Poster Presentation Lorne Infection and Immunity 2013

Antibody modulation of innate immune responses to blood stage malaria (#165)

Jingling Zhou 1 , Ludlow E Ludlow 2 , Wina Hasang 2 , Stephen J Rogerson 2 , Anthony Jaworowski 1 3
  1. Burnet Institute, Melbourne, VIC, Australia
  2. Department of Medicine, University of Melbourne, Melbourne, Vic, Aus
  3. Department of Infectious Disease and Dept of Immunology, Monash University, Melbourne, Vic, Aus

Cytophilic antibodies to are thought to be protective against pregnancy-associated malaria in part by promoting phagocytosis of infected erythrocytes (IE). The effect of opsonisation by such antibodies on pro-inflammatory cytokine (PIC) production is not clear. We studied the effect of opsonization of IE with immune serum on cytokine responses using human monocyte-derived macrophages (MDM) exposed to E infected with the CS2 strain of Plasmodium falciparum. Since HIV infection increases the risk and severity of pregnancy-associated malaria by poorly defined mechanisms, we measured the effect of HIV infection of macrophages on cytokine production.

Unopsonised IE induced secretion of IL-6 (median=622pg/ml [IQR=1,250-240], n=9), but not IL-1b or TNFa, whereas opsonised IE induced secretion of IL-1b (18.6 pg/mL [34.2-14.4]), TNFa (113pg/ml [421-17.0]) and increased IL-6 (2195 pg/mL [4,658-1,095]) by MDM. Both IE and opsonised IE, however, induced similar robust IL-6, TNF and IL-1â mRNA expression and activated NF-kB to a similar extent, suggesting opsonization affects post-transcriptional events. IgG-opsonized, but not unopsonized, CS2 IE activated caspase-1 cleavage and enzymatic activity in MDM showing that Fcγ receptor-mediated phagocytosis activates the inflammasome. MDM attached to IgG-coated surfaces however secreted IL-1b in response to unopsonized IE, suggesting that internalization of IE is not an absolute requirement for inflammasome activation and IL-1b secretion. IgG-opsonised CS2 did not induce cytokine production from MyD88-/- mouse macrophages suggesting a MyD88-dependent receptor recognizes IE on the surface of macrophages.  HIV-1 infection significantly inhibited phagocytosis of opsinised-IE, decreased secretion of IL-6 and IL-1β.

We conclude that a MyD88 dependent surface receptor activates NFkB in response to IE and stimulates PIC mRNA expression. IgG opsonization is required for inflammasome activity and IL-1b secretion. HIV infection of macrophages inhibits IE clearance and innate immune responses to IE.