Although the host type-2 immune response can mediate protective immunity against intestinal nematode parasites, the mechanisms involved remain uncertain and as yet effective vaccines have not been developed. While type 1 innate immune mechanisms of host resistance against microbial pathogens, such as many viruses and bacteria, are well described, relatively little is know regarding type 2 innate immune mechanisms of resistance to multicellular parasites. In natural infections, helminths often invade the skin, migrate to the lung, and then enter the intestine. Although previous studies have primarily examined worm expulsion in the enteric region, recent studies suggest that the lung may be a significant and novel target for enhancing worm expulsion. In the proposed studies, we will examine the innate immune cell populations mediating accelerated worm expulsion in the lung after secondary inoculation. Previous studies indicate that the intestinal nematode parasite, N. brasiliensis, is rapidly expulsed through immune mechanisms in the lung after secondary but not primary inoculation. This response occurs independently of adaptive immunity, with persistent innate immune cell populations likely mediating the rapid expulsion. We will utilize a novel adoptive transfer system developed in our laboratory where macrophages transferred from lungs of primed donor mice mediate accelerated worm expulsion in na?ve recipients. In complementary in vitro culture systems the primed effector macrophages adhere to N. brasiliensis larvae, causing impaired metabolism and increased larval mortality. These in vivo and in vitro model systems will be used to investigate mechanisms of macrophage-mediated worm damage and accelerated expulsion. In the first aim, we will interrogate the immune milieu supporting effector macrophage development after primary inoculation. Intriguingly, we show in the preliminary results that neutrophils are essential for development of these effector macrophages. We will characterize this interaction and also examine other potential immune cell interactions. This effector macrophage population retains a long- lived persistent phenotype capable of mediating accelerated worm expulsion. We will examine the plasticity of this population and its capacity to maintain this phenotype in different immune microenvironments. In the second aim, we will investigate the actual innate immune mechanisms that contribute to worm expulsion during the secondary response. Using in vitro and in vivo model systems, we will examine how macrophages mediate accelerated worm expulsion. We will focus on specific candidate molecules and metabolic pathways that may be important in this macrophage effector function. We will further examine whether specific innate immune cell populations interact with effector macrophages to ultimately contribute to accelerated expulsion. Thus, the model systems that we have developed in our laboratory provide the necessary tools to explore type 2 innate immune mechanisms of helminth resistance and the proposed experiments will provide important insights into this little studied yet highly significant area of immunity and infectious disease.
Helminth parasites infect more than 2 billion people worldwide causing considerable morbidity, impaired child development, and potentially increased susceptibility to other infectious diseases. Despite this, the immune response is not yet well understood with arguably insufficient knowledge to develop effective immunotherapies against disease. In this proposal we will focus on immune mechanisms that mediate worm damage and expulsion and by using a model system developed in our laboratory, we will elucidate the function of immune cell populations in mediating accelerated worm expulsion after exposure to helminth infection.
|Mishra, P K; Palma, M; Bleich, D et al. (2014) Systemic impact of intestinal helminth infections. Mucosal Immunol 7:753-62|
|Chen, Fei; Wu, Wenhui; Millman, Ariel et al. (2014) Neutrophils prime a long-lived effector macrophage phenotype that mediates accelerated helminth expulsion. Nat Immunol 15:938-46|