Communication between intestinal commensal bacteria and the host via membrane vesicles

Posted by Kasra

Releasing outer membrane vesicles or OMVs of by bacteria can be considered one of their protein secretion pathways. This pathway is especially important for carrying messages to longer distances than what other mechanisms such as type III secretion system can do.

Although the gut is largely colonized, there is not much of direct cell to cell contact between the microbiota and the host cells due to presence of a thick mucosal layer and other factors. In a recent study, Shen et al. show that bacterial OMVs can make up for this distance and allow for communication between the microbiota and host. They show that orally administered OMVs collected from Bacteroides fragilis can protect mice from chemically induced colitis. Furthermore, they show that this protection is dependent on presence of a capsular polysaccharide (PSA) on the OMV surface. Shen et al. suggest that PSA-containing OMVs are picked up by dendritic cells and induce IL-10 production, thus ameliorating colitis. Specifically, they show that production of IL-10 by DCs is dependent on recognition of PSA by TLR2. Therefore, stimulation of TLR2 by B. fragilis OMVs leads to tolerance instead of inflammation, which is necessary for homeostatic maintenance of the gut.

 

Top shows B. fragilis releasing OMVs. Bottom shows purified B. fragilis OMVs from wildtype and non-PSA producing strains. From Shen et al. Cell host & Microbe. Oct. 2012

Shen Y, Torchia ML, Lawson GW, Karp CL, Ashwell JD, & Mazmanian SK (2012). Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell host & microbe, 12 (4), 509-20 PMID: 22999859

ResearchBlogging.org

Advertisements

Phosphatases for and against: Trichuris vs. Leishmania

Posted by Kasra

Trichuris trichiura adult male

Trichuris trichiura adult male – Image taken from DPDx

Trichuris, is an intestinal roundworm, also known as whipworm, that can be transmitted through ingestion of food contaminated with its eggs. The larvae hatch inside the small intestine and complete their life cycle to adults in the cecum. After maturation, which can take about 3 months, the female worm lays thousands of eggs per day. The parasite can stay in the intetine between 1-5 years. Trichuris trichiura is a parasite of humans, while Trichuris muris is a mouse parasite, used usually as the animal model to study its infection.

In contrast to intracellular pathogens, a Th1 response is non-protective in infection with large extracellular pathogens such as intestinal helminths. For instance, during infection with Trichuris muris, a Th2 response comprising IL-4 and Ig-E production leads to resolution of infection, while a Th1 response comprising IFN-gamma, IL-12 and IL-18 is not protective.

S Hadidi et al. look at regulation of the immune response to T. muris and focus on the importance of the macrophage lipid phosphatase Ship1. Ship1 or Sh-2 containing inositol 5′ phosphatase 1 is a regulator of the PI3K pathway. Hadidi et al. show that Ship1 expression is upregulated steadily following T. muris infection. Ship1-/- mice have higher parasite burden and IFN-gamma while lower levels of IL-13. Also, Ship1-/- macrophages produce more IL-12. Blocking IL-12 or IFN-gamma by blocking antibodies rescued the phenotype by reducing worm burden and increase in IL-13. Thus, they found how activity of this phosphatase can direct the immune response against T. muris infection. It would be very interesting now to see what stimuli induce upregulation of Ship1 and also what are this enzyme’s substrates, which are so important for production of IL-12 by macrophages.

Similar to this story, a few years ago, Abu-Dayyeh et al. and Gomez et al. showed that activating phosphatases is important for Leishmania to establish its infection. Being an intracellular parasite, a Th1 response, with large amounts of IFN-gamma would be protective against Leishmania. So in this context, Leishmania-mediated activation of many phosphatases (most importantly SHP-1) leading to inhibition of IL-12 production leads to disease progression, because it skews the immune response towards Th2. In this situation, Leishmania takes advantage of the phosphatase’s function.

Hadidi S, Antignano F, Hughes MR, Wang SK, Snyder K, Sammis GM, Kerr WG, McNagny KM, & Zaph C (2012). Myeloid cell-specific expression of Ship1 regulates IL-12 production and immunity to helminth infection. Mucosal immunology, 5 (5), 535-43 PMID: 22535180

Abu-Dayyeh I, Shio MT, Sato S, Akira S, Cousineau B, & Olivier M (2008). Leishmania-induced IRAK-1 inactivation is mediated by SHP-1 interacting with an evolutionarily conserved KTIM motif. PLoS neglected tropical diseases, 2 (12) PMID: 19104650
Gomez MA, Contreras I, Hallé M, Tremblay ML, McMaster RW, & Olivier M (2009). Leishmania GP63 alters host signaling through cleavage-activated protein tyrosine phosphatases. Science signaling, 2 (90) PMID: 19797268
ResearchBlogging.org

From Ivory Towers to Public Tribunes

Posted by Kasra

This is in continuation of a post by my old friend and classmate in his new exciting blog Genophoria. He expressed his rightful concerns about the rise of “Entertainment Science”, where he says scientists are coming out of their Ivory towers and shouting out their impressive and sometimes controversial findings to the public. It often happens that these controversial findings, or at least their conclusions in that regard are wrong. Scientists can accept that. Science is by nature self-correcting. But at the same time, for the public, they lose their credibility as truth-seekers which they claim to be.

It just happens that at this very time, PNAS has published a study on the statistics of retracted publications. Let’s not exaggerate. The percentage of retracted papers compared to number of publications is very very small. Still, their results were a bit surprising at least to me: 67% of them were retracted due to misconduct, either fraud or suspected fraud. Only 20% or so were due to error. Many questions arise: Has it always been like this? Only is it because there are more publications now and more screening? What percentage goes unnoticed? Most importantly, what were the underlying reasons for these fraudulent publications? Were they desperate Postdocs or PIs trying to win a Cell or a Nature to renew a fellowship or a grant? Or were they seeking something further, a socioeconomical, political or cultic purpose beyond science? These questions seek immediate attention and hopefully clear answers. Without any doubt, the fight for budget has become fiercer; and no, most scientists can no longer live in ivory towers, indifferent to the public and their attention – if they ever did. By the way, hadn’t you said earlier that by turning away from the public we turned from high-ranked academics into socially excluded geeks? We need to interact with the public, to rebuke false claims and promote logical thinking. I guess as you say, we are doing it wrong.

If the scientific community is willing to share the excitement of discoveries and controversies with the public, it should be more stringent in the peer-reviewing process of such claims. In retrospect, how many of the fraudulent retracted papers can be labelled as editorial or peer-review failures? Publishing in high-impact journals is getting harder and harder. But maybe during the peer-review, there should be a new focus on skepticism and a shrewd eye for biased claims, besides asking for more and more control experiments. At the same time, when presenting discoveries to the press, more transparency and accuracy about their nature and details are needed, so that a susceptibility SNP doesn’t turn into a cancer gene and an in vitro-tested compound into its ultimate cure.

Fang FC, Steen RG, & Casadevall A (2012). Misconduct accounts for the majority of retracted scientific publications. Proceedings of the National Academy of Sciences of the United States of America PMID: 23027971

ResearchBlogging.org