Lymphatic filariasis: perspectives on lymphatic remodeling and contractile dysfunction in filarial disease pathogenesis

Abstract

Lymphatic filariasis, one of the most debilitating diseases associated with the lymphatic system, affects over a hundred million people worldwide and manifests itself in a variety of severe clinical pathologies. The filarial parasites specifically target the lymphatics and impair lymph flow, which is critical for the normal functions of the lymphatic system in maintenance of body fluid balance and physiological interstitial fluid transport. The resultant contractile dysfunction of the lymphatics causes fluid accumulation and lymphedema, one of the major pathologies associated with filarial infection. In this review, we take a closer look at the contractile mechanisms of the lymphatics, its altered functions, and remodeling during an inflammatory state and how it relates to the severe pathogenesis underlying a filarial infection. We further elaborate on the complex host-parasite interactions, and molecular mechanisms contributing to the disease pathogenesis. The overall emphasis is on elucidating some of the emerging concepts and new directions that aim to harness the process of lymphangiogenesis or enhance contractility in a dysfunctional lymphatics, thereby restoring the fluid imbalance and mitigating the pathological conditions of lymphatic filariasis.

Keywords: filarial pathogenesis; host parasite interaction; inflammation; lymphatic contraction; molecular mechanisms.

Figure 1

Different stages of lymphatic vessel remodeling and modulation of lymphatic flow during progression of filarial infection. A. Normal lymphatic collecting vessel showing normal flow patterns and lymphatic drainage regulated by the unidirectional valves in the absence of filarial parasitic infection. B. Onset and progression of acute filarial infection with microfilariae and adult worms lodged within the vessel. Normal host immune response is initiated. Slight hypertrophy of the lymphatic muscle cell layers is observed with a partial impairment of lymph flow. C. Chronic filarial infection results in a major host immune response due to toxins released by dead or live parasites. Various immune cells are observed at the site of infection leading to a strong inflammatory reaction. Secondary infections with bacteria harboring Wolbachia exacerbates the condition leading to a chronic infection state or elephantiasis. The lymphatic vessels exhibit largely dysfunctional valves, vessel dilation, impaired lymphatic muscle contractility and insufficient drainage. The resultant fluid accumulation and retrograde lymph flow associated with severe lymphedema. Activation and remodeling of lymphatic endothelial cells during this chronic stage could potentially result in either endothelial dysfunction or promote lymphangiogenesis.

Figure 2

Schematic showing the synergetic roles of a plethora of signaling molecules and pathways that contribute to the onset and progression of filariasis. A. Complex interplay of cytokines and chemokines and associated immune cells triggered by different stages of the worm maintain the balance between a filaricidal or antifilaricidal host response. B. Specific parasitic toxins or excretory secretory products act through yet unidentified receptors on lymphatic muscle and endothelial cells to impair lymphatic contractile function.