Global proteomic analysis is not limited to the examination of known set of factors, and therefore has been a transformative technology that facilitates the identification of novel disease pathways and markers. In this study we employed mass spectrometry-based proteomics to better understand pregnancy malaria pathogenesis by identifying biomarkers associated with inflammation and anemia during placental malaria. We found that SA in infected primigravidae is associated with a significant change in proteins involved in lipid metabolism. Several previous studies found that severe infections or chronic inflammatory diseases other than malaria will also modulate the expression of proteins involved in lipid metabolism. During severe sepsis or chronic inflammation, pro-inflammatory cytokine and triglyceride (TG) levels are increased, while HDL-cholesterol, Apo-AI, Apo-B and LPa levels are decreased 
. Among patients under intensive care for severe sepsis, low levels of Apo-AI are associated with exacerbations of inflammation and poor prognosis 
Changes in lipid parameters have also previously been described in malaria-infected individuals. In several hospital-based studies of mild and severe malaria cases, TG levels were increased and HDL-cholesterol levels were decreased 
. In a study of asymptomatic children harboring low parasite levels, malaria treatment was followed by increases in HDL-cholesterol, LDL-cholesterol and total cholesterol levels, and a decrease in TG concentrations 
. However, these changes were not associated with improvements in hemoglobin levels or other clinical parameters.
We earlier showed that SA is associated with high TNF-α levels in primigravid but not in multigravid women with PM, suggesting a role for other factors in the pathogenesis of SA. Apo-AI is a candidate factor for such a role. Apo-AI binds T cells in vitro
and blocks contact with monocytes, thereby playing an anti-inflammatory role by inhibiting TNF-α and IL-1β production by monocytes 
. Levels of pro-inflammatory cytokines and lipids change during chronic inflammatory diseases like rheumatoid arthritis (RA) 
. Apo-AI levels decrease in the plasma but increase in synovial fluid of patients with active rheumatoid arthritis 
. Immunohistological studies have co-localized Apo-AI with T lymphocytes and macrophages in the inflamed synovium from patients with active arthritis but not patients with inactive arthritis, suggesting that Apo-AI may have a role in limiting inflammation 
. In parallel, TNF-α inhibits the expression of Apo-AI transcription in a dose-dependent manner 
suggesting a counter-regulatory relationship between TNF-α and Apo-AI during inflammatory responses.
Cytokines have a major role in stimulating the production of acute phase proteins (APP) as part of the host immune response to infection (reviewed in 
), but prolonged inflammatory immune responses may be harmful to the host. Like albumin, Apo-AI is classified as a negative APP. While the role of negative APP is unclear, reduced levels of negative APP with anti-inflammatory activity, such as Apo-AI and transthyretin, may promote pro-inflammatory responses 
. This may be useful during the acute response to infection, but a prolonged pro-inflammatory environment may be deleterious to the host, leading to poor outcomes like anemia and impaired growth 
Several studies have identified associations between inflammatory immune responses and disease severity during malaria infection. In particular, TNF-α has been found to have both protective and harmful effects. TNF-α promotes parasite killing and has a protective role in controlling parasite levels, but high TNF-α levels have been associated with severe malaria syndromes like severe anemia and cerebral malaria 
. In this study, Apo-AI levels negatively correlate with TNF-α levels in all women. Among primigravid women but not multigravid women, Apo-AI levels are significantly lower during SA. Multigravid women have specific immunity to placental parasites and are able to rapidly clear the infection, unlike primigravid women who lack specific immunity and often experience a prolonged pro-inflammatory state during PM. Moreover, a previous study demonstrated that the recovery in plasma lipoprotein levels after P. vivax
infection is a slow process, with levels returning to normal 12 months after treatment 
. We propose that the longer duration of PM or more frequent infection in primigravid women results in longer exposure to a proinflammatory environment that could lead to excessive reductions in Apo-AI levels and increases in the risk of SA.