Synergism ofGamma Interferon and Interleukin-5 in the Control of MurineFilariasis

Abstract

There has been a prevailing perception that Th1 and Th2 immune responses induce antagonistic immune effector mechanisms during an infection. We investigated the role of the Th1 cytokine gamma interferon (IFN-␥) and the Th2 cytokine interleukin-5 (IL-5) in murine filariasis infections with the rodent filarial nematode Litomosoides sigmodontis with regard to immune responses to the parasite. Earlier data showed an important role for IL-5 and IFN-␥ in effective immune responses to filarial infection. Therefore, in this study it was asked whether IL-5 and IFN-␥ act synergistically or antagonistically. Indeed, IL-5 as well as IFN-␥ knockout (KO) mice show a higher worm load than the wild-type controls. IFN-␥/IL-5 double-KO mice had a significantly higher worm load than any of the single-KO mice, suggesting a synergism between IFN-␥ and IL-5 in controlling worm infection. Neutrophils are known to play an important role for the containment and encapsulation process of the worms. In infected IFN-␥ KO, IL-5 KO, and IFN-␥/IL-5 double-KO mice, neutrophils were significantly reduced in chemotactic activity levels compared to controls. In addition, the level of phagocytosis activity of neutrophils from IFN-␥/IL-5 double-KO mice was further decreased in comparison to that of the single-KO mice. Levels of tumor necrosis factor alpha, which is an important factor for neutrophil activation, were found to be reduced in macrophages from KO mice. In conclusion, these results argue for immune effector mechanisms in murine filarial infection that are dependent on both IFN-␥ and IL-5. Synergistic effects of the two cytokines may be mediated, at least in part, by neutrophils for the control of adult worms.There has been a common view that Th1 and Th2 immune responses act antagonistically toward each other. For example, a strong Th1 immune response is necessary for an effective immune reaction to Mycobacterium leprae. A Th2 response led to high level of susceptibility during this infection, and animals as well as humans were unable to control the infection (23,29,44). In C57BL/6 mice Leishmania major induces an effective Th1 immune response, while in BALB/c mice a nonprotective Th2 immune response is induced (1,14,38). Moreover, in this model it was shown that gamma interferon (IFN-␥) as a typical Th1 cytokine and interleukin-5 (IL-5) as a typical Th2 cytokine have antagonistic effects (38). In contrast, a strong Th2 immune response was reported to be important for survival of an infection with Schistosoma mansoni. Survival was attributed to the ability of Th2 cells to secrete cytokines that were antiinflammatory. A failure to produce anti-inflammatory cytokines (because of IL-4 deficiency) led to elevated production of inflammatory cytokines such as IFN-␥ and the death of the animals (8, 9, 15).Human filariasis puts at risk more than a 1 billion people and affects over 180 million people. Analysis of the role of the Th1 cytokine IFN-␥ and the Th2 cytokine IL-4 in a non-fullypermissive filarial model using Brugia malayi demonstrated tha...

Removal of Regulatory T Cell Activity Reverses Hyporesponsiveness and Leads to Filarial Parasite Clearance In Vivo

“…Of particular note was the increase in IL-5, a key cytokine in the development of immunity to L. sigmodontis larval stages, both in vaccination models and in primary infections (54 -56, 68). IL-5 is also strongly involved in the lethal response to adult L. sigmodontis worms after the establishment of patent infections (55,68). The increased production of IL-5 is therefore a likely candidate for orchestrating the clearance of adult worms after Ab treatments.…”

Helminth Infections and Host Immune Regulation

“…The L. sigmodontis model has shed light on mechanisms of immunity, specifically demonstrating that a mixed Th1/Th2 response is necessary to achieve protection. While IL-4-or IL-5-deficient mice are more susceptible to this infection (158,264), the susceptibility of IFN-␥/IL-5 double-deficient mice is further increased (240), arguing that combinations of Th1 and Th2 elements are required for protection. As in filariainfected humans, L. sigmodontis-infected mice develop an antigen-specific hypoproliferative defect alongside an expansion of regulatory T cells (277,278,280) and alternatively activated macrophages (279).…”

Role of Eosinophils and Neutrophils in Innate and Adaptive Protective Immunity to LarvalStrongyloides stercoralisin Mice

“…IL-5 has been associated with both eosinophil-mediated (27) and neutrophil-mediated (3,52,53) killing of nematode parasites. Therefore, it is possible that in the S. stercoralis mouse model IL-5 is required for eosinophils and neutrophils in the innate response and for neutrophils in the adaptive response.…”

“…Neutrophils have also been associated, based on histological analyses, with killing larval Ancylostoma caninum in mice (59). Finally, mice deficient in gamma interferon and IL-5 have a defect in neutrophil function which results in increased survival of Litomosoides sigmodontis (3,52,53). Therefore, the alterations in parasite survival observed in naïve or immunized mice deficient in or depleted of IL-5 may ultimately be caused by a defect in either eosinophils or neutrophils.…”