Sunday, November 11, 2012

The puzzling Vomocytosis


      Late, late, late.... The post is now out at the last moment of the week. I know, i was supposed to be posting earlier. I was out this week, on a conference and have kept busy for a few days. But then, i just have thinks to talk about. Cause posting things here, at least in part helps me to analyze and remember concepts. Thats the way, it works for me.

Table 1: First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine
        Well, i don't have much to say as a breaking news of the week. But then the RTS,S vaccine seems to be failing from what was expected from it. 4 species P. falciparum, P. vivax, P. ovale and P. malariae are well known pathogens of malaria. P. knowlesi is a recent discovery in the list of pathogens and seen commonly in the South Asian regions. RTS is a hybrid polypeptide consisting of a portion of the circumsporozoite protein (CS), a sporozoite surface antigen of the malaria parasite P. falciparum strain NF54, fused to the amino-terminal end of the hepatitis B virus S protein. AS01 adjuvant System consists of a liquid suspension of liposomes with two immunostimulant components: 3’-O-desacyl-4’-monophosphoryl lipid A (MPL) and Quillaja saponaria 21 (QS21). The first results of the vaccine results was published in NEJM. The preliminary results was encouraging (See Table 1). As can be seen, the vaccine efficacy against clinical and severe malaria of nearly 50% among children 5 to 17 months of age.

      However the second end point published on November 2012 in NEJM, show that the vaccine efficacy in the second year, has dropped further. The study is a US$200 million project funded by the Bill gates foundation. Bill gates said "The efficacy came back lower than we had hoped, but developing a vaccine against a parasite is a very hard thing to do, The trial is continuing and we look forward to getting more data to help determine whether and how to deploy this vaccine". David Kaslow has a defensive statement to make "We always want to see high levels of protection, but I think we have shown again that RTS,S has an acceptable safety profile, and helps to provide protection against clinical malaria in the population". The completed data will be obtained only by 2014, which means much remains to be seen. As Kaslow says "To jump to conclusions is a disservice to the public". For source of information see here and here.

     The second highly discussed article of the week is by Joel V. Weinstock in Nature. The article discussed the approach of administering helminthic parasites (Preferentially as microscopic eggs) to people who have autoimmune disorders. Autoimmunity is a problem posed by the immune system chiefly because the cells of the immune system are improperly regulated. The infection by the worm can somehow dampens the extra immune response possibly by training Treg cells. The method has been found to be safe with very little side effects. That means i could think about administering a simple helminthic egg and treat people with conditions like asthma and Inflammatory bowel disease. Oh yes, a lot of work has been done before this on the subject. The most famous of this series include the hookworm administration to fight asthma. But retrospectively i could find many articles that argue against the hypothesis (Reference here and here). Probably this article will stimulate the search for a ground solid evidence.

     The last part of my post is Vomocytosis. You have most possibly heard of terms such as phagocytosis, pinocytosis, Endocytosis, exocytosis and more. But then this is most probably a new term for you. The term is not as famous as the others that i just mentioned. I just looked up into the Pubmed and found that there are just 3 articles (As of today on Nov 11, 2012) that talk about it. This pertains to a special feature exhibited by Cryptococcus neoformans, called as "Non-lytic exocytosis" or "Vomocytosis". I have previously written a post on a special set of cells called Titan cells, where you can give a background reading.

Fig 1: Vomocytosis
      A wide set of earlier laboratory investigations have pointed to a phenomenon where the phagosome containing C. neoformans undergoes acidification, fusion with lysosomes, and maturation. The punch line is almost any pathogen that wants to survive inside a phagocytic cell will interfere at least with one of the process there. Instead Cryptococcus enjoys sitting inside a fully mature vacuole without being effected. The secret lies in ability to produce highly powerful anti-oxidants that probably deconstructs the long time acidification. And when the fungus is interested in getting out of the vacuole at will. The mechanism of coming out without lysing the cell or interruption with cellular phagosome is called as Non lytic exocytosis or vomocytosis. This mechanism allows direct lateral spread of the fungus from one cell to another, first shown by Ma etal. This lateral transfer is not effected by cytochalasin D. That means the process is independent of actin based movement unlike other lateral pathogen transfer. The paper (from BMC) also shows 2 movie files on the lateral fungal transfer. You really need to give a look.

      Not much is known about the mechanism of vomocytosis. Its an open research question. What we know is, the phagosome containing the pathogen slowly swells due to secretion of capsular polysaccharide by the yeast. This swelling is followed by expulsion approximately after six hours, with a sudden expulsion. The pH of phagosome is thought to play an influential role. Neutralization of pH of vacuole can change the osmotic conditions which may in turn explain a sudden burst. A very detailed molecular study by Chayakulkeeree etal showed that cryptococcal expulsion from macrophages is CnPlb1 (Secreted phospholipase B1) -dependent (CnSEC14-1-dependent CnPlb1 secretion pathway).

     So i thought, what exactly does this CnPlb1 do? But then i couldn't find much data on its enzymatic activity. Nor am aware if the gene has been cloned and studied. But what i could find was CnPlb1 can reacylate lysophospholipids and reverse the damage caused to neutrophils by other secreted cryptococcal components (Djordjevic). Thats just interesting.

   The take home message is simple. Cryptococcus can get out of a macrophage by the mechansim called as vomocytosis, which is important in lateral transfer and dispersion of fungus within host. Is vomocytosis blocked by our immune system. Otherwise how do you explain Cryptococcal infection in Immunocompromised hosts only. Perhaps, much remains to be learnt.
Nicola AM, Robertson EJ, Albuquerque P, Derengowski Lda S, & Casadevall A (2011). Nonlytic exocytosis of Cryptococcus neoformans from macrophages occurs in vivo and is influenced by phagosomal pH. mBio, 2 (4) PMID: 21828219

Chayakulkeeree M, Johnston SA, Oei JB, Lev S, Williamson PR, Wilson CF, Zuo X, Leal AL, Vainstein MH, Meyer W, Sorrell TC, May RC, & Djordjevic JT (2011). SEC14 is a specific requirement for secretion of phospholipase B1 and pathogenicity of Cryptococcus neoformans. Molecular microbiology, 80 (4), 1088-101 PMID: 21453402

Further reading:

1. Hansong Ma, Joanne E Croudace, David A Lammas and Robin C May. Direct cell-to-cell spread of a pathogenic yeast. BMC Immunology (2007), 8:15. Link

2. Sabiiti W, May RC. Mechanisms of infection by the human fungal pathogen Cryptococcus neoformans. Future Microbiology. (2012 Nov) ;7 (11): 1297-313. Link

3. Julianne Teresa Djordjevic. Role of phospholipases in fungal fitness, pathogenicity, and drug development – lessons from Cryptococcus neoformans. Front. Microbio., 11 November 2010. Link

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