Filariasis and malaria infection are co-endemic in many regions of the world, including subsaharan Africa. Data from a matched prospective longitudinal study of filaria-positive (FP) and filaria-negative (FN) subjects during an entire malaria transmission season demonstrated no difference in the number of episodes of malaria, time to first malaria episode or malaria parasitemia at the time of symptoms between the two groups. Interestingly, plasma levels of IP-10 and IL1Ra, two cytokines that are strongly associated with clinical severity in malaria, were decreased in the FP subjects (GM 2130 and 82 pg/ml, respectively) during acute clinical malaria as compared to the FN subjects (GM 5308 and 489 pg/ml;p = 0.001 and 0.003, respectively), although neither the level of malaria parasitemia nor the presence of fever was correlated with increased levels of pro-inflammatory cytokines. These findings are consistent with prior findings demonstrating a decrease in the in vitro production of IP-10 by PBMC from FP individuals in response to malaria antigen and provide further in vivo evidence that pre-existent filarial infection can modulate the immune response to incoming malaria parasites. Despite these immunologic differences, there appears to be little, if any, effect of chronic filarial infection on the susceptibility to or clinical manifestations of acute malaria infection. The mechanisms underlying the modulation of both the malaria-specific immune response and the course of clinical malaria in the context of concomitant helminth infection are poorly understood. We used multiparameter flow cytometry to characterize the quality and the magnitude of malaria-specific T cell responses in filaria-infected and -uninfected individuals with concomitant asymptomatic Plasmodium falciparum malaria in Mali. In comparison with filarial-uninfected subjects, filarial infection was associated with higher ex vivo frequencies of CD4(+) cells producing IL-4, IL-10, and IL-17A (p = 0.01, p = 0.001, and p = 0.03, respectively). In response to malaria Ag stimulation, however, filarial infection was associated with lower frequencies of CD4(+) T cells producing IFN-γ, TNF-α, and IL-17A (p <0.001, p = 0.04, and p = 0.04, respectively) and with higher frequencies of CD4(+)IL10(+)T cells (p = 0.0005). Importantly, filarial infection was associated with markedly lower frequencies of malaria Ag-specific Th1 (p <0.0001), Th17 (p = 0.012), and """"""""TNF-α"""""""" (p = 0.0008) cells, and a complete absence of malaria-specific multifunctional Th1 cells. Filarial infection was also associated with a marked increase in the frequency of malaria-specific adaptive regulatory T/Tr1 cells (p = 0.024), and the addition of neutralizing anti-IL-10 Ab augmented the amount of Th1-associated cytokine produced per cell. Thus, among malaria-infected individuals, concomitant filarial infection diminishes dramatically the frequencies of malaria-specific Th1 and Th17 T cells, and alters the quality and magnitude of malaria-specific T cell responses. Antigen presenting cell (APC dysfunction has been postulated to mediate some of the parasite-specific T cell unresponsiveness seen in patent filarial infection. We have shown that live microfilariae of Brugia malayi induce caspase-dependent apoptosis in human monocyte-derived dendritic cells (DCs) in vitro. This study addresses whether apoptosis observed in vitro extends to patent filarial infections in humans and is reflected in the number of circulating myeloid DCs (mDCs;CD11c(-)CD123(lo)) in peripheral blood of infected microfilaremic individuals. Utilizing flow cytometry to identify DC subpopulations (mDCs and plasmacytoid DCs pDCs) based on expression of CD11c and CD123, we found a significant increase in numbers of circulating mDCs (CD11c(+)CD123(lo)) in filaria-infected individuals compared with uninfected controls from the same filaria-endemic region of Mali. Total numbers of pDCs, monocytes, and lymphocytes did not differ between the two groups. To investigate potential causes of differences in mDC numbers between the two groups, we assessed chemokine receptor expression on mDCs. Our data indicate that filaria-infected individuals had a lower percentage of circulating CCR1(+) mDCs and a higher percentage of circulating CCR5(+) mDCs and pDCs. Finally, live microfilariae of B. malayi were able to downregulate cell-surface expression of CCR1 on monocyte-derived DCs and diminish their calcium flux in response to stimulation by a CCR1 ligand. These findings suggest that microfilaria are capable of altering mDC migration through downregulation of expression of some chemokine receptors and their signaling functions. These observations have major implications for regulation of immune responses to these long-lived parasites. Annual mass treatment with albendazole and ivermectin is the mainstay of current strategies to interrupt transmission of Wuchereria bancrofti in Africa. More-effective microfilarial suppression could potentially reduce the time necessary to interrupt transmission, easing the economic burden of mass treatment programs in countries with limited resources.To determine the effect of increased dose and frequency of albendazole-ivermectin treatment on microfilarial clearance, 51 W. bancrofti microfilaremic residents of an area of W. bancrofti endemicity in Mali were randomized to receive 2 doses of annual, standard-dose albendazole-ivermectin therapy (400 mg and 150 μg/kg;n = 26) or 4 doses of twice-yearly, increased-dose albendazole-ivermectin therapy (800 mg and 400 μg/kg;n = 25). Although microfilarial levels decreased significantly after therapy in both groups, levels were significantly lower in the high-dose, twice-yearly group at 12, 18, and 24 months. Furthermore, there was complete clearance of detectable microfilariae at 12 months in the 19 patients in the twice-yearly therapy group with data available at 12 months, compared with 9 of 21 patients in the annual therapy group (P <.001, by Fisher's exact test). This difference between the 2 groups was sustained at 18 and 24 months, with no detectable microfilariae in the patients receiving twice-yearly treatment. Worm nests detectable by ultrasonography and W. bancrofti circulating antigen levels, as measured by enzyme-linked immunosorbent assay, were decreased to the same degree in both groups at 24 months, compared with baseline. These findings suggest that increasing the dosage and frequency of albendazole-ivermectin treatment enhances suppression of microfilariae but that this effect may not be attributable to improved adulticidal activity.

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Support Year
4
Fiscal Year
2011
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$297,965
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Sangare, Moussa Brema; Coulibaly, Yaya Ibrahim; Coulibaly, Siaka Yamoussa et al. (2018) A cross-sectional study of the filarial and Leishmania co-endemicity in two ecologically distinct settings in Mali. Parasit Vectors 11:18
Dolo, Housseini; Coulibaly, Yaya Ibrahim; Kelly-Hope, Louise et al. (2018) Factors Associated with Wuchereria bancrofti Microfilaremia in an Endemic Area of Mali. Am J Trop Med Hyg 98:1782-1787
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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
Coulibaly, Yaya Ibrahim; Dembele, Benoit; Diallo, Abdallah Amadou et al. (2013) Wuchereria bancrofti transmission pattern in southern Mali prior to and following the institution of mass drug administration. Parasit Vectors 6:247
Metenou, Simon; Babu, Subash; Nutman, Thomas B (2012) Impact of filarial infections on coincident intracellular pathogens: Mycobacterium tuberculosis and Plasmodium falciparum. Curr Opin HIV AIDS 7:231-8

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