Neutrophils - an understudied bystander in dengue?

Dengue is a mosquito-borne viral disease which causes significant morbidity and mortality each year. Previous research has proposed several mechanisms of pathogenicity that mainly involve the dengue virus and host humoral immunity. However, innate immune cells, such as neutrophils, may also play an important role in dengue, albeit a much less defined role. In this review, we discuss the emerging roles of neutrophils in dengue and their involvement in pathologies associated with severe dengue. We also describe the potential use of several neutrophil proteins as biomarkers for severe dengue. These studies suggest that neutrophils are important players in dengue, and a better understanding of neutrophil-dengue biology is urgently needed.

Correction: Understanding antibody-dependent enhancement in dengue: Are afucosylated IgG1s a concern?

[This corrects the article DOI: 10.1371/journal.ppat.1011223.].

Malaria in Pregnancy: From Placental Infection to Its Abnormal Development and Damage.

Malaria remains a global health burden with Plasmodium falciparum accounting for the highest mortality and morbidity. Malaria in pregnancy can lead to the development of placental malaria, where P. falciparum-infected erythrocytes adhere to placental receptors, triggering placental inflammation and subsequent damage, causing harm to both mother and her infant. Histopathological studies of P. falciparum-infected placentas revealed various placental abnormalities such as excessive perivillous fibrinoid deposits, breakdown of syncytiotrophoblast integrity, trophoblast basal lamina thickening, increased syncytial knotting, and accumulation of mononuclear immune cells within intervillous spaces. These events in turn, are likely to impair placental development and function, ultimately causing placental insufficiency, intrauterine growth restriction, preterm delivery and low birth weight. Hence, a better understanding of the mechanisms behind placental alterations and damage during placental malaria is needed for the design of effective interventions. In this review, using evidence from human studies and murine models, an integrated view on the potential mechanisms underlying placental pathologies in malaria in pregnancy is provided. The molecular, immunological and metabolic changes in infected placentas that reflect their responses to the parasitic infection and injury are discussed. Finally, potential models that can be used by researchers to improve our understanding on the pathogenesis of malaria in pregnancy and placental pathologies are presented.

Unraveling the Immunopathogenesis and Genetic Variants in Vasculitis Toward Development of Personalized Medicine.

Leukocytoclastic vasculitis (LCV) is a systemic autoimmune disease characterized by the inflammation of the vascular endothelium. Cutaneous small vessel vasculitis (CSVV) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) are two examples of LCV. Advancements in genomic technologies have identified risk haplotypes, genetic variants, susceptibility loci and pathways that are associated with vasculitis immunopathogenesis. The discovery of these genetic factors and their corresponding cellular signaling aberrations have enabled the development and use of novel therapeutic strategies for vasculitis. Personalized medicine aims to provide targeted therapies to individuals who show poor response to conventional interventions. For example, monoclonal antibody therapies have shown remarkable efficacy in achieving disease remission. Here, we discuss pathways involved in disease pathogenesis and the underlying genetic associations in different populations worldwide. Understanding the immunopathogenic pathways in vasculitis and identifying associated genetic variations will facilitate the development of novel and targeted personalized therapies for patients.

Factors influencing phagocytosis of malaria parasites: the story so far.

There are seven known species of Plasmodium spp. that can infect humans. The human host can mount a complex network of immunological responses to fight infection and one of these immune functions is phagocytosis. Effective and timely phagocytosis of parasites, accompanied by the activation of a regulated inflammatory response, is beneficial for parasite clearance. Functional studies have identified specific opsonins, particularly antibodies and distinct phagocyte sub-populations that are associated with clinical protection against malaria. In addition, cellular and molecular studies have enhanced the understanding of the immunological pathways and outcomes following phagocytosis of malaria parasites. In this review, an integrated view of the factors that can affect phagocytosis of infected erythrocytes and parasite components, the immunological consequences and their association with clinical protection against Plasmodium spp. infection is provided. Several red blood cell disorders and co-infections, and drugs that can influence phagocytic capability during malaria are also discussed. It is hoped that an enhanced understanding of this immunological process can benefit the design of new therapeutics and vaccines to combat this infectious disease.

Immuno-modulatory effects of macluraxanthone on macrophage phenotype and function.

Macluraxanthone was previously reported to have many biological activities, including anti-cholinesterase, anti-oxidant, anti-cancer, anti-malarial and anti-inflammatory effects. The aim of the current study was to further characterise the effect of macluraxanthone on human macrophage, a type of immune cell that has been implicated in the development of various inflammatory diseases. The expression of surface markers and cytokine production by THP-1 human macrophages following treatment with macluraxanthone were investigated. Macluraxanthone was shown to promote polarisation of M1-like pro-inflammatory macrophages by increasing the percentage of macrophages expressing CD86, while decreasing their CD14, CD11b and CD80 expression. However, in the presence of the pro-inflammatory stimulus lipopolysaccharide, macluraxanthone significantly decreased TNF-α and IL-10 cytokine production.

Nanoparticles in influenza subunit vaccine development: Immunogenicity enhancement.

The threat of novel influenza infections has sparked research efforts to develop subunit vaccines that can induce a more broadly protective immunity by targeting selected regions of the virus. In general, subunit vaccines are safer but may be less immunogenic than whole cell inactivated or live attenuated vaccines. Hence, novel adjuvants that boost immunogenicity are increasingly needed as we move toward the era of modern vaccines. In addition, targeting, delivery, and display of the selected antigens on the surface of professional antigen-presenting cells are also important in vaccine design and development. The use of nanosized particles can be one of the strategies to enhance immunogenicity as they can be efficiently recognized by antigen-presenting cells. They can act as both immunopotentiators and delivery system for the selected antigens. This review will discuss on the applications, advantages, limitations, and types of nanoparticles (NPs) used in the preparation of influenza subunit vaccine candidates to enhance humoral and cellular immune responses.

Combining Understanding of Immunological Mechanisms and Genetic Variants Toward Development of Personalized Medicine for Psoriasis Patients.

Psoriasis is multifactorial disease with complex genetic predisposition. Recent advances in genetics and genomics analyses have provided many insights into the relationship between specific genetic predisposition and the immunopathological mechanisms driving psoriasis manifestation. Novel approaches which utilize array-based genotyping technologies such as genome-wide association studies and bioinformatics tools for transcriptomics analysis have identified single nucleotide polymorphisms, genes and pathways that are associated with psoriasis. The discovery of these psoriasis-associated susceptibility loci, autoimmune targets and altered signaling pathways have provided opportunities to bridge the gap of knowledge from sequence to consequence, allowing new therapeutic strategies for the treatment of psoriasis to be developed. Here, we discuss recent advances in the field by highlighting how immune functions associated with psoriasis susceptibility loci may contribute to disease pathogenesis in different populations. Understanding the genetic variations in psoriasis and how these may influence the immunological pathways to cause disease will contribute to the efforts in developing novel and targeted personalized therapies for psoriasis patients.

High numbers of circulating pigmented polymorphonuclear neutrophils as a prognostic marker for decreased birth weight during malaria in pregnancy.

During gestational malaria, Plasmodium falciparum-infected erythrocytes can sequester within the placenta, contributing to poor pregnancy outcomes, especially low birth weight. In children and non-pregnant adults, pigmented leukocytes may serve as markers of sequestered parasite burden and predict clinical outcomes. Here, we investigated circulating pigmented leukocyte numbers as predictors of clinical outcomes in pregnant women presenting with malaria at enrolment. The number of circulating pigmented neutrophils at enrolment negatively correlated with birth weight (Rho=-25, P=.04), suggesting these cells may have a pathogenic role in, and could serve as prognostic markers for, malaria-associated low birth weight.

Soluble CD163, a product of monocyte/macrophage activation, is inversely associated with haemoglobin levels in placental malaria.

In Plasmodium falciparum malaria, activation of monocytes and macrophages (monocytes/macrophages) can result in the production of various inflammatory mediators that contribute to immunopathology. Soluble CD163 (sCD163) is a specific marker of monocyte/macrophage activation typically found at increased levels during various inflammatory conditions and can be associated with poor clinical outcomes. To better understand the relationships between levels of sCD163 and clinical parameters in women with placental malaria, we measured plasma sCD163 levels in maternal peripheral and placental blood compartments at delivery and determined their correlations with birth weight and maternal haemoglobin concentrations. sCD163 levels were negatively correlated with birth weight only in the placental compartment (r = -0.145, p = 0.03) and were inversely correlated with maternal haemoglobin concentrations, both in peripheral blood (r = -0.238, p = 0.0004) and in placental blood (r = -0.259, p = 0.0001). These inverse relationships suggest a potential role for monocyte/macrophage activation in the pathogenesis of malaria in pregnancy, particularly in relation to malaria-associated anaemia.

Plasmodium falciparum malaria elicits inflammatory responses that dysregulate placental amino acid transport.

Placental malaria (PM) can lead to poor neonatal outcomes, including low birthweight due to fetal growth restriction (FGR), especially when associated with local inflammation (intervillositis or IV). The pathogenesis of PM-associated FGR is largely unknown, but in idiopathic FGR, impaired transplacental amino acid transport, especially through the system A group of amino acid transporters, has been implicated. We hypothesized that PM-associated FGR could result from impairment of transplacental amino acid transport triggered by IV. In a cohort of Malawian women and their infants, the expression and activity of system A (measured by Na⁺-dependent ¹4C-MeAIB uptake) were reduced in PM, especially when associated with IV, compared to uninfected placentas. In an in vitro model of PM with IV, placental cells exposed to monocyte/infected erythrocytes conditioned medium showed decreased system A activity. Amino acid concentrations analyzed by reversed phase ultra performance liquid chromatography in paired maternal and cord plasmas revealed specific alterations of amino acid transport by PM, especially with IV. Overall, our data suggest that the fetoplacental unit responds to PM by altering its placental amino acid transport to maintain adequate fetal growth. However, IV more profoundly compromises placental amino acid transport function, leading to FGR. Our study offers the first pathogenetic explanation for FGR in PM.

Monocytes and macrophages in malaria: protection or pathology?

Recruitment and activation of monocytes and macrophages are essential for clearance of malaria infection, but these have also been associated with adverse clinical outcomes. In this review we discuss recent discoveries on how distinct molecular interactions between monocytes, macrophages, and malaria parasites may alter the balance between protection and pathology in malaria-infected individuals. The immunopathology of severe malaria often originates from excessive immune activation by parasites. The involvement of monocytes and macrophages in these events is highlighted, and priorities for future research to clarify the roles of these cells in malaria are proposed. Knowledge of the factors influencing the balance between protection and pathology can assist in the design of therapeutics aimed at modulating monocyte and macrophage functions to improve outcomes.