|Siracusa, Mark - JOHNS HOPKINS U,BALTIMORE|
|Southard, Teresa - JOHNS HOPKINS U,BALTIMORE|
|Brayton, Cory - JOHNS HOPKINS U,BALTIMORE|
|Scott, Alan - JOHNS HOPKINS U,BALTIMORE|
Submitted to: Infection and Immunity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: May 27, 2008
Publication Date: June 27, 2008
Citation: Reece, J.J., Siracusa, M.C., Southard, T.L., Brayton, C.F., Urban Jr, J.F., Scott, A.L. 2008. Hookworm-induced persistent changes to the immunological environment of the lung. Infection and Immunity. 76(8):3511-24. Interpretive Summary: An interesting and seemingly contradictory relationship exists between allergies and infectious diseases. People infected with parasitic worms appear to have decreased allergic responses to environmental and food allergens. To evaluate this concept experimentally, mice were infected with a hookworm, Nippostrongylus brasiliensis, and exposed to dust mite allergen to model exposure of humans to worms and common allergens. The level of inflammation in the lungs, and cellular and molecular markers of allergic disease were measured. The hookworm travels through the lung very quickly after infection and then migrates to the intestine before expulsion. Although the worm is in the lungs for a very short time, changes in immune functions persisted over a month after infection. In addition, the changes induced by the worm reduced the lung response to dust mite allergen. The apparent mechanism of action included a reduction in inflammatory cells into the lungs and the activation of some resident cells to metabolize arginine in ways that contribute to tissue remodeling. The analysis included a characterization of the overall immune response using microarray technology. These results indicate that the worm infection changes the cellular and molecular pattern normally observed when allergens challenge the lung surface. These results are important as a model of human allergic disease, and provide researchers with a target to alter dysfunctional immune responses with products that mimic exposure to worms, including those introduced into the diet.
Technical Abstract: Results from epidemiological and laboratory studies indicate that immunological changes that ensue from a Th2-biased helminth infection result in a decrease in the intensity of subsequent Th2 responses. The Nippostrongylus brasiliensis (Nb) mouse model was used to study molecular and cellular changes in the lungs that accompany the protective effect of a helminth infection. Nb infection resulted in persistent changes to the immunological environment of the lung that were maintained through 36 days post-infection. The alterations were characterized by a sustained increase in the transcription of both Th2 (IL-4, IL-13, IL-5, IL-21, CCL11/Eotaxin) and Th1 (IFN, IL-12) cytokines. In addition, there was a significant increase in the number of CD11c+, F4/80+ alveolar macrophages with ~75% displaying an alternatively activated phenotype characterized by transcription of ym1, ym2, fizz1, and arg1 and increased surface expression of Mrc1 and Class II MHC. To test the functional significance of these cellular and molecular changes, Nb-infected mice were subsequently sensitized and challenged with house dust mite allergen. Nippostrongylus brasiliensis-infected mice showed a significant reduction in lung eosinophilia and overall airway responsiveness after allergen challenge compared to uninfected animals. This reduced allergic response in infected mice was accompanied by significant changes in the nature and number of genes that were up- and down-regulated 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 molecular and cellular changes play a role in modulating a subsequent allergen-induced inflammatory response.