Date Published: May 29, 2007
Publisher: Public Library of Science
Author(s): Jessica Keen, Lena Serghides, Kodjo Ayi, Samir N Patel, John Ayisi, Anne van Eijk, Richard Steketee, Venkatachalam Udhayakumar, Kevin C Kain, Patrick E Duffy
Abstract: BackgroundPrimigravid (PG) women are at risk for pregnancy-associated malaria (PAM). Multigravid (MG) women acquire protection against PAM; however, HIV infection impairs this protective response. Protection against PAM is associated with the production of IgG specific for variant surface antigens (VSA-PAM) expressed by chondroitin sulfate A (CSA)-adhering parasitized erythrocytes (PEs). We hypothesized that VSA-PAM-specific IgG confers protection by promoting opsonic phagocytosis of PAM isolates and that HIV infection impairs this response.Methods and FindingsWe assessed the ability of VSA-PAM-specific IgG to promote opsonic phagocytosis of CSA-adhering PEs and the impact of HIV infection on this process. Opsonic phagocytosis assays were performed using the CSA-adherent parasite line CS2 and human and murine macrophages. CS2 PEs were opsonized with plasma or purified IgG subclasses from HIV-negative or HIV-infected PG and MG Kenyan women or sympatric men. Levels of IgG subclasses specific for VSA-PAM were compared in HIV-negative and HIV-infected women by flow cytometry. Plasma from HIV-negative MG women, but not PG women or men, promoted the opsonic phagocytosis of CSA-binding PEs (p < 0.001). This function depended on VSA-PAM-specific plasma IgG1 and IgG3. HIV-infected MG women had significantly lower plasma opsonizing activity (median phagocytic index 46 [interquartile range (IQR) 18–195] versus 251 [IQR 93–397], p = 0.006) and levels of VSA-PAM-specific IgG1 (mean fluorescence intensity [MFI] 13 [IQR 11–20] versus 30 [IQR 23–41], p < 0.001) and IgG3 (MFI 17 [IQR 14–23] versus 28 [IQR 23–37], p < 0.001) than their HIV-negative MG counterparts.ConclusionsOpsonic phagocytosis may represent a novel correlate of protection against PAM. HIV infection may increase the susceptibility of multigravid women to PAM by impairing this clearance mechanism.
Partial Text: In malaria-endemic areas, pregnant women are more likely to acquire malaria and to have higher parasite burdens than nonpregnant individuals . Pregnancy-associated malaria (PAM), especially in primigravidae, has profound maternal and fetal health consequences including maternal anaemia and delivery of low birth-weight infants [2,3]. The effects of HIV infection on maternal health are superimposed on those of malaria in sub-Saharan Africa, where approximately 1 million pregnancies each year are complicated by malaria-HIV coinfection . HIV infection in pregnancy is associated with higher rates of clinical malaria, higher parasite densities (both peripheral and placental), and a higher risk of maternal anaemia and low birth-weight infants . While HIV infection affects all gravidities, the HIV-associated risk of malaria is consistently greater in multigravidae .
In this study we demonstrate that CSA-binding PEs are cleared by opsonic phagocytosis in a sex-specific and parity-dependent manner, and that VSA-PAM-specific IgG1 and IgG3 mediate this response. In addition, we demonstrate that plasma from HIV-infected MG women had significantly lower opsonizing activity than HIV-negative MG women, and this defect was associated with lower levels of VSA-PAM-specific IgG1 and IgG3.