Filariasis and malaria infection are co-endemic in many regions of the world, including subsaharan Africa. We have previously shown that pre-existent filarial infection does not influence susceptibility to malaria infection, but may lower the threshold parasitemia at which clinical symptoms occur. Interestingly, neither the level of malaria parasitemia, nor the presence of fever, was correlated with increased levels of pro-inflammatory cytokines, although 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). All other cytokine levels measured were comparable between the two groups. 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. To examine the chronic effects of pre-existent filarial infection on the immune response to malaria, filaria antigen- specific and malaria antigen-specific cytokine responses were examined in 19 FN and 19 FP individuals prior to the malaria transmission season. Of note, the Fil+ group mounted a markedly diminished IL-12p70, IFN- and IP10 response following MalAg stimulation compared to the Fil- group but a significantly higher IL-10 response. Whereas, anti-TGF- had little effect, anti-IL10 antibodies induced a significant reversal of the MalAg specific down-regulation of IL-12p70, IFN-, and IP10. Taken together these data demonstrate that filarial infections clearly modulate the Pf-specific IL-12p70-IFN- axis known to be pivotal for resistance to malarial parasites and do so in an IL10-dependent manner (Metenou et al 2009 J Immunol). To examine this filaria-induced immune suppression at the single cell level, multiparameter flow cytometry was used to characterize the types of effector (Th1, Th2 and Th17), and regulatory cells in filaria-infected and uninfected individuals at homeostasis (in the absence of stimulation). Filarial infection was associated with a higher frequency of total CD4+ cells producing IL-4, IL-10 and IL-17A and IL-10/IL-4 in unstimulated cultures. Interestingly, frequencies of Th17 and adaptive T regulatory cells, but not classical Th1 or Th2 cells were increased in Fil+ subjects. Although the frequency of natural T regulatory cells 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 mean fluorescence intensity of IL-10-producing adaptive T regs in Fil+. In summary, at homeostasis, filaria infection is associated with expanded adaptive T regulatory but not classical Th2cells (Metenou et al J Immunol 2010). Antigen presenting cell (APC) dysfunction has been postulated to mediate some of the parasite-specific T cell responsiveness seen in patient filarial infection, and we have previously shown that live microfilariae of B. malayi can induce caspase-dependent apoptosis of monocyte-derived dendritic cells (DC) in vitro. To determine whether this phenomenon extends to patent filarial infection in humans, flow cytometry was used to identify DC populations in filaria-infected subjects. Myeloid DC (mDC) were significantly increased in filaria-infected subjects;however, infected subjects had a lower percentage of CCR1+ mDC and a higher percentage of CCR5+ mDC and plasmacytoid DC than uninfected controls. Furthermore, live B. malayi mf were able to downregulate CCR1 on the surface of mDC and diminish calcium flux in response to CCr1 ligand, suggesting that mf are capable of altering mDC migration through downregulation of chemokine receptor expression and signaling. Albendazole and ivermectin are currently used in combination for annual mass treatment of Wuchereria bancrofti (Wb) infection in Africa. Although the drugs have been donated, the cost of such programs is very high and has proven to be a major impediment to the success of programs in countries with limited financial resources. To determine the effect of increased dose and frequency of albendazole/ivermectin (A/I) treatment on microfilarial clearance, 51 Wb microfilaremic residents of an endemic area in Mali, were randomized to receive two doses of standard annual A/I therapy (400 mg/150 mcg/kg;n=26) or four doses of twice-yearly increased dose A/I therapy (800 mg/400 mcg/kg;n=25). Although microfilarial levels decreased significantly following 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 mf at 12 months in the 19 subjects in the twice-yearly group with data available at 12 months as compared to 9/21 in the annual group (p<0.001, Fishers exact test). This difference between the two groups was sustained at 18 and 24 months with no detectable mf in the subjects receiving twice-yearly therapy. Worm nests detectable by ultrasound and Wb circulating antigen levels were decreased to the same degree in both groups at 24 months as compared to baseline. These findings suggest that increasing the dose and frequency of A/I treatment enhances suppression of microfilarial levels, but that this effect may not be due to improved adulticidal activity (Dembele et al. Clin Infect Dis 2010). Month 30 and 36 data analysis is currently underway.

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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
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