An enduring association? Microfilariae and immunosupression in lymphatic filariasis

O’Connor, Richard A.; Jenson, Jessica S.; Osborne, Julie; Devaney, Eileen

doi:10.1016/j.pt.2003.09.017

Cited by 28 publications

(21 citation statements)

References 54 publications

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“…The time of onset of microfilaremia is also associated with maximal immune suppression in a range of animal models (17,(25)(26)(27)(28). In agreement with these findings, studies in mice using i.v.…”

supporting

confidence: 61%

“…Studies in humans and animal models have demonstrated that immune inhibition extends to many arms of the immune response, including DC (33,46), macrophages/monocytes (12,47), and T cells (7,48), and that parasites secrete numerous molecules to aid in this task (45). These and other studies indicate that the mechanisms of filarial suppression differ according to the stage of the life cycle, and that patency is a turning point at which maximal suppression occurs (17,(25)(26)(27)(28). Using L. sigmodontis infection of susceptible BALB/c mice to follow the development of filarial infection to patency, we have previously demonstrated that immune regulation takes hold as the infection progresses.…”

Section: Discussionmentioning

confidence: 92%

“…There is clear evidence during human infection that APC function is compromised (11,12), and rodent models of filarial infection have demonstrated a variety of mechanisms by which filarial parasites immunosuppress their host (13)(14)(15)(16)(17)(18)(19). Mosquito-borne Brugia malayi L3 larvae are able to down-regulate expression of MHC class I and class II on human Langerhans cells and to inhibit their ability to activate T cells in vitro (20), whereas the same parasites, if injected into the murine peritoneal cavity, induce suppressive nematode-elicited macrophages (NeM) 3 that are able to block T cell proliferative responses (21).…”

mentioning

confidence: 99%

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F4/80+ Alternatively Activated Macrophages Control CD4+ T Cell Hyporesponsiveness at Sites Peripheral to Filarial Infection

Taylor

Harris

Nair

et al. 2006

The Journal of Immunology

105

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Both T cells and APC have been strongly implicated in the immune suppression observed during filarial nematode infections, but their relative roles are poorly understood, particularly in regard to timing and locality of action. Using Litomosoides sigmodontis infection of susceptible BALB/c mice, we have studied the progression of filarial immunosuppression leading to patent infection with blood microfilaremia. Patent infection is associated with decreased immune responsiveness in the draining thoracic lymph nodes (tLN) and intrinsically hyporesponsive CD4+ T cells at the infection site. We now show that we are able to separate, both in time and space, different suppressive mechanisms and cell populations that contribute to filarial hyporesponsiveness. L. sigmodontis infection recruited a F4/80+ population of alternatively activated macrophages that potently inhibited Ag-specific CD4+ T cell proliferative responses even in the presence of competent naive APC. T cell responsiveness was partially restored by neutralizing TGF-β, but not by blocking IL-10 or CTLA-4 signaling. During prepatent infection, the macrophage population was restricted to the infection site. However, once infection became patent with systemic release of microfilariae, the suppressive macrophage activity extended peripherally into the tLN. In contrast, the hyporesponsive CD4+ T cell phenotype remained localized at the infection site, and the tLN CD4+ T cell population recovered full Ag responsiveness in the absence of suppressive macrophages. Filarial immunosuppression, therefore, evolves over time at sites increasingly distal to infection, and the mechanisms of filarial down-regulation are dependent on proximity to the infection site.

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supporting

confidence: 61%

Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 99%

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F4/80+ Alternatively Activated Macrophages Control CD4+ T Cell Hyporesponsiveness at Sites Peripheral to Filarial Infection

Taylor

Harris

Nair

et al. 2006

The Journal of Immunology

105

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“…TGF-␤1 has been shown to inhibit protective immune responses to infections with a number of intracellular pathogens, including Plasmodium (35,36,38,48). Chronic filarial infections in humans and laboratory animals have been shown to induce increased production of IL-10 and TGF-␤ by regulatory T cells, which is thought to facilitate the chronic course of filarial infection (2,13,34,40). Taken together, these results suggest that immunosuppressive cytokines induced during helminth infection mediate helminth-associated immunosuppression.…”

Section: Vol 73 2005 Modulation Of Antimalarial Immunity By Nematodmentioning

confidence: 85%

Impairment of Protective Immunity to Blood-Stage Malaria by Concurrent Nematode Infection

et al. 2005

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Helminthiases, which are highly prevalent in areas where malaria is endemic, have been shown to modulate or suppress the immune response to unrelated antigens or pathogens. In this study, we established a murine model of coinfection with a gastrointestinal nematode parasite, Heligmosomoides polygyrus, and the blood-stage malaria parasite Plasmodium chabaudi AS in order to investigate the modulation of antimalarial immunity by concurrent nematode infection. Chronic infection with the nematode for 2, 3, or 5 weeks before P. chabaudi AS infection severely impaired the ability of C57BL/6 mice to control malaria, as demonstrated by severe mortality and significantly increased malaria peak parasitemia levels. Coinfected mice produced significantly lower levels of gamma interferon (IFN-␥) during P. chabaudi AS infection than mice infected with malaria alone. Concurrent nematode infection also suppressed production of type 1-associated, malaria-specific immunoglobulin G2a. Mice either infected with the nematode alone or coinfected with the nematode and malaria had high transforming growth factor ␤1 (TGF-␤1) levels, and concurrent nematode and malaria infections resulted in high levels of interleukin-10 in vivo. Splenic CD11c ؉ dendritic cells (DC) from mice infected with malaria alone and coinfected mice showed similarly increased expression of CD40, CD80, and CD86, but DC from coinfected mice were unable to induce CD4 ؉ T-cell proliferation and optimal IFN-␥ production in response to the malaria antigen in vitro. Importantly, treatment of nematode-infected mice with an anthelmintic drug prior to malaria infection fully restored protective antimalarial immunity and reduced TGF-␤1 levels. These results demonstrate that concurrent nematode infection strongly modulates multiple aspects of immunity to bloodstage malaria and consequently impairs the development of protective antimalarial immunity.

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“…Brattig et al [26] reported that blood cells from patients with Onchocerca volvulus, when incubated in vitro with the WSP, produced high levels of IL-10 and the authors suggest that Wolbachia may contribute to the downregulation of pro-inflammatory mediators, thus establishing the necessary homeostasis for chronic infection. O'Connor et al [32] reviewed the role of NO in filarial disease, reporting evidence that several filarial antigens (microfilarial extracts, filarial cystatins) are capable of inducing NO production in vivo and in vitro. The authors suggest that this, in turn, may induce peripheral tolerance through NO-mediated apoptosis of antigen-specific T lymphocytes.…”

Section: Implications For the Immunopathology Of Filariasismentioning

confidence: 99%

Wolbachia and Its Implications for the Immunopathology of Filariasis

Genchi¹,

Kramer²,

Sassera³

et al. 2012

EMIDDT

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Filarial infections are characterized by immunopathological phenomena, that are responsible for the onset of often dramatic pathological outcomes, such as blindness (Onchocerca volvulus) and elephantiasis (W. bancrofti). In addition, the long-term survival (as long as 10 years) of these parasites in otherwise immunocompetent hosts indicates that these nematodes are capable of manipulating the host immune response. The ground-breaking discovery of the bacterial endosymbiont Wolbachia, which resides in most filarial nematodes causing disease, has led to increasing interest in the role it may play in immuno-modulation, pro-inflammatory pathology and other aspects of filarial infection. Indeed, Wolbachia has been shown to be responsible for exacerbating inflammation (as in river blindness), while at the same time blocking efficient elimination of parasites through the host immune response (Onchocerca ochengi). While studies aimed at identifying Wolbachia as a potential target for anti-filarial therapy are at the forefront of current research, understanding its role in the immunology of filarial infection is a fascinating field that has yet to uncover many secrets.

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An enduring association? Microfilariae and immunosupression in lymphatic filariasis

Cited by 28 publications

References 54 publications

F4/80+ Alternatively Activated Macrophages Control CD4+ T Cell Hyporesponsiveness at Sites Peripheral to Filarial Infection

F4/80+ Alternatively Activated Macrophages Control CD4+ T Cell Hyporesponsiveness at Sites Peripheral to Filarial Infection

Impairment of Protective Immunity to Blood-Stage Malaria by Concurrent Nematode Infection

Wolbachia and Its Implications for the Immunopathology of Filariasis

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