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Simon Metenou,
Benoit Dembele,
Siaka Konate,
Housseini Dolo,
Yaya I Coulibaly,
Abdallah A Diallo,
Lamine Soumaoro,
Michel E Coulibaly,
Siaka Y Coulibaly, Dramane Sanogo,
Salif S Doumbia,
Sekou F Traoré,
Siddhartha Mahanty,
Amy Klion,
Thomas B Nutman
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ABSTRACT: 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.
The Journal of Immunology 03/2011; 186(8):4725-33. · 5.79 Impact Factor
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Benoit Dembele,
Yaya I Coulibaly,
Housseini Dolo,
Siaka Konate,
Siaka Y Coulibaly, Dramane Sanogo,
Lamine Soumaoro,
Michel E Coulibaly,
Salif Seriba Doumbia,
Abdallah A Diallo,
Sekou F Traore,
Adama Diaman Keita,
Michael P Fay,
Thomas B Nutman,
Amy D Klion
[show abstract]
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ABSTRACT: 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.
Clinical Infectious Diseases 11/2010; 51(11):1229-35. · 9.15 Impact Factor
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Roshanak Tolouei Semnani,
Lily Mahapatra,
Benoit Dembele,
Siaka Konate,
Simon Metenou,
Housseini Dolo,
Michel E Coulibaly,
Lamine Soumaoro,
Siaka Y Coulibaly, Dramane Sanogo,
Salif Seriba Doumbia,
Abdallah A Diallo,
Sekou F Traoré,
Amy Klion,
Thomas B Nutman,
Siddhartha Mahanty
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ABSTRACT: 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.
The Journal of Immunology 10/2010; 185(10):6364-72. · 5.79 Impact Factor
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Simon Metenou,
Benoit Dembele,
Siaka Konate,
Housseini Dolo,
Siaka Y Coulibaly,
Yaya I Coulibaly,
Abdallah A Diallo,
Lamine Soumaoro,
Michel E Coulibaly, Dramane Sanogo,
Salif S Doumbia,
Sekou F Traoré,
Siddhartha Mahanty,
Amy Klion,
Thomas B Nutman
[show abstract]
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ABSTRACT: Despite the well-documented immune suppression associated with human helminth infections, studies characterizing the immune response at the single-cell level are scanty. We used multiparameter flow cytometry to characterize the type of effector (Th1, Th2, and Th17) and regulatory (natural T regulatory cells [nTregs] and adaptive Treg cells [aTreg/type 1 regulatory cells (Tr1s)]) CD4(+) and CD8(+) T cells in filaria-infected (Fil(+)) and -uninfected (Fil(-)) individuals at homeostasis (in the absence of stimulation). Frequencies of CD4(+) lymphocytes spontaneously producing IL-4, IL-10, and IL-17A were significantly higher in Fil(+), as were those of IL-10(+)/IL-4(+) double-producing CD4(+) cells. Interestingly, frequencies of Th17 and aTreg/Tr1s but not classical Th1 or Th2 cells were significantly increased in Fil(+) compared to Fil(-) individuals. Although the frequency of nTreg was increased in Fil(+), IL-10 was overwhelmingly produced by CD4(+)CD25(-) cells. Moreover, the concentration of IL-10 produced spontaneously in vitro strongly correlated with the integrated geometric mean fluorescence intensity of IL-10-producing aTreg/Tr1s in Fil(+). Together, these data show that at steady state, IL-10-producing aTreg/Tr1 as well as nTreg and effector Th17 CD4(+) cells are expanded in vivo in human filarial infections. Moreover, we have established baseline ex vivo frequencies of effector and Tregs at homeostasis at a population level.
The Journal of Immunology 03/2010; 184(9):5375-82. · 5.79 Impact Factor
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Simon Metenou,
Benoit Dembélé,
Siaka Konate,
Housseini Dolo,
Siaka Y Coulibaly,
Yaya I Coulibaly,
Abdallah A Diallo,
Lamine Soumaoro,
Michel E Coulibaly, Dramane Sanogo,
Salif S Doumbia,
Marissa Wagner,
Sekou F Traoré,
Amy Klion,
Siddhartha Mahanty,
Thomas B Nutman
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ABSTRACT: The effect of filarial infections on malaria-specific immune responses was investigated in Malian villages coendemic for filariasis (Fil) and malaria. Cytokines were measured from plasma and Ag-stimulated whole blood from individuals with Wuchereria bancrofti and/or Mansonella perstans infections (Fil(+); n = 19) and those without evidence of filarial infection (Fil(-); n = 19). Plasma levels of IL-10 (geometric mean [GM], 22.8 vs 10.4) were higher in Fil(+) compared with Fil(-), whereas levels of IFN-inducible protein (IP)-10 were lower in Fil(+) (GM, 66.3 vs 110.0). Fil(+) had higher levels of spontaneously secreted IL-10 (GM, 59.3 vs 6.8 pg/ml) and lower levels of IL-2 (1.0 vs 1.2 pg/ml) than did Fil(-). Although there were no differences in levels of Staphylococcus aureus enterotoxin B-induced cytokines between the two groups, Fil(+) mounted lower IL-12p70 (GM, 1.11 vs 3.83 pg/ml; p = 0.007), IFN-gamma (GM, 5.44 vs 23.41 pg/ml; p = 0.009), and IP-10 (GM, 29.43 vs 281.7 pg/ml; p = 0.007) responses following malaria Ag (MalAg) stimulation compared with Fil(-). In contrast, Fil(+) individuals had a higher MalAg-specific IL-10 response (GM, 7318 pg/ml vs 3029 pg/ml; p = 0.006) compared with those without filarial infection. Neutralizing Ab to IL-10 (but not to TGFbeta) reversed the down-regulated MalAg-specific IFN-gamma and IP-10 (p < 0.001) responses in Fil(+). Together, these data demonstrate that filarial infections modulate the Plasmodium falciparum-specific IL-12p70/IFN-gamma secretion pathways known to play a key role in resistance to malaria and that they do so in an IL-10-dependent manner.
The Journal of Immunology 07/2009; 183(2):916-24. · 5.79 Impact Factor
