Helminths and their implication in sepsis - a new branch of their immunomodulatory behaviour?

Abstract

The prevalence of autoimmune and allergic disorders has dramatically increased in developed countries, and it is believed that our 'cleaner living' reduces exposure to certain microorganisms and leads to deviated and/or reduced regulation of the immune system. In substantiation of this health hygiene hypothesis, multiple epidemiological studies and animal models have characterized the protective immune responses induced by helminths during auto-inflammatory disorders. The beneficial effects of such helminths, like schistosomes and filariae, are thought to lie in their immunomodulatory capacity, which can be induced by different life-cycle stages or components thereof. In addition to suppressing autoimmunity recent evidence indicates that concurrent helminth infections also counterbalance exacerbated pro-inflammatory immune responses that occur during sepsis, improving survival. As with allergy, epidemiological studies have observed a steady rise in severe sepsis cases and although this may have resulted from several factors (immunosuppressive drugs, chemotherapy, transplantation, increased awareness and increased surgical procedures), it is tempting to hypothesize that the lack of helminth infections in Western countries may have contributed to this phenomenon. This review summarizes how helminths modulate host immunity during sepsis, such as manipulating macrophage activation and provides an overview about the possible implications that may arise during overwhelming bacterial co-infections.

Keywords: CARS; SIRS; helminth; hygiene hypothesis; immunomodulation; sepsis.

Fig 1

Possible mechanisms by which helminths reduce excessive immune responses to Gram-negative bacteria. Lipopolysaccharide (LPS) from Gram-negative bacteria is bound by LPS binding protein (LBP) and forms a complex with MD2 and TLR4 on the surface of macrophages. TLR4 stimulation induces the release of pro-inflammatory cytokines and nitric oxide (NO) that lead to the recruitment of additional phagocytes like neutrophils (NO). Classical macrophages (MO) and neutrophils facilitate the bacterial clearance by phagocytosis and the production of anti-microbial products like NO. However, excessive inflammation, as it occurs during sepsis, activates neutrophils in the periphery and prevents their recruitment to the site of infection, impairing bacterial clearance. Excessive peripheral inflammation further triggers coagulation resulting in hypoperfusion of organs, organ failure and death. Helminth infections interfere with the development of excessive immune responses in different ways. Prevention of LPS induced TLR4 activation either by competing with LBP to bind LPS (FhDM-1) or blocking of TLR4 (chitohexase) reduce macrophage activation. Similarly, continuous signalling via TLR4 or TLR2 as it may occur during bacterial translocation or release of endosymbiotic Wolbachia bacteria that are present in most filarial nematode species may induce tolerance mechanisms in macrophages that prevent an excessive stimulation. It can be further speculated that helminth-induced regulatory T-cells and production of TGF-β and IL-10 counter-regulate inflammatory immune responses. Helminth induced Type 2 immune responses and helminth products (chitoexaose) further induce alternatively activated macrophages (AAM). AAM contribute to the anti-inflammatory cytokine production, reduce NO levels due to their arginase expression that competes with iNOS for arginine thus reducing inflammation and promoting wound healing. Although AAM have an impaired phagocytic capacity recent reports suggest that AAM can be reprogrammed into classical macrophages with potent anti-microbial mechanisms. Preventing excessive peripheral inflammation may furthermore facilitate the recruitment of neutrophils to the site of infection and improve bacterial clearance and local confinement of the infection. Accordingly, coagulation should be diminished and organ perfusion improved. Additionally, hookworm derived anti-coagulant factor rNAPc2 further inhibits coagulation directly. Helminth infection and helminth derived products may help to maintain immunological homeostasis during bacterial infections by preventing excessive inflammatory immune responses, the development of coagulation and improve sepsis pathology.

Fig 2

Possible impact of a helminth infection on the SIRS and CARS phase of sepsis. Initial helminth infections often induce a transient pro-inflammatory immune response that is followed by an anti-inflammatory, regulatory phase if the infection proceeds towards a chronic state. Upon bacterial induced sepsis an initial excessive pro-inflammatory immune response develops (SIRS, systemic inflammatory response syndrome) that is followed by a compensatory anti-inflammatory response syndrome (CARS) (solid red line). Without intervention excessive inflammation during SIRS may lead to severe pathology and death. In cases of CARS anti-inflammatory immune responses impair adaptive and innate immune responses and increase the risk for co-infections or the activation of dormant infections that cannot be controlled and lead to death. Due to the broad spectrum of immunomodulatory properties of helminths, it is now hypothesised that such parasitic infections could lead to dampened pro-inflammatory SIRS and CARS phases. This improved immunological homeostasis would therefore result in milder pathology and a reduced risk for opportunistic infections thus improving sepsis survival (solid green line). However, not all helminth infections appear to benefit the host and some appear to actually impair the initial bacterial control. Consequently, this facilitates bacterial replication and systemic translocation, leading to aggravated immune responses (SIRS) or the development of stronger immune paralysis (CARS), both of which result in an increased risk of mortality (dashed green line). Adapted from (Hotchkiss et al. 2009).