Schistosomes in the Lung: Immunobiology and Opportunity

Abstract

Schistosome infection is a major cause of global morbidity, particularly in sub-Saharan Africa. However, there is no effective vaccine for this major neglected tropical disease, and re-infection routinely occurs after chemotherapeutic treatment. Following invasion through the skin, larval schistosomula enter the circulatory system and migrate through the lung before maturing to adulthood in the mesenteric or urogenital vasculature. Eggs released from adult worms can become trapped in various tissues, with resultant inflammatory responses leading to hepato-splenic, intestinal, or urogenital disease - processes that have been extensively studied in recent years. In contrast, although lung pathology can occur in both the acute and chronic phases of schistosomiasis, the mechanisms underlying pulmonary disease are particularly poorly understood. In chronic infection, egg-mediated fibrosis and vascular destruction can lead to the formation of portosystemic shunts through which eggs can embolise to the lungs, where they can trigger granulomatous disease. Acute schistosomiasis, or Katayama syndrome, which is primarily evident in non-endemic individuals, occurs during pulmonary larval migration, maturation, and initial egg-production, often involving fever and a cough with an accompanying immune cell infiltrate into the lung. Importantly, lung migrating larvae are not just a cause of inflammation and pathology but are a key target for future vaccine design. However, vaccine efforts are hindered by a limited understanding of what constitutes a protective immune response to larvae. In this review, we explore the current understanding of pulmonary immune responses and inflammatory pathology in schistosomiasis, highlighting important unanswered questions and areas for future research.

Keywords: Katayama syndrome; acute; helminth; lung; pulmonary; schistosomiaisis.

Figure 1

Overview of lung immune responses during S. mansoni infection. Lung immune responses differ depending on the life cycle stage of the parasite, broadly characterised into acute (pre-patent and post-patent) and chronic phases. (A) Pulmonary symptoms vary, with cough and breathlessness during the acute phase in response to larval migration, maturation, and initial egg production. In chronic disease pulmonary hypertension is the key pulmonary pathology. Lesions may be observed in lung radiographs in all stages, although with differing aetiology in response to migrating larvae, worms, or eggs. (B) Human immune responses can be split into acute and chronic infection, often assayed systemically. Broadly, an early eosinophilic response with mixed type-1/type-2 cytokines makes way for a type-2/regulatory response to schistosome eggs, with tissue granulomas. (C) Murine immune responses can be more accurately demarcated into stage-specific responses, with a muted type-1/type-2 response to lung migrating larvae making way to a systemically driven dominant type-2 response upon egg production. In response to pulmonary egg deposition, chronic responses in the lung display type-1/type-2 cytokine production and granulomatous inflammation.