The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched in 2000 with the goal of stopping transmission of lymphatic filariasis (LF) through yearly mass drug administration (MDA). Although preliminary surveys of the human population in Mali suggested that Wuchereria bancrofti (W. bancrofti) infection was highly endemic in the Sikasso district, baseline entomological data were required to confirm high levels of transmission prior to selection of villages in this region for a study of the impact of MDA on transmission of LF by anopheline vectors. W. bancrofti transmission was assessed in 2001 (pre-MDA) and 2002 (post-MDA) in the Central District of Sikasso in southern Mali by dissection of Anopheles mosquitoes caught using the human landing catch (HLC) method. The relative frequencies and molecular forms of An. gambiae complex were determined. The majority (86%) of the anopheline vectors captured were identified as An. gambiae complex, and these accounted for >90% of the entomological inoculation rate (EIR) during both years of the study. There was a dramatic decrease in the number of An. gambiae complex mosquitoes captured and in the An. gambiae complex infectivity rates following MDA, accounting for the observed decrease in EIR in 2002 (from 12.55 to 3.79 infective bites per person during the transmission season). An. funestus complex mosquitoes were responsible for a low level of transmission, which was similar during both years of the study (1.2 infective bites per person during the transmission season in 2001 and 1.03 in 2002). Based on the entomological data from this study, the district of Sikasso was confirmed as an area of high W. bancrofti transmission. This led to the selection of this area for a multi-national study on the effects of MDA on LF transmission by anopheline vectors. Comparison of vector transmission parameters prior to and immediately following the first round of MDA demonstrated a significant decrease in overall transmission. Importantly, the dramatic variability in EIR over the transmission season suggests that the efficacy of MDA can be maximized by delivering drug at the beginning of the rainy season (just prior to the peak of transmission). Regulatory T cells (Tregs) and particularly Foxp3-expressing Tregs are known to increase during chronic infection, although the exact mechanisms that contribute to their accumulation and mode of action remain unclear. We used flow cytometry and microarray analyses to delineate the phenotype and transcriptional profiles of Tregs in the setting of chronic filarial infection. Using cells from 18 filaria-infected (Fil+) and 19 filaria-uninfected (Fil-) subjects, we found that the frequencies of Foxp3+ Treg expressing CTLA-4, GITR, LAG-3, and IL-10 were significantly higher in Fil+ compared with Fil- subjects. Microarray analysis revealed that, compared with those from Fil-, Foxp3-expressing Treg populations in Fil+ subjects were more heterogeneous and had higher expression of IL-10, CCL-4, IL-29 and CTLA-4, molecules that have been implicated in immune suppression. Moreover, Foxp3-expressing Tregs from Fil+ subjects had markedly upregulated activation-induced apoptotic genes with concomitant down regulation of cell survival genes. To determine whether the expression of apoptotic genes was due to activation, we stimulated Foxp3-expressing Tregs purified from blood bank donors with anti-CD3/CD28 coated beads and using Quantitative Real Time PCR, assessed the expression of some of the genes upregulated in microarray analysis. To this end, we found that the expression of CTLA-4, CDk8, RAD50, TNFRSF1A, FOXO3 and RHOA was significantly upregualated in stimulated cells compared with unstimulated. Taken together, our results suggest that in patent filarial infection, the expanded nTreg populations are heterogeneous, short-lived, activated and express higher level of regulatory molecules, suggesting a higher turnover, compared to cells from uninfected subjects.

Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$242,189
Indirect Cost
City
State
Country
Zip Code
Metenou, Simon; Coulibaly, Yaya I; Sturdevant, Daniel et al. (2014) Highly heterogeneous, activated, and short-lived regulatory T cells during chronic filarial infection. Eur J Immunol 44:2036-47
Metenou, Simon; Dembele, Benoit; Konate, Siaka et al. (2009) Patent filarial infection modulates malaria-specific type 1 cytokine responses in an IL-10-dependent manner in a filaria/malaria-coinfected population. J Immunol 183:916-24
Keiser, Paul B; Coulibaly, Yaya; Kubofcik, Joseph et al. (2008) Molecular identification of Wolbachia from the filarial nematode Mansonella perstans. Mol Biochem Parasitol 160:123-8