A link between Il-1beta and helminth chronicity

Posted by Kasra

In contrary to many bacterial infections (TB put aside) helminth infections have the reputation of being chronic, not causing much short term damage and manipulating the host immune response. A Th2 response is canonically considered to be protective against helminth infection. However, there is a twist. In a recent publication in PLoS Pathogens, Zaiss et al. show that the worm alters the strength of the immune response a

Zaiss et al.  infect mice with Heligmosomoides polygyrus bakeri , which is a murine helminth parasite with phenotypes similar to those of humans. Within a few days they observe increased levels of IL-1beta in the peritoneum as well as the small intestine tissue. IL1-beta is a strong and tightly regulated pro-inflammatory cytokine. They authors suggest this cytokine to be produced by macrophages and DCs in the in the intestine. When infecting IL1-beta-/- mice the worm burden and amount of eggs shed in the feces drops drastically.

When purifying  spleen and mesenteric lymph node T cells from H. polygyrus infected IL1beta-/- mice, they see a larger population of IL-4 and IL-13 producing cells compared to wildtype mice, suggesting a stronger Th2 immune response. Following this up, they also observe an increase in IL-25 and IL-33, other Th2 cytokines. The authors show that the intestinal epithelial cells express the receptor for IL-1beta and could be producing these cytokines. Surprisingly, looking at IL-25 and IL-33 knock-out mice shows that only IL-25 reduces worm burden and not IL-33. Finally, the authors show that IL-1beta can attenuates the type 2 innate lymphoid cells (ILC2) which also contribute to the Th2 response to the infection. Together the authors suggest that induction of IL-1beta by the helminth dampens the Th2 response and results in helminth chronicity.

A schematic of proposed mechanism for immune response to H. polygyrus bakeri. From Zaiss MM et al., PLoS Pathog 9(8): e1003531. doi:10.1371/journal.ppat.1003531

As I mentioned above, IL1-beta secretion is very tightly regulated. A Pathogen-Associated-Molecular Pattern (PAMP) is required for its expression and a secondary signal through the inflammasome is required for its maturation and release. It appears that H. polygyrus provides both of the signals. Observing inflammasome activation by helminths is rather new. Doing a quick Pubmed search for  ‘inflammasome AND helminth’ I only found two papers, but I guess the list would grow. Pinning down the mechanisms by which the worms manage to activate this pathway would be very interesting, and also we would need to see if similar to H. polygyrus other worms also abuse this pathway in their benefit.

Zaiss MM, Maslowski KM, Mosconi I, Guenat N, Marsland BJ, & Harris NL (2013). IL-1β Suppresses Innate IL-25 and IL-33 Production and Maintains Helminth Chronicity. PLoS pathogens, 9 (8) PMID: 23935505

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Helminths release anti-microbial peptide-like molecules that are immunomodulatory

Posted by Kasra

In this paper, the authors have studied peptides that are found secreted by helminths Schistosoma mansonai and Fasciola hepatica and closely resemble mammalian antimicrobial peptidescathelidins to be precise.

First, the backgrounds: S. mansonai and F. hepatica are both trematodes or flukes. Their cyst form can be ingested via contaminated food or water and in the gut they hatch and can migrate to the liver. Like many other parasites, they don’t kill but cause morbidity. They are categorized as neglected tropical diseases and their infections are treatable and obviously preventable.

Anti-microbial peptides are very diverse in sequence and functions among different organisms, but there are similarities in their secondary and tertiary structures. They are produced by many multicellular organisms and their activities can range from bacteriocidal to immune modulatory. Some peptides can have both functions simultaneously,

Thivierge et al. start their paper by an interesting notion: the similarity of the innate immune response to helminths with the immune response to wounds and tissue injury. They are both anti-inflammatory and pro-Th2. Skewing the immune response from Th1 to Th2 and thus leading to less pathology as well as parasite chronicity is a recurring theme in parasite immunology. Read a full review here.

The peptides studied in this paper have similar secondary structure to alpha helical mammalian antimicrobial peptides (Cathelicidins) such as LL-37 and BMAP-28. A feature of these peptides is presence of amphi-pathic helices (hydrophobic on one side and hydrophilic on another side). This was also seen in the predicted secondary structures of peptides that were found to be secreted from S. mansonai and F. hepatica. 

Following this, the authors studied the peptides for a variety of anti-microbial and toxicity activities that are seen with mammalian peptides and found none to be present even at high doses (things such as pore formation, . However, what they did find was the peptides’ ability to modulate functions of immune cells. In this particular case they report inhibition of TNF secretion by macrophages and alteration of antibody secretion by B cells.

Similar secondary structure among mammalian and helminth peptides. (A) shows mammalian peptides with hydrophilic areas marked green and hydrophobic areas marked red. The dotted line and arrows in (B) show hydrophobic patches in the helmnith peptides. From Thivierge et al. 2013. PLoS Negl Trop Dis 7(7): e2307. doi:10.1371/journal.pntd.0002307

What the authors argue from their results is that the similar structure of these peptides to mammalian peptides and yet lack of toxicity allows them to effectively manipulate the immune response in their favor. These modulations could help in blunting of a strong Th1 response with lots of damage to the parasite as well as the host tissue and a milder response leading to parasite chronicity. Knocked-out parasites will better show the extent of importance of these peptides. Nontheless, longterm co-evolution of host and parasites has given rise to these peptides: they are nontoxic and modulatory at least in vitro.  This means plenty of potential in biotech and pharmaceutics!

Thivierge K, Cotton S, Schaefer DA, Riggs MW, To J, Lund ME, Robinson MW, Dalton JP, & Donnelly SM (2013). Cathelicidin-like Helminth Defence Molecules (HDMs): Absence of Cytotoxic, Anti-microbial and Anti-protozoan Activities Imply a Specific Adaptation to Immune Modulation. PLoS neglected tropical diseases, 7 (7) PMID: 23875042

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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

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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
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