms of escape and virulence

The study established that C. neoformans releases numerous proteins into macrophages affecting the interactions with host cells. Each of these proteins now needs to be investigated independently to undrstand how they contribute to the escape process.

The mass spectrometric analysis also identified peptides which are associated with hypothetical proteins. Since their existence as proteins has not been yet fully confirmed, finding such peptides is a strong indication that these hypothetical proteins indeed deserve attention.

Finally, the study showed the power of mass spectroscopy, as it was able to identify a tiny percentage of fungal peptides within the enormous mass of host macrophage peptides. The technique used could be applied to other microbial pathogens to facilitate similarly exciting discoveries.


About the author of this story

Carolina Coelho was always interested in microbes and the diseases they cause. She completed a degree in Pharmaceutical Sciences at the University of Porto, Portugal. She further did her graduate studies in joint mentorship from Teresa Gonçalves at the University of Coimbra and Arturo Casadevall at Albert Einstein College of Medicine, Bronx, and continued research into the pathogenesis of Cryptococcus neoformans with Arturo Casadevall, who is now at Johns Hopkins Bloomberg School of Public Health, in Baltimore. Carolina just started her own research group at MRC Centre for Medical Mycology, where she studies the immunity to C. neoformans infections since this pathogen is responsible for almost 200,000 deaths each year, more than any other fungal pathogen.

Arturo Casadevall is a professor of medicine at the Johns Hopkins School of Medicine. He holds a joint appointment in molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health. His research focuses on how microbes cause disease and how the immune system defends itself. His team is currently engaged in understanding how hosts defend against the fungus C. neoformans.

About this blog section

The section #FascinatingMicrobes for the #FEMSmicroBlog explains the science behind a paper and highlights the significance and broader context of a recent finding. One of the main goals is to share the fascinating spectrum of microbes across all fields of microbiology.

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