Monocytes and macrophages contribute to the dysfunction of immune responses in human filariasis. During patent infection monocytes encounter microfilariae in the blood, an event that occurs in asymptomatically infected filariasis patients that are immunologically hyporeactive.
To determine whether blood microfilariae directly act on blood monocytes and in vitro generated macrophages to induce a regulatory phenotype that interferes with innate and adaptive responses.
Monocytes and in vitro generated macrophages from filaria non-endemic normal donors were stimulated in vitro with Brugia malayi microfilarial (Mf) lysate. We could show that monocytes stimulated with Mf lysate develop a defined regulatory phenotype, characterised by expression of the immunoregulatory markers IL-10 and PD-L1. Significantly, this regulatory phenotype was recapitulated in monocytes from Wuchereria bancrofti asymptomatically infected patients but not patients with pathology or endemic normals. Monocytes from non-endemic donors stimulated with Mf lysate directly inhibited CD4 + T cell proliferation and cytokine production (IFN-γ, IL-13 and IL-10). IFN-γ responses were restored by neutralising IL-10 or PD-1. Furthermore, macrophages stimulated with Mf lysate expressed high levels of IL-10 and had suppressed phagocytic abilities. Finally Mf lysate applied during the differentiation of macrophages in vitro interfered with macrophage abilities to respond to subsequent LPS stimulation in a selective manner.
Conclusively, our study demonstrates that Mf lysate stimulation of monocytes from healthy donors in vitro induces a regulatory phenotype, characterized by expression of PD-L1 and IL-10. This phenotype is directly reflected in monocytes from filarial patients with asymptomatic infection but not patients with pathology or endemic normals. We suggest that suppression of T cell functions typically seen in lymphatic filariasis is caused by microfilaria-modulated monocytes in an IL-10-dependent manner. Together with suppression of macrophage innate responses, this may contribute to the overall down-regulation of immune responses observed in asymptomatically infected patients.
Lymphatic filariasis is a parasitic disease that affects over one million people worldwide, causing chronic morbidity in the majority of infected individuals. A certain proportion of individuals develop asymptomatic infection that allows persistence of the parasite and therefore transmission of disease through the blood-circulating microfilariae. We show that monocytes and macrophages, innate effector cells that circulate in the blood, migrate or reside in tissues and come into contact with microfilariae, can be stimulated by microfilarial (Mf) lysate in vitro to develop a regulatory phenotype via expression of PD-L1 and IL-10. Significantly, this regulatory monocyte phenotype was directly reflected in monocytes isolated from filaria asymptomatically infected patients in the absence of external stimuli. Mf lysate-modulated monocytes inhibited adaptive immune functions, some of which could be restored by neutralisation of IL-10. Mf lysate-modulated macrophages had reduced phagocytic capacity, while macrophages differentiated in the presence of Mf lysate displayed significantly inhibited innate responses to LPS stimulation. This suggests that microfilariae modulate the innate response by acting on macrophage differentiation and macrophages themselves, and modulate the adaptive CD4 + T cell response by acting on monocytes. The phenotypic pattern observed by modulated monocytes is recapitulated in vivo in active infection. This highlights a previously unclear mechanism of immune modulation by the parasite.