While it is well established that infection with the rodent hookworm Nippostrongylus brasiliensis induces a strongly polarized Th2 immune response, little is known about the innate host-parasite interactions that lead to the development of this robust Th2 immunity. We exploited the transient pulmonary phase of N. brasiliensis development to study the innate immune responses induced by this helminth parasite in wild-type (WT) and severe-combined immune deficient (SCID) BALB/c mice. Histological analysis demonstrated that the cellular infiltrates caused by N. brasiliensis transit through the lungs were quickly resolved in WT mice but not in SCID mice. Microarray-based gene expression analysis demonstrated that there was a rapid induction of genes encoding molecules that participate in innate immunity and in repair/remodeling during days 2 to 4 postinfection in the lungs of WT and SCID mice. Of particular note was the rapid upregulation in both WT and SCID mice of the genes encoding YM1, FIZZ1, and Arg1, indicating a role for alternatively activated macrophages (AAMs) in pulmonary innate immunity. Immunohistochemistry revealed that nearly all alveolar macrophages became YM1-producing AAMs as early as day 2 postinfection. While the innate responses induced during the lung phase of N. brasiliensis infection were similar in complexity and magnitude in WT and SCID mice, only mice with functional T cells were capable of maintaining elevated levels of gene expression beyond the innate window of reactivity. The induction of alternatively activated alveolar macrophages could be important for dampening the level of inflammation in the lungs and contribute to the long-term decrease in pulmonary inflammation that has been associated with helminth infections.The cells and molecules that comprise the innate immune responses are the first line of defense against invading pathogenic organisms. In addition, innate immune mechanisms are important for the elimination of the myriad of nonpathogenic substances to which we are continuously exposed. In those circumstances in which the effector mechanisms of the innate response are not sufficient to fully eliminate a pathogen challenge, the same cells and molecules function to efficiently activate the antigen-specific adaptive arm of the immune response. In recent years, it has become clear that different modes of activation of innate immunity have a profound influence on the magnitude and the nature of subsequent adaptive responses (9,32,69).Parasitic nematodes are among the strongest natural inducers of polarized Th2 immune responses (2, 40, 60). Infection of mice with the intestinal nematode parasite Nippostrongylus brasiliensis has been used extensively to study the regulation of immunoglobulin E synthesis (31) and Th2 immunity in general (19,33). Despite the longstanding use of N. brasiliensis as a model, little is known about the innate immune responses that precede the induction of a highly polarized adaptive Th2 response to N. brasiliensis challenge. Indeed, there are only limite...

A blood-stage vaccine based on Plasmodium falciparum merozoite surface protein 3 (MSP3) was tested for efficacy in a primate model. Aotus nancymai monkeys were vaccinated with yeast-expressed MSP3 before a lethal challenge with Plasmodium falciparum parasites. Five of 7 control monkeys had acute infections and required treatment to control parasitemia. Only 1 of 7 monkeys vaccinated with MSP3 required this treatment. The efficacy of the MSP3 vaccination appeared to be comparable to that of MSP1(42), a leading asexual vaccine candidate, in response to which 2 monkeys experienced acute infections. In the MSP3-vaccinated group, protection correlated with prechallenge titers of antibody to MSP3. In the MSP1 and control groups, protection correlated with antibody to MSP3 raised by challenge infection.

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.Historically, an infection with one or multiple helminth parasites has been essentially universal for human populations. It is estimated that a majority of living humans have a history of or are currently infected with a helminth parasite, with the highest prevalence of exposure in developing areas (11). A number of important helminth parasites such as hookworm, Ascaris, and Schistosoma have incorporated a short-term residence in the lungs as an obligate phase of their life cycle. The significance of the lung phase to the developmental biology of these parasites has not been clearly defined. Equally unclear is the impact that the pulmonary phase has on the immunobiology and pathogenesis of infection and the nature and extent to which the immunological environment of the lung is altered by these transient exposures. If significant changes to the pulmonary environment do ensue, to what extent do they influence the level and nature of the responses to subsequent challenges from bacteria, fungi, viruses, and allergens?In recent decades, the incidence and prevalence of allergy and asthma have increased dramatically in industrialized nations, with no comparable increase in developing regions of the world (3, 9, 10, 39). Although a number of factors have been proposed to explain this difference in disease prevalence in developed and developing regions, incl...