IFN-γ and IL-10 Mediate Parasite-Specific Immune Responses of Cord Blood Cells Induced by Pregnancy-Associated Plasmodium falciparum Malaria

Abstract

Available evidence suggests that immune cells from neonates born to mothers with placental Plasmodium falciparum (Pf) infection are sensitized to parasite Ag in utero but have reduced ability to generate protective Th1 responses. In this study, we detected Pf Ag-specific IFN-γ+ T cells in cord blood from human neonates whose mothers had received treatment for malaria or who had active placental Pf infection at delivery, with responses being significantly reduced in the latter group. Active placental malaria at delivery was also associated with reduced expression of monocyte MHC class I and II in vivo and following short term in vitro coculture with Pf Ag compared with levels seen in neonates whose mothers had received treatment during pregnancy. Given that APC activation and Th1 responses are driven in part by IFN-γ and down-regulated by IL-10, we examined the role of these cytokines in modulating the Pf Ag-specific immune responses in cord blood samples. Exogenous recombinant human IFN-γ and neutralizing anti-human IL-10 enhanced T cell IFN-γ production, whereas recombinant human IFN-γ also restored MHC class I and II expression on monocytes from cord blood mononuclear cells cocultured with Pf Ag. Accordingly, active placental malaria at delivery was associated with increased frequencies of Pf Ag-specific IL-10+CD4+ T cells in cord blood mononuclear cell cultures from these neonates. Generation and maintenance of IL-10+ T cells in utero may thus contribute to suppression of APC function and Pf Ag-induced Th1 responses in newborns born to mothers with placental malaria at delivery, which may increase susceptibility to infection later in life.

Cord blood Streptococcus pneumoniae-specific cellular immune responses predict early pneumococcal carriage in high-risk infants in Papua New Guinea

“…Similar phenomena have been shown for helminths and malarial parasitic infections in pregnancy, where pathogen‐specific T cell responses induced in utero have long‐term negative consequences for the infants' susceptibility and development of immune responses to these parasites 41, 42, 43, 44, 45, 46, 47, 48, 49. Accordingly, in‐utero infection with cytomegalovirus (CMV) has been found to result in in‐utero activation of fetal CMV T cell responses that, compared to adult responses, are ‘functionally exhausted’, with a limited capacity to control CMV replication 50, 51.…”

Malaria parasite tyrosyl-tRNA synthetase secretion triggers pro-inflammatory responses

“…The host immune system is hijacked by parasite-derived factors to assist in cytoadherence, for example, by cytokine-induced increased expression of a range of adhesion molecules 16,[18][19][20][21][22][23][24][25] . Numerous field reports on human malaria and mouse model studies have shown that malaria infection alters host cytokine profiles by modulating dendritic cells and macrophages 16,[18][19][20][21][22][23][24][25] . This is presumably done to aid in parasite survival and transmission.…”

“…In fact, malaria as a disease has been looked up on as a manifestation of enhanced pro-inflammatory cytokine production in host 16,[34][35][36][37][38][39][40][41][42] . For example, the clinical manifestations of severe malaria can be correlated with induction of strong pro-inflammatory responses in which plasma levels of circulating TNF-α, IFN-γ and IL-6 increase significantly [19][20][21] . Pathways that propel host immune cell activation in malaria remain mysterious in context of parasitederived protein antigens.…”

“…Most malaria pathology results from an acute inflammatory spurt, followed by activation of the host immune system and dysregulated cytokine release [14][15][16][17][18] . Human patient studies and mouse malaria models have consistently suggested that infection by the malaria parasite triggers an increase in the levels of numerous pro-inflammatory agents including tumour necrosis factor (TNF-α), interferon gamma (IFN-γ) and interleukin 6 (IL-6) in blood plasma [19][20][21] . Although pro-inflammatory cytokines have a major role in patho-physiology of malaria disease [16][17][18][19][20][21] , the molecular mechanisms of cytokine release from immune cells remains largely unclear.…”

“…Human patient studies and mouse malaria models have consistently suggested that infection by the malaria parasite triggers an increase in the levels of numerous pro-inflammatory agents including tumour necrosis factor (TNF-α), interferon gamma (IFN-γ) and interleukin 6 (IL-6) in blood plasma [19][20][21] . Although pro-inflammatory cytokines have a major role in patho-physiology of malaria disease [16][17][18][19][20][21] , the molecular mechanisms of cytokine release from immune cells remains largely unclear. Until now, several parasite-derived molecular agents have been implicated in triggering cytokine release [22][23][24][25] , but parasitesecreted protein(s) that potentially trigger specific cytokine secretion from host immune cells are less well understood.…”