Degradation of the intestinal mucus barrier by whipworm

Posted by: Kasra

I wrote recently about modulation of the host by intestinal worm Trichuris muris. Here is another brilliant study looking at the secreted proteins of this nematode and how they interact with the small intestine mucus.

 Hasnain et al. published in PLoS NTD that secreted proteins of T. muris contain serine proteases that are able to degrade the mucus barrier, especially Muc2. Interestingly, they observed that the components of the mucus barrier are different during acute versus chronic infection. When worm expulsion begins in acute infection of T. muris, Muc5a is also detected in the mucus, a protein which is normally not expressed in the intestinal mucus but in the lung. Muc5a is resistant to degradation by serine proteases of the parasite and probably helps in worm expulsion. This specific host response and change in mucus does not happen during chronic infection which results in continued stay of the worm in the intestine.

Secreted Proteins of T. muris degrade the mucus in chronic but not acute infection. This is due to upregulation of Muc5a in acute infection, which is resistant to the proteases. From Hasnain et al. PLoS NTD, doi:10.1371/journal.pntd.0001856.g003

Below is a schematic diagram of the structure of the mucus layer during acute and chronic infection and how Excreted Secreted Proteins (ESPs) of the parasite interact with it.

A schematic of how the mucus layer looks like during acute or chronic infection with T. muris. From Hasnain et al. PLoS NTD doi:10.1371/journal.pntd.0001856.g003

Hasnain SZ, McGuckin MA, Grencis RK, & Thornton DJ (2012). Serine Protease(s) Secreted by the Nematode Trichuris muris Degrade the Mucus Barrier. PLoS neglected tropical diseases, 6 (10) PMID: 23071854

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