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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Immunology meets epidemiology: A closer look at super spreaders

Posted by Kasra

Recent work by Gopinath et al. published in PLoS Pathogens touches a crucial issue in epidemiology of infectious diseases. We tend to look at infectious diseases as infecting everyone more or less uniformly. But many studies have shown that a great extent of heterogeneity exists in the amount of pathogen that is spread from infected individuals. The common rule is a 80-20 rule: it says that 20% of infected individuals account for 80% of disease spread. To learn more about this phenomenon and the research behind it, you can have a look at this comment published in Nature news and views. This rule appears to stand for many infectious diseases capable of causing epidemics. Therefore, studying and identifying the super spreaders –  or as this study puts them super shedders –  is of critical importance.  This study has tried to shed some light on the differences of the immune system of these individuals compared to normal shedders.

The authors use a special model of Salmonella enterica infection of mice where longterm infection was sustainable without the mice succumbing to disease. They then compared mice that very high numbers of bacteria present in their stool (two logs higher than what is normally expected of moderate shedders) with normally infected mice.

Comparing the immune response between moderate and supper shedders, the authors find that although the bacterial load in the gastrointestinal tract is highly different between the two groups of mice, the amount of bacteria in systemic organs such as the spleen is the same, so is the overall appearance of the mice. However, they find an enhanced innate immune response in the supper shedders marked with higher IL-6, a pro-inflammatory cytokine, in the serum and more neutrophils in the blood and other organs. On the other hand, they observe a reduction in the ratio of Th1 lymphocytes to regulatory T cells. The authors also found Th1 cells to be less responsive to proliferation-inducing cytokine IL-2.

Interestingly, the authors were able to induce some of the super shedder ‘characteristics’ by giving streptomycin to moderate shedder mice, probably giving room for Salmonella to expand in the altered microbiota. This further suggests that the observed immune characteristics are due to the bacterial load present in the gut. Finally, they look at the possible connection between neutrophil expansion and reduction in Th1 responsiveness.

Immunological differences between super shedder and moderate shedder Salmonella infected mice

The authors argue that to the be able to contain such a high bacterial load in the body, the organism would either have a weaker inflammatory response, or a way to dampen adaptive response to reduce the cost of high inflammation to the body. This is among the first steps in understanding the nature of the immune response in super spreaders. It would be interesting to see if this is a general theme in all host-pathogen interactions when super spreading occurs, or if it is different with every pathogen. This kind of research can importantly lead to better understanding of the immune response and hopefully also molecular markers that would help rapid identification the super spreaders and better control of disease outbreaks.

Gopinath S, Hotson A, Johns J, Nolan G, & Monack D (2013). The Systemic Immune State of Super-shedder Mice Is Characterized by a Unique Neutrophil-dependent Blunting of TH1 Responses. PLoS pathogens, 9 (6) PMID: 23754944

Galvani AP, & May RM (2005). Epidemiology: dimensions of superspreading. Nature, 438 (7066), 293-5 PMID: 16292292

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