Monday, June 25, 2012

Clash of the titan- Survival strategy for Cryptococcus

Welcome back,

      As i was browsing through my blog, i noticed that i have completed a total of 25 posts (That's a silver jubilee). The 25th post was on a new technology of DNA sequencing. The response was great. What a great way to celebrate silver jubilee. Let me not dwell on the matter, but i noticed that i had posted only one post on "Mycology". So this time i decided to write on Cryptococcus. This blog-post has to do with a paper in "Eukaryotic cell" by Kirsten Nielsen, titled "Titan Cells Confer Protection from Phagocytosis in Cryptococcus neoformans Infections".

      Cryptococcus commonly known to be a yeast has its telomorphic state belonging to genus Filobasidiella. The fungal spores are usually inhaled as it is present widely in environment. In healthy individuals infection is cleared, or can remain in a latent form for prolonged periods of time. Both ways, the infection is not serious enough or clinically apparent in immuno-competent hosts. However, immuno-compromised individuals are at risk (Source). Typically, the spread of C. neoformans is limited to the lung and lymph nodes, but hematogenous dissemination may result in the seeding of other organs (Source). It is a well known fact that the cryptococcus neoformans has affinity to sphingolipids. The increased density of sphingolipid molecules correlates with thickening of the cell wall, hence with its biosynthesis (Source). The CNS has a high density of sphingolipids and hence a natural tendency for the pathogen to reside in CNS.

        As Dr Nielsen puts it "While most healthy individuals are resistant to Cryptococcus infections, the fungus can cause deadly disease for those with already weak immune systems".

Fig 1: Pathogenesis of Cryptococcus (Source James W. Kronstad etal).

        Though C neoformans has been the leader of fungal meningitis, a closely related species C gattii is now gaining importance. Classically, C neoformans was proposed to have 3 important virulence factors (Link).
  1. Growth at 37°C
  2. Capsule synthesis
  3. Melanin formation
Titan cells:

          Titan cells are an alternative nomenclature for giant cells formed in experimental infections of mice. This later was found to be important in human infections as well. Studies have shown that, the titan cell are a reproducible phenomenon, but their proportion is highly variable. cAMP signaling pathway is required for cryptococcal giant/titan cell formation. Members involved in the cAMP signaling pathway have been known to affect giant/titan cell formation. This includes Ste3a and Gpr5 (G-protein coupled receptors), transcription factor Rim101. Other proteins involved in cellular enlargement, like G1 cyclins, Rho-GTPases, and GTPases-activating proteins, suggests that titan formation requires the interplay of different pathways in the cell (Source).


Photo 1: Heterogeneity of fungal population extracted from the lungs of infected mice

Photo 2: Interaction between macrophages and cryptococcal giant/titan cells.

Photo 3: Titan cells (Source from Omics Group, Science blog)

        The summary of paper is that the titan cells were nearly 10-20 times the size of a normal cell, which is way too large for the immune system to get hold of and phagocytose. The point is the fungus beats the defence by sheer size. The more interesting fact is that the titan cell formation also conferred protection from phagocytosis to normal-size cryptococcal cells. It was also mentioned in the paper that the titan cells are crucial for Cryptococcus to survive phagocytosis, but that titan cell size in itself is not sufficient to provide the observed cross-protection of normal-size cryptococcal cells. There seems to be a missing link.

Photo 4: "Titan cells" protect the fungus Cryptococcus neoformans during infection.

        “This tells us that titan cell formation is an important aspect of the interaction between the human/host and the organism that allows Cryptococcus to cause disease,” said Nielsen. “This information will help us find new ways to treat Cryptococcus infections that are very difficult to treat with currently available drugs.” (Source).

       The bottom line is that a few titan/ giant cells formed by Cryptococcus neoformans is a survival strategy for the fungus, that helps in colonizing the pulmonary sites, and promotes the entire population survival.

Laura H. Okagaki, & Kirsten Nielsen (2012). Titan cells confer protection from phagocytosis in Cryptococcus neoformans infections Eukaryotic cell DOI: 10.1128/EC.00121-12

Further Reading:

1. James Kronstad, Won Hee Jung, Guanggan Hu. Beyond the Big Three: Systematic Analysis of Virulence Factors in Cryptococcus neoformans. Volume 4, Issue 4, 16 October 2008, Pages 308–310. Link

2. Oscar Zaragoza. Multiple disguises for the same party: the concepts of morphogenesis and phenotypic variations in Cryptococcus neoformans. Frontiers in Fungi and their Interactions. Link

3. Okagaki etal.  Cryptococcal Titan Cell Formation Is Regulated by G-Protein Signaling in Response to Multiple Stimuli. Eukaryot Cell. 2011 October; 10(10): 1306–1316. Link