Article

Hookworm-Induced Persistent Changes to the Immunological Environment of the Lung

Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA.
Infection and immunity (Impact Factor: 4.16). 09/2008; 76(8):3511-24. DOI: 10.1128/IAI.00192-08
Source: PubMed

ABSTRACT A number of important helminth parasites of humans have incorporated short-term residence in the lungs as an obligate phase of their life cycles. The significance of this transient pulmonary exposure to the infection and immunity is not clear. Employing a rodent model of infection with hookworm (Nippostrongylus brasiliensis), we characterized the long-term changes in the immunological status of the lungs induced by parasite infection. At 36 days after infection, alterations included a sustained increase in the transcription of both Th2 and Th1 cytokines as well as a significant increase in the number and frequency of alveolar macrophages displaying an alternatively activated phenotype. While N. brasiliensis did not induce alternate activation of lung macrophages in STAT6(-/-) animals, the parasite did induce a robust Th17 response in the pulmonary environment, suggesting that STAT6 signaling plays a role in modulating Th17 immunity and pathology in the lungs. In the context of the cellular and molecular changes induced by N. brasiliensis infection, there was a significant reduction in overall airway responsiveness and lung inflammation in response to allergen. In addition, the N. brasiliensis-altered pulmonary environment showed dramatic alterations in the nature and number of genes that were up- and downregulated in the lung in response to allergen challenge. The results demonstrate that even a transient exposure to a helminth parasite can effect significant and protracted changes in the immunological environment of the lung and that these complex molecular and cellular changes are likely to play a role in modulating a subsequent allergen-induced inflammatory response.

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    • "An interesting possibility is that the Th2 response in the lung modifies the environment of the lung so that it is no longer supportive of N. brasiliensis development. Experiments by Reece et al. (2008) investigate the impact of N. brasiliensis infection on the lung environment using mRNA transcript level analysis of cytokines found that N. brasiliensis infection induces the development of alternately activated macrophages (AAMs) in a STAT6 dependent manner. This finding builds on the earlier work of Marsland et al. (2008) who also investigated lung pathology and saw the induction of alternately AAMs after N. brasiliensis infection . "
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    • "During nematode infections, macrophages acquire a special phenotype (named alternatively activated macrophages; AAMs) in response to the Th2 cytokines IL-4 and -13 (Loke et al. 2007; Reece et al. 2008; Siracusa et al. 2008; Gordon 2003). They are characterized by the expression of arginase-1, RELM-α, and YM-1, effector molecules involved in wound healing and protection against nematodes (Kreider et al. 2007). "
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    • "It should be noted that unlike the long-term changes observed in the lungs of mice infected with Nb alone (Reece et al., 2008), co-infected mice rapidly down-regulate expression of IL-4 and markers characterizing AAMs. Nb infection induces physical damage to the lung caused by larval migration (Marsland et al., 2008; Reece et al., 2008), and so one could attribute the enhanced Mtb growth observed in co-infected animals to the overall deterioration of lung function and not specifically to AAMs. However, the fact that co-infected IL-4R / mice were able to restrict Mtb Ar ticle 1871 In vitro studies have shown that virulent strains of Mtb can induce the production of Th2 cytokines, whereas avirulent strains tend to elicit Th1 cytokines (Manca et al., 2004; Freeman et al., 2006; Rook, 2007). "
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