Filaria-Induced Monocyte Dysfunction and Its Reversal following Treatment

Abstract

Monocyte dysfunction in filarial infection has been proposed as one mechanism underlying the diminished antigen-specific T-cell response seen in patent lymphatic filariasis. Cytokine/chemokine production and gene expression in monocytes from filaria-infected patients and uninfected healthy donors were assessed unstimulated and in response to stimulation with Staphylococcus aureus Cowan I bacteria plus gamma interferon both before and 8 months following treatment. Monocytes from filaria-infected individuals were studded with intracellular microfilarial antigens. Furthermore, monocytes from these individuals were less capable of producing interleukin-8 (IL-8), Exodus II, MIP-1␣, MIP-1␤, and IL-1␣ and preferentially expressed genes involved in apoptosis and adhesion compared with monocytes from uninfected donors. Eight months following treatment with a single dose of ivermectin-albendazole, some of these defects were reversed, with monocyte production of IL-8, IL-1␣, MIP-1␣, and IL-10 being comparable to that seen in the uninfected controls. In addition, a marked increase in mRNA expression of genes associated with protein metabolism, particularly heat shock proteins, was seen compared with pretreatment expression. These data suggest that the function and gene expression of monocytes in filaria-infected patients are altered but that this dysfunction is partially reversible following antifilarial treatment.

Functional and Phenotypic Characteristics of Alternative Activation Induced in Human Monocytes by Interleukin-4 or the Parasitic Nematode Brugia malayi

“…These data found parallels with human filarial infection, in which monocytes from patients with patent lymphatic filarial infections had significantly enhanced expression of ARG1 and diminished expression of NOS2 (5). The difference in detection of ARG1 at the mRNA level in monocytes of these filarial infected individuals (and not those generated in vitro) is perhaps due to the state of chronic infection and the fact that monocytes of microfilaremic individuals are studded with internalized filarial antigens (45). By modeling filaria-induced changes in monocytes in vitro, we have shown that mf induce monocyte phenotypes similar to those induced by IL-4, with upregulated expression of CCL15, CCL17, CCL18, CCL22, CD274, and CD273.…”

“…In fact, monocytes from filaria-infected individuals are laden with filarial antigen, exhibit diminished expression of genes involved in antigen presentation and processing, and produce fewer proinflammatory cytokines in response to surface receptor cross-linking (45). In addition, monocytes from filaria-infected individuals have a lower expression of Toll-like receptors (TLRs), leading to diminished cytokine production in response to TLR engagement (4).…”

Human Monocyte Subsets at Homeostasis and Their Perturbation in Numbers and Function in Filarial Infection

“…In fact, monocyte dysfunction in filarial infection is one of several mechanisms proposed to explain parasite antigen-specific T cell hyporesponsiveness seen with patent lymphatic filariasis (19). It has previously been demonstrated that monocytes from filaria-infected individuals are studded with internalized filarial antigens, have diminished expression of genes involved in antigen presentation and processing, and produce fewer proinflammatory cytokines in response to surface receptor cross-linking (19,20).…”

Heightened Measures of Immune Complex and Complement Function and Immune Complex–Mediated Granulocyte Activation in Human Lymphatic Filariasis

“…Granule proteins also induce monocyte recruitment and enhance macrophage antimicrobial activity. Because monocyte extravasation and macrophage function depend on neutrophils and their secreted products 37 and monocyte dysfunction in filarial infection has been proposed as one mechanism underlying the diminished antigen-specific T cell response seen in patent LF, 38 we examined the effect of ICs on granular protein release. We found that ICs from patients with LF (INF and CPDT) increased release of granular proteins from normal granulocytes.…”