The global prevalence of soil transmitted helminth infections is estimated at two billion individuals infected, with an estimated 870 million children at risk of becoming infected. Helminth infections can lead to significant malnutrition, growth retardation, severe immunopathology, and exert enormous economic burdens on local communities. Helminth parasites take complex migratory cycles through multiple tissues before entering the intestine of their host. To combat these challenges, the mammalian immune system has evolved mechanisms to maintain a delicate balance between promoting beneficial inflammation needed to reduce parasitic burdens and limiting pathologic inflammation to maintain tissue integrity. The importance of maintaining this balance is evident by the severe pathology that presents in patients exhibiting dysregulated immune responses to helminths. Despite the importance of balancing protective and pathologic responses in the context of helminth infections, the cellular and molecular events that regulate these pathways remain unknown. It is well established that T helper type 2 (TH2) cytokine responses, characteristics of helminth-induced immunity in humans and mice, are required to both promote worm clearance and limit infection-induced tissue damage. An emerging body of literature has now shown that type 2 cytokine-activated macrophages operate as critical regulators of these distinct pathways. In addition, our recent work has also demonstrated that interactions between neutrophils and lung macrophages are required for macrophages to acquire anti-Nippostrongylus brasiliensis (Nb) effector functions in the airways. Moreover, our preliminary data suggest that interactions with basophil populations are required for macrophages to initiate wound healing responses in the lung. Collectively these studies provide the hypothesis that coordinated interactions with Nb-primed innate immune cell populations are necessary for macrophages to acquire host protective effector functions. This will be directly tested in Aim 1 of this proposal focused on interrogating the accessory cells necessary to promote macrophage activation in the lung following Nb infection. It is well established that long-lived tissue-derived macrophages (TD-Macs) populate the lungs during fetal development, while monocyte-derived macrophages (Mo-Macs) accumulate in tissue environments in the context of ongoing inflammation. Further, it has been demonstrated that TD-Macs and Mo-Macs can exhibit distinct phenotypes in the context of helminth infections. Despite these advances the distinct contributions of TD-Macs and Mo-Macs to anti-helminth immunity and tissue integrity remain unknown. This will be directly tested in Aim 2 of this proposal focused on elucidating the distinct and common effector functions of lung macrophage populations following Nb infection.
These aims will be addressed employing the collective intellectual and scientific resources of the Siracusa and Gause laboratories and the results of these studies will increase our understanding of how pulmonary macrophages are programed in the context of acute inflammation.
Helminth parasites infect approximately 2 billion people worldwide and represent a significant health and economic challenge. While multiple studies have demonstrated an essential role for lung macrophages in promoting protective immunity and initiating wound healing following infection, the specific macrophage populations and accessory cells that promote these pathways remain unknown. This proposal will combine hypothesis-driven experiments and state-of-the-art discovery based methodologies to investigate how tissue- and monocyte-derived lung macrophages cooperate with accessory cells to promote host protective responses following a helminth challenge.
|Yap, George S; Gause, William C (2018) Helminth Infections Induce Tissue Tolerance Mitigating Immunopathology but Enhancing Microbial Pathogen Susceptibility. Front Immunol 9:2135|
|Inclan-Rico, Juan M; Siracusa, Mark C (2018) First Responders: Innate Immunity to Helminths. Trends Parasitol 34:861-880|