In areas where polyparasitism is highly prevalent, the impact of multiple parasites on the host response is underestimated. In particular, the presence of helminth infection coincident with malaria profoundly alters the production of malaria-specific IFN-γ, IL-12p70, CXCL9, CXCL10 and CXCL11, cytokines/chemokines known to be critical in mediating malaria-specific immunity. In order to elucidate the mechanisms underlying the suppression of malaria-specific cytokines/chemokines, we assessed the expression of malaria-specific IL-12Rβ1, IL-12Rβ2 and interferon regulatory factor (IRF)-1 in blood obtained from 18 filaria-infected (Fil(+)) and 17 filaria-uninfected (Fil(-)) individuals in a filaria-malaria co-endemic region of Mali. We found that Fil(+) individuals had significantly lower RNA expression of IRF-1 but not IL-12Rβ1 or IL-12Rβ2 in response to malaria antigen stimulation. We also measured the frequency of IL-12-producing DCs from these subjects and found that Fil(+) subjects had lower frequencies of IL-12(+) mDCs after malaria antigen stimulation than did the Fil(-) subjects. Modeling these data in vitro, we found that mDCs pre-exposed to live microfilariae not only produced significantly lower levels of CXCL-9, CXCL-10, IL-12p35, IL-12p40, IL-12p19 and CXCL-11 following stimulation with malaria antigen but also markedly downregulated the expression of IRF-1, IRF-2 and IRF-3 compared with microfilaria-unexposed mDCs. siRNA-inhibition of irf-1 in mDCs downregulated the production of IL-12p70 through repression of IL-12p35. Our data demonstrate that the modulation of IRFs seen in filarial (and presumably other tissue-invasive helminths) infection underlies the suppression of malaria-specific cytokines/chemokines that play a crucial role in immunity to malaria. 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-gamma;, TNF-alpha;, 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-alpha (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. In many regions of the world, including sub-Saharan Africa, concomitant infection with multiple parasites is common. In order to examine the effects of filariasis, a chronic helminth infection, on immune responses and clinical manifestations of acute malaria infection, the authors followed 31 filaria-infected (FIL+) and 31 filaria-uninfected (FIL-) individuals living in a malaria-endemic area of Mali through an entire malaria transmission season for the development of clinical malaria (fever or other symptoms of malaria in the setting of detectable blood parasites). Serum levels of inflammatory cytokines previously associated with severe malaria were decreased in FIL+ subjects at the time of acute clinical malaria. Although there were no differences between FIL+ and FIL- subjects with respect to the time to first episode of malaria or the number or severity of malaria episodes, filarial infection appeared to protect against the development of anemia during the malaria transmission season. These findings demonstrate that chronic filarial infection modulates the immune response to acute malaria. The apparent effect on anemia is intriguing and deserves further study.

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Sissoko, Mahamadou S; Healy, Sara A; Katile, Abdoulaye et al. (2017) Safety and efficacy of PfSPZ Vaccine against Plasmodium falciparum via direct venous inoculation in healthy malaria-exposed adults in Mali: a randomised, double-blind phase 1 trial. Lancet Infect Dis 17:498-509
Coulibaly, Yaya I; Coulibaly, Siaka Y; Dolo, Housseini et al. (2016) Dynamics of antigenemia and transmission intensity of Wuchereria bancrofti following cessation of mass drug administration in a formerly highly endemic region of Mali. Parasit Vectors 9:628
Yooseph, Shibu; Kirkness, Ewen F; Tran, Tuan M et al. (2015) Stool microbiota composition is associated with the prospective risk of Plasmodium falciparum infection. BMC Genomics 16:631
Coulibaly, Yaya I; Dembele, Benoit; Diallo, Abdallah Amadou et al. (2015) The Impact of Six Annual Rounds of Mass Drug Administration on Wuchereria bancrofti Infections in Humans and in Mosquitoes in Mali. Am J Trop Med Hyg 93:356-60
Doumbo, Safiatou; Tran, Tuan M; Sangala, Jules et al. (2014) Co-infection of long-term carriers of Plasmodium falciparum with Schistosoma haematobium enhances protection from febrile malaria: a prospective cohort study in Mali. PLoS Negl Trop Dis 8:e3154
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
Dolo, Housseini; Coulibaly, Yaya I; Dembele, Benoit et al. (2012) Filariasis attenuates anemia and proinflammatory responses associated with clinical malaria: a matched prospective study in children and young adults. PLoS Negl Trop Dis 6:e1890
Metenou, Simon; Kovacs, Michael; Dembele, Benoit et al. (2012) Interferon regulatory factor modulation underlies the bystander suppression of malaria antigen-driven IL-12 and IFN-? in filaria-malaria co-infection. Eur J Immunol 42:641-50

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