Asymptomatic Malaria Infection Is Maintained by a Balanced Pro- and Anti-inflammatory Response

Abstract

Background Pro- and anti-inflammatory cytokines are important mediators of immunity and are associated with malaria disease outcomes. However, their role in the establishment of asymptomatic infections, which may precede the development of clinical symptoms, is not as well-understood. Methods We determined the association of pro and anti-inflammatory cytokines and other immune effector molecules with the development of asymptomatic malaria. We measured and compared the plasma levels of pro-inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukin (IL)-6, IL-12p70, IL-17A, and granzyme B, the anti-inflammatory cytokine IL-4 and the regulatory cytokine IL-10 from children with asymptomatic malaria infections (either microscopic or submicroscopic) and uninfected controls using Luminex. Results We show that individuals with microscopic asymptomatic malaria had significantly increased levels of TNF-α and IL-6 compared to uninfected controls. Children with either microscopic or submicroscopic asymptomatic malaria exhibited higher levels of IFN-γ, IL-17A, and IL-4 compared to uninfected controls. The levels of most of the pro and anti-inflammatory cytokines were comparable between children with microscopic and submicroscopic infections. The ratio of IFN-γ/IL-10, TNF-α/IL-10, IL-6/IL-10 as well as IFN-γ/IL-4 and IL-6/IL-4 did not differ significantly between the groups. Additionally, using a principal component analysis, the cytokines measured could not distinguish amongst the three study populations. This may imply that neither microscopic nor submicroscopic asymptomatic infections were polarized toward a pro-inflammatory or anti-inflammatory response. Conclusion The data show that asymptomatic malaria infections result in increased plasma levels of both pro and anti-inflammatory cytokines relative to uninfected persons. The balance between pro- and anti-inflammatory cytokines are, however, largely maintained and this may in part, explain the lack of clinical symptoms. This is consistent with the generally accepted observation that clinical symptoms develop as a result of immunopathology involving dysregulation of inflammatory mediator balance in favor of pro-inflammatory mediators.

Inflammatory cytokine responses in children with asymptomatic malaria infection living in rural, semi-urban and urban areas in south-eastern Gabon

“…It has been suggested that the cytokine network as a whole (not just one cytokine) may contribute to serious illness [32]. Moreover, a recent study has showed that asymptomatic malaria among children is maintained by a homeostasis between pro-and anti-inflammatory cytokine responses [16]. This can explain the minimally but significantly increased levels of IL-6 and IL-10 observed in our asymptomatic P. falciparuminfected children.…”

“…Also, significantly high levels of IL-10 and IL-4 were observed in asymptomatic cases compared to healthy individuals, whereas levels of T helper type 1 (Th1) cytokines such as IFN-γ and tumor necrosis factor (TNF)-α and Th17 (IL-17, IL-23) were higher in symptomatic patients compared to healthy controls and asymptomatic individuals [17,18]. During asymptomatic P. vivax infection lower levels of the regulatory T cell (T reg ) cytokine IL-10 have been observed compared to controls [19], whereas in another study no significant difference in IL-10 levels was found between asymptomatic cases and uninfected controls [16]. Conversely, an overall reduction in proinflammatory cytokines (TNF, IFN-γ, IL-6) and increased levels of regulatory cytokines (IL-10 and TGF-β) were observed when compared with those of the symptomatic groups [20].…”

“…Finding cytokines which can constitute biomarkers would be an asset to prevent severe forms of the disease by allowing the diagnosis and indirectly the control of asymptomatic P. falciparum infections [15]. A recent study reported that in asymptomatic malaria there is a balance between pro-and anti-inflammatory cytokines [16]. Also, significantly high levels of IL-10 and IL-4 were observed in asymptomatic cases compared to healthy individuals, whereas levels of T helper type 1 (Th1) cytokines such as IFN-γ and tumor necrosis factor (TNF)-α and Th17 (IL-17, IL-23) were higher in symptomatic patients compared to healthy controls and asymptomatic individuals [17,18].…”

Elevated Levels of the Endothelial Molecules ICAM-1, VEGF-A, and VEGFR2 in Microscopic Asymptomatic Malaria

“…Even though the inverse association between VEGF-A and age was a bit moderate, it could denote that age is a contributing factor to the levels of VEGF-A and may impact angiogenesis, endothelial cell activation, and repair of damaged endothelial cells. Probably, it could also imply that repeated exposure to the parasite will result in tolerance, leading to a decrease in inflammation or a balanced pro- and anti-inflammatory response [ 50 , 51 ]. For instance, in a previous study, levels of VEGF-A were comparable between pregnant women with asymptomatic malaria and healthy controls [ 52 ], implying that for persons in endemic areas, continuous exposure to malaria will lead to the establishment of immunological tolerance as one ages.…”

High infectious disease burden as a basis for the observed high frequency of asymptomatic SARS-CoV-2 infections in sub-Saharan Africa

“…Clinical pathology associated with some infectious diseases can be traced to a dysregulation of the immune responses that are elicited against the infecting pathogens. Persistent or chronic exposure of persons to these infectious pathogens, however, causes a state of immunological tolerance to pathogen-induced inflammation 23 , 24 . For disease conditions such as malaria, the inflammatory immune response mounted against the parasite can result in immunopathology if not properly regulated 25 , 26 .…”