SummaryCytokine and chemokine levels were studied in infants (<5 years) with uncomplicated (MM) and severe malaria tropica (SM), and in Plasmodium falciparum infection-free controls (NEG). Cytokine plasma levels of interleukin (IL)-10, IL-13, IL-31 and IL-33 were strongly elevated in MM and SM compared to NEG (P < 0·0001). Inversely, plasma concentrations of IL-27 were highest in NEG infants, lower in MM cases and lowest in those with SM (P < 0·0001, NEG compared to MM and SM). The levels of the chemokines macrophage inflammatory protein (MIP3)-a/C-C ligand 20 (CCL20), monokine induced by gamma interferon (MIG)/CXCL9 and CXCL16 were enhanced in those with MM and SM (P < 0·0001 compared to NEG), and MIP3-a/CCL20 and MIG/CXCL9 were correlated positively with parasite density, while that of IL-27 were correlated negatively. The levels of 6Ckine/ CCL21 were similar in NEG, MM and SM. At 48-60 h post-anti-malaria treatment, the plasma concentrations of IL-10, IL-13, MIG/CXCL9, CXCL16 and MIP3-a/CCL20 were clearly diminished compared to before treatment, while IL-17F, IL-27, IL-31 and IL-33 remained unchanged. In summary, elevated levels of proinflammatory and regulatory cytokines and chemokines were generated in infants during and after acute malaria tropica. The proinflammatory type cytokines IL-31 and IL-33 were enhanced strongly while regulatory IL-27 was diminished in those with severe malaria. Similarly, MIP3-a/ CCL20 and CXCL16, which may promote leucocyte migration into brain parenchyma, displayed increased levels, while CCL21, which mediates immune surveillance in central nervous system tissues, remained unchanged. The observed cytokine and chemokine production profiles and their dynamics may prove useful in evaluating either the progression or the regression of malarial disease.

This study examined the development and persistence of immunity in humans presenting defined states of Onchocerca volvulus infection, i.e. in exposed endemic control individuals without microfilaridermia and clinical disease, in patients with patent or post‐patent onchocerciasis, and in patients concurrently infected with Mansonella perstans. Onchocerca volvulus antigen (OvAg)‐specific cellular reactivity was significantly diminished in microfilariae (mf)‐positive patients, while the highest reactivity was measured in exposed but mf‐negative endemic controls, those being free of any clinical signs of onchocercal disease. In patients who became post‐patent, responses to OvAg were significantly augmented, but did not approach entirely the magnitude observed in endemic controls. In onchocerciasis patients with concurrent mansonelliasis, cellular unresponsiveness to OvAg persisted, even when mf of O. volvulus were eliminated permanently by repeated ivermectin therapy. Cells from mf‐positive onchocerciasis patients produced significantly less interferon‐γ (IFN‐γ) (P<0·01) and interleukin‐5 (IL‐5) (P<0·05) in response to OvAg than those taken from endemic controls or post‐patent individuals in whom IFN‐γ and IL‐5 production was similarly high. In contrast, both OvAg‐driven as well as spontaneous IL‐10 secretion was higher in mf‐positive patients than in endemic controls or post‐patent cases. In all individuals examined, serological recognition of OvAg by immunoglobulins was dominated by IgG4; in mf‐positive patients OvAg of 205 000–12 000 molecular weight (MW) were strongly bound. In post‐patent individuals, and similarly in endemic controls, OvAg recognition by IgG4 varied from intense (with numerous antigens being recognized) to weak or absent antigen binding. Significantly elevated OvAg‐specific IgG isotypes were measured in mf‐positive onchocerciasis patients in comparison with endemic controls or post‐patent individuals (with the exception of IgG3). IgG1, IgG2 and IgE were higher, but IgG4 was lower in endemic controls compared with post‐patent onchocerciasis patients. The ratios of IgG4/IgG1 differed (P<0·001) between endemic controls and mf‐positive or post‐patent onchocerciasis patients, with IgG4/IgG1 ratios of R<3·0 being characteristic for endemic controls and post‐patent O. volvulus infection. In conclusion, this cross‐sectional immunoepidemiological investigation showed that distinct states of O. volvulus infection correlate with a particular cellular and humoral immune response. The mf‐free condition appeared to be associated with a vigorous parasite‐specific cellular reactivity and a particular cytokine production profile, while concurrent M. perstans infection depressed OvAg‐specific cellular responsiveness. Antibody responses, in all likelihood, reflected the intensity and state of infection, and not the degree of acquired immunity protective against parasite aggregation.

This study investigated the effect of maternal Onchocerca volvulus infection on humoral and cellular responsiveness in newborn children and their mothers. Onchocerca volvulus-specific IgG isotypes and IgE were significantly elevated in infected mothers and their infants. One year post partum, O. volvulus-specific IgG4 was strongly reduced in children of infected mothers, while IgG1 responses weakened only slightly. Umbilical cord mononuclear blood cells (UCBC) and peripheral blood cells (PBMC) from mothers proliferated in response to phytohaemagglutinin (PHA), concanavalin A (Con A), and the bacterial antigens streptolysin-O (SL-O) or purified protein derivative (PPD). UCBC from neonates born to O. volvulus-infected mothers responded lower (P < 0.01) to Con A (at 5 micrograms/ml), PPD (at 10 and 50 micrograms/ml) and O. volvulus-derived antigens (OvAg) (at 35 micrograms/ml), and in parallel, a diminished cellular reactivity (P < 0.01) by PBMC was observed to OvAg in mothers positive for O. volvulus. Several Th1-type (IL-2, IL-12, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha)) and Th2-type (IL-4, IL-5, IL-10, IL-13) cytokines were secreted by UCBC and PBMC in response to OvAg, bacterial SL-O and PHA. OvAg did not stimulate IL-2 and none of the mitogens or antigens induced production of IL-4 in neonates. In response to OvAg, substantially elevated (P < 0.01) amounts of IFN-gamma were produced by UCBC from newborns of O. volvulus-infected mothers. UCBC secreted low levels of IL-5 and IL-13, while higher amounts of IL-10 were found (P < 0. 01) in newborns from onchocerciasis-free mothers. In conclusion, maternal O. volvulus-infection will sensitize in utero parasite-specific cellular immune responsiveness in neonates and activate OvAg-specific production of several Th1- and Th2-type cytokines.

BackgroundDiagnostics provide a means to measure progress toward disease elimination. Many countries in Africa are approaching elimination of onchocerciasis after successful implementation of mass drug administration programs as well as vector control. An understanding of how markers for infection such as skin snip microfilaria and Onchocerca volvulus-specific seroconversion perform in near-elimination settings informs how to best use these markers.MethodsAll-age participants from 35 villages in Togo were surveyed in 2013 and 2014 for skin snip Onchocerca volvulus microfilaria and IgG4 antibody response by enzyme-linked immunosorbent assay (ELISA) to the Onchocerca volvulus-specific antigen Ov16. A Gaussian mixture model applying the expectation-maximization (EM) algorithm was used to determine seropositivity from Ov16 ELISA data. For a subset of participants (n = 434), polymerase chain reaction (PCR) was performed on the skin snips taken during surveillance.ResultsWithin the 2,005 participants for which there was Ov16 ELISA data, O. volvulus microfilaremia prevalence and Ov16 seroprevalence were, 2.5 and 19.7 %, respectively, in the total population, and 1.6 and 3.6 % in children under 11. In the subset of 434 specimens for which ELISA, PCR, and microscopy data were generated, it was found that in children under 11 years of age, the anti-Ov16 IgG4 antibody response demonstrate a sensitivity and specificity of 80 and 97 %, respectively, against active infections as determined by combined PCR and microscopy on skin snips. Further analysis was performed in 34 of the 35 villages surveyed. These villages were stratified by all-age seroprevalence into three clusters: < 15 %; 15–20 %; and > 20 %. Age-dependence of seroprevalence for each cluster was best reflected by a two-phase force-of-infection (FOI) catalytic model. In all clusters, the lower of the two phases of FOI was associated with a younger age group, as reflected by the seroconversion rates for each phase. The age at which transition from lower to higher seroconversion, between the two phases of FOI, was found to be highest (older) for the cluster of villages with < 15 % seroprevalence and lowest (younger) for the cluster with the highest all-age seroprevalence.ConclusionsThe anti-Ov16 IgG4 antibody response is an accurate marker for active infection in children under 11 years of age in this population. Applying Ov16 surveillance to a broader age range provides additional valuable information for understanding progression toward elimination and can inform where targeted augmented interventions may be needed. Clustering of villages by all-age sero-surveillance allowed application of a biphasic FOI model to differentiate seroconversion rates for different age groups within the village cluster categories.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1623-1) contains supplementary material, which is available to authorized users.