CXC Ligand 9 Response to Malaria during Pregnancy Is Associated with Low-Birth-Weight Deliveries

ABSTRACTPlacental infection withPlasmodium falciparumis associated with increased levels of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ), and previous studies have associated increased levels of these cytokines with low birth weight (LBW), especially for malaria-infected primigravidae. To define the contribution of TNF-α and IFN-γ networks to placental-malaria-associated LBW, we measured chemokines induced by TNF-α and IFN-γ and related them to birth weight in a birth cohort of 782 mother-infant pairs residing in an area ofP. falciparumholoendemicity in Tanzania. Among primigravidae, levels of CCL2, CXC ligand 9 (CXCL9), and CXCL13 were significantly higher during malaria infection in both the placenta and peripheral blood. Placental CXCL9 and CXCL13 levels were also higher in placental blood from secundigravidae and multigravidae. In multivariate analyses adjusted for known predictors of birth weight, malaria-infected primigravidae with placental CXCL9 levels in the lowest tertile gave birth to babies who weighed 610 g more than babies born to mothers with high CXCL9 levels. CXCL9 expression is induced by IFN-γ, and the strong association between birth weight and placental CXCL9 is consistent with previous observations relating IFN-γ to poor pregnancy outcomes.

Download Full-text

Placental Tumor Necrosis Factor Alpha but Not Gamma Interferon Is Associated with Placental Malaria and Low Birth Weight in Malawian Women

Infection and Immunity ◽

10.1128/iai.71.1.267-270.2003 ◽

2003 ◽

Vol 71 (1) ◽

pp. 267-270 ◽

Cited By ~ 98

Author(s):

Stephen J. Rogerson ◽

Heidi C. Brown ◽

Elena Pollina ◽

Elizabeth T. Abrams ◽

Eyob Tadesse ◽

...

Keyword(s):

Birth Weight ◽

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Placental Blood ◽

Factor Alpha ◽

Ifn Γ ◽

Necrosis Factor

ABSTRACT Malaria in pregnancy predisposes to maternal anemia and low birth weight (LBW). We examined the possible roles of the cytokines tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) in these adverse outcomes. We measured cytokine concentrations in placental, peripheral, and cord blood plasma in relation to malaria parasitemia and placental monocyte accumulation in 276 Malawian women. Maternal hemoglobin concentration, human immunodeficiency virus status, and infant birth weight were determined. Concentrations of TNF-α in placental blood were correlated with densities of Plasmodium falciparum-infected erythrocytes (P < 0.0001) and of intervillous monocyte infiltrates (P < 0.0001) on placental histology. Peripheral blood TNF-α concentrations were relatively low and were weakly associated with malaria. TNF-α concentrations were higher in placental blood, where they were strongly associated with malaria. Placental plasma TNF-α levels were higher in women who had LBW babies (P = 0.0027), women with febrile symptoms (P < 0.0001), and teenage mothers (P = 0.04) than in other women. The presence of TNF-α in cord blood was not associated with malaria infection. IFN-γ levels were infrequently elevated, and elevated IFN-γ levels were not associated with poor pregnancy outcomes. Placental production of TNF-α, but not of IFN-γ, may be implicated in impaired fetal growth in Malawian women.

Download Full-text

Fetal Responses during Placental Malaria Modify the Risk of Low Birth Weight

Infection and Immunity ◽

10.1128/iai.00964-07 ◽

2008 ◽

Vol 76 (4) ◽

pp. 1527-1534 ◽

Cited By ~ 24

Author(s):

Edward R. Kabyemela ◽

Michal Fried ◽

Jonathan D. Kurtis ◽

Theonest K. Mutabingwa ◽

Patrick E. Duffy

Keyword(s):

Birth Weight ◽

Low Birth Weight ◽

Placental Malaria ◽

Interleukin 10 ◽

Protective Role ◽

High Rate ◽

Necrosis Factor Alpha ◽

Relative Contribution ◽

Strong Positive Relationship ◽

Ifn Γ

ABSTRACT Inflammation during placental malaria (PM) is associated with low birth weight (LBW), especially during the first pregnancy, but the relative contribution of maternal or fetal factors that mediate this effect remains unclear and the role of gamma interferon (IFN-γ) has been controversial. We examined the relationship of maternal and cord plasma levels of IFN-γ, tumor necrosis factor alpha, interleukin-10, ferritin, and leptin to birth weight for Tanzanian women delivering in an area where there is a high rate of malaria transmission. The placental levels of inflammatory cytokines, including IFN-γ, increased significantly during PM in primigravid and multigravid women but not in secundigravid women. PM also increased maternal peripheral levels of all inflammatory markers except IFN-γ but had strikingly little effect on cord levels of these proteins. In a multivariate analysis, placental IFN-γ was negatively associated (P = 0.01) and cord ferritin was positively associated (P < 0.0001) with birth weight in infected (PM-positive [PM+]) first-time mothers. This relationship was not observed in other mothers, consistent with the epidemiology of PM and disease. Cord leptin had a strong positive relationship with birth weight in offspring of PM-negative women (P = 0.02 to P < 0.0001) but not in offspring of PM+ women (all differences were not significant) in the three gravidity groups. The results confirmed that placental IFN-γ is related to LBW due to PM during first pregnancies and suggest that fetal ferritin plays a protective role. Because fetal cells are a source of placental IFN-γ and cord ferritin, the fetal response to PM may modify the risk of LBW.

Download Full-text

Changes in Antigen-Specific Cytokine and Chemokine Responses to Plasmodium falciparum Antigens in a Highland Area of Kenya after a Prolonged Absence of Malaria Exposure

Infection and Immunity ◽

10.1128/iai.01924-14 ◽

2014 ◽

Vol 82 (9) ◽

pp. 3775-3782 ◽

Cited By ~ 6

Author(s):

Lyticia A. Ochola ◽

Cyrus Ayieko ◽

Lily Kisia ◽

Ng'wena G. Magak ◽

Estela Shabani ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Severe Disease ◽

Clinical Malaria ◽

Necrosis Factor Alpha ◽

Content Type ◽

Highland Area ◽

Cytokine Responses ◽

Increased Risk ◽

Tnf Α ◽

Ifn Γ

ABSTRACTIndividuals naturally exposed toPlasmodium falciparumlose clinical immunity after a prolonged lack of exposure.P. falciparumantigen-specific cytokine responses have been associated with protection from clinical malaria, but the longevity ofP. falciparumantigen-specific cytokine responses in the absence of exposure is not well characterized. A highland area of Kenya with low and unstable malaria transmission provided an opportunity to study this question. The levels of antigen-specific cytokines and chemokines associated in previous studies with protection from clinical malaria (gamma interferon [IFN-γ], interleukin-10 [IL-10], and tumor necrosis factor alpha [TNF-α]), with increased risk of clinical malaria (IL-6), or with pathogenesis of severe disease in malaria (IL-5 and RANTES) were assessed by cytometric bead assay in April 2008, October 2008, and April 2009 in 100 children and adults. During the 1-year study period, none had an episode of clinicalP. falciparummalaria. Two patterns of cytokine responses emerged, with some variation by antigen: a decrease at 6 months (IFN-γ and IL-5) or at both 6 and 12 months (IL-10 and TNF-α) or no change over time (IL-6 and RANTES). These findings document thatP. falciparumantigen-specific cytokine responses associated in prior studies with protection from malaria (IFN-γ, TNF-α, and IL-10) decrease significantly in the absence ofP. falciparumexposure, whereas those associated with increased risk of malaria (IL-6) do not. The study findings provide a strong rationale for future studies of antigen-specific IFN-γ, TNF-α, and IL-10 responses as biomarkers of increased population-level susceptibility to malaria after prolonged lack ofP. falciparumexposure.

Download Full-text

Complex T Cell Interactions Contribute to Helicobacter pylori Gastritis in Mice

Infection and Immunity ◽

10.1128/iai.01269-12 ◽

2012 ◽

Vol 81 (3) ◽

pp. 740-752 ◽

Cited By ~ 31

Author(s):

Brian M. Gray ◽

Clinton A. Fontaine ◽

Sara A. Poe ◽

Kathryn A. Eaton

Keyword(s):

T Cells ◽

Helicobacter Pylori ◽

T Cell ◽

Published Data ◽

Proinflammatory Response ◽

Necrosis Factor Alpha ◽

Content Type ◽

Tnf Α ◽

Ifn Γ ◽

H Pylori

ABSTRACTDisease due to the gastric pathogenHelicobacter pylorivaries in severity from asymptomatic to peptic ulcer disease and cancer. Accumulating evidence suggests that one source of this variation is an abnormal host response. The goal of this study was to use a mouse model ofH. pylorigastritis to investigate the roles of regulatory T cells (Treg) as well as proinflammatory T cells (Th1 and Th17) in gastritis, gastric T cell engraftment, and gastric cytokine production. Our results support published data indicating that severe gastritis in T cell recipient mice is due to failure of Treg engraftment, that Treg ameliorate gastritis, and that the proinflammatory response is attributable to interactions between several cell subsets and cytokines. We confirmed that gamma interferon (IFN-γ) is essential for induction of gastritis but showed that IFN-γ-producing CD4 T cells are not necessary. Interleukin 17A (IL-17A) also contributed to gastritis, but to a lesser extent than IFN-γ. Tumor necrosis factor alpha (TNF-α) and IL-17F were also elevated in association with disease. These results indicate that whileH. pylori-specific CD4+T cells and IFN-γ are both essential for induction of gastritis due toH. pylori, IFN-γ production by T cells is not essential. It is likely that other proinflammatory cytokines, such as IL-17F and TNF-α, shown to be elevated in this model, also contribute to the induction of disease. We suggest that gastritis due toH. pyloriis associated with loss of immunoregulation and alteration of several cytokines and cell subsets and cannot be attributed to a single immune pathway.

Download Full-text

Placental Cytokine and Chemokine Profiles Reflect Pregnancy Outcomes in Women Exposed to Plasmodium falciparum Infection

Infection and Immunity ◽

10.1128/iai.01922-14 ◽

2014 ◽

Vol 82 (9) ◽

pp. 3783-3789 ◽

Cited By ~ 18

Author(s):

Arnaud Chêne ◽

Valérie Briand ◽

Samad Ibitokou ◽

Sébastien Dechavanne ◽

Achille Massougbodji ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Birth Weight ◽

Low Birth Weight ◽

Gestational Age ◽

Pregnancy Outcomes ◽

Preterm Births ◽

Interleukin 10 ◽

Maternal Anemia ◽

Content Type ◽

Ifn Γ

ABSTRACTPregnancy-associated malaria (PAM) can lead to severe complications for both mother and baby. Certain placental cytokine/chemokine profiles have been shown to reflect poor pregnancy outcomes, including maternal anemia and low birth weight. In intervillous plasma samples from 400 Beninese women living in an area wherePlasmodium falciparumis endemic, we quantified 16 cytokines/chemokines. We assessed their profiles in groups with PAM, with maternal anemia, with preterm births, or with a low birth weight for gestational age. Repeated ultrasound measurements ensured that prematurity and low birth weight were highly accurate. Preliminary analyses revealed trends for lower cytokine/chemokine concentrations in placental plasma associated both with babies with low birth weight for gestational age and withP. falciparuminfection during pregnancy, while, as a function of the latter, the concentration of gamma interferon (IFN-γ)-inducible protein 10 (IP-10) was higher. Multivariate analyses showed that (i) higher placental plasma interleukin-10 (IL-10) levels were associated withP. falciparuminfections and (ii) independently ofP. falciparuminfections, lower concentrations of both IFN-γ and IL-5 were associated with low birth weight for gestational age. Our data further strengthen the idea that IL-10 and IP-10 could be useful diagnostic markers ofP. falciparuminfection during pregnancy. The concentrations of cytokines/chemokines in placental plasma may represent previously unrecognized markers of poor fetal growth.

Download Full-text

Discrimination between Active and Latent Tuberculosis Based on Ratio of Antigen-Specific to Mitogen-Induced IP-10 Production

Journal of Clinical Microbiology ◽

10.1128/jcm.02758-14 ◽

2014 ◽

Vol 53 (2) ◽

pp. 504-510 ◽

Cited By ~ 30

Author(s):

Yun Hee Jeong ◽

Yun-Gyoung Hur ◽

Hyejon Lee ◽

Sunghyun Kim ◽

Jang-Eun Cho ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Interleukin 2 ◽

Induced Responses ◽

Necrosis Factor Alpha ◽

Content Type ◽

Monocyte Chemoattractant Protein 1 ◽

Tnf Α ◽

Release Assay ◽

Ltbi Group ◽

Ifn Γ

Mycobacterium tuberculosisis the major causative agent of tuberculosis (TB). The gamma interferon (IFN-γ) release assay (IGRA) has been widely used to diagnose TB by testing cell-mediated immune responses but has no capacity for distinguishing between active TB and latent TB infection (LTBI). This study aims to identify a parameter that will help to discriminate active TB and LTBI. Whole-blood samples from 33 active TB patients, 20 individuals with LTBI, and 26 non-TB controls were applied to the commercial IFN-γ release assay, QuantiFERON-TB Gold In-Tube, and plasma samples were analyzed for interleukin-2 (IL-2), IL-6, IL-8, IL-10, IL-13, tumor necrosis factor-alpha (TNF-α), IFN-γ, monokine induced by IFN-γ (MIG), interferon gamma inducible protein 10 (IP-10), interferon-inducible T cell alpha chemoattractant (I-TAC), and monocyte chemoattractant protein 1 (MCP-1) by using a commercial cytometric bead array. TheMycobacterium tuberculosisantigen-specific production of most of the assayed cytokines and chemokines was higher in the active TB than in the LTBI group. The mitogen-induced responses were lower in the active TB than in the LTBI group. When the ratio of TB-specific to mitogen-induced responses was calculated, IL-2, IL-6, IL-10, IL-13, TNF-α, IFN-γ, MIG, and IP-10 were more useful in discriminating active TB from LTBI. In particular, most patients showed higher IP-10 production toMycobacterium tuberculosisantigens than to mitogen at the individual level, and the ratio for IP-10 was the strongest indicator of active infection versus LTBI with 93.9% sensitivity and 90% specificity. In conclusion, the ratio of the TB-specific to the mitogen-induced IP-10 responses showed the most promising accuracy for discriminating active TB versus LTBI and should be further studied to determine whether it can serve as a biomarker that might help clinicians administer appropriate treatments.

Download Full-text

The Predominant CD4+ Th1 Cytokine Elicited to Chlamydia trachomatis Infection in Women Is Tumor Necrosis Factor Alpha and Not Interferon Gamma

Clinical and Vaccine Immunology ◽

10.1128/cvi.00010-17 ◽

2017 ◽

Vol 24 (4) ◽

Cited By ~ 11

Author(s):

Stephen J. Jordan ◽

Kanupriya Gupta ◽

Brian M. O. Ogendi ◽

Rakesh K. Bakshi ◽

Richa Kapil ◽

...

Keyword(s):

T Cells ◽

Chlamydia Trachomatis ◽

Tumor Necrosis ◽

Necrosis Factor Alpha ◽

Content Type ◽

Tnf Α ◽

Th1 Cytokine ◽

Factor Alpha ◽

Ifn Γ ◽

Necrosis Factor

ABSTRACT Chlamydia trachomatis infection is the most prevalent bacterial sexually transmitted infection and can cause significant reproductive morbidity in women. There is insufficient knowledge of C. trachomatis-specific immune responses in humans, which could be important in guiding vaccine development efforts. In contrast, murine models have clearly demonstrated the essential role of T helper type 1 (Th1) cells, especially interferon gamma (IFN-γ)-producing CD4+ T cells, in protective immunity to chlamydia. To determine the frequency and magnitude of Th1 cytokine responses elicited to C. trachomatis infection in humans, we stimulated peripheral blood mononuclear cells from 90 chlamydia-infected women with C. trachomatis elementary bodies, Pgp3, and major outer membrane protein and measured IFN-γ-, tumor necrosis factor alpha (TNF-α)-, and interleukin-2 (IL-2)-producing CD4+ and CD8+ T-cell responses using intracellular cytokine staining. The majority of chlamydia-infected women elicited CD4+ TNF-α responses, with frequency and magnitude varying significantly depending on the C. trachomatis antigen used. CD4+ IFN-γ and IL-2 responses occurred infrequently, as did production of any of the three cytokines by CD8+ T cells. About one-third of TNF-α-producing CD4+ T cells coproduced IFN-γ or IL-2. In summary, the predominant Th1 cytokine response elicited to C. trachomatis infection in women was a CD4+ TNF-α response, not CD4+ IFN-γ, and a subset of the CD4+ TNF-α-positive cells produced a second Th1 cytokine.

Download Full-text

Specific Human and Candida Cellular Interactions Lead to Controlled or Persistent Infection Outcomes during Granuloma-Like Formation

Infection and Immunity ◽

10.1128/iai.00807-16 ◽

2016 ◽

Vol 85 (1) ◽

Cited By ~ 10

Author(s):

Barbara Misme-Aucouturier ◽

Marjorie Albassier ◽

Nidia Alvarez-Rueda ◽

Patrice Le Pape

Keyword(s):

Immune Cells ◽

Immune Cell ◽

Human Peripheral Blood ◽

Cell Interaction ◽

Cellular Interactions ◽

Necrosis Factor Alpha ◽

Content Type ◽

Tnf Α ◽

Ifn Γ

ABSTRACT A delayed type of multicellular process could be crucial during chronic candidiasis in determining the course of infection. This reaction, consisting of organized immune cells surrounding the pathogen, initiates an inflammatory response to avoid fungal dissemination. The goal of the present study was to examine, at an in vitro cellular scale, Candida and human immune cell interaction dynamics during a long-term period. By challenging human peripheral blood immune cells from 10 healthy donors with 32 Candida albicans and non-albicans (C. glabrata, C. tropicalis, C. parapsilosis, C. dubliniensis, C. lusitaniae, C. krusei, and C. kefyr) clinical isolates, we showed that Candida spp. induced the formation of granuloma-like structures within 6 days after challenge, but their sizes and the respective fungal burdens differed according to the Candida species. These two parameters are positively correlated. Phenotypic characteristics, such as hypha formation and higher axenic growth rate, seem to contribute to yeast persistence within granuloma-like structures. We showed an interindividual variability of the human response against Candida spp. Higher proportions of neutrophils and elevated CD4+/CD8+ T cell ratios during the first days after challenge were correlated with early production of gamma interferon (IFN-γ) and associated with controlled infection. In contrast, the persistence of Candida could result from upregulation of proinflammatory cytokines such as interleukin-6 (IL-6), IFN-γ, and tumor necrosis factor alpha (TNF-α) and a poor anti-inflammatory negative feedback (IL-10). Importantly, regulatory subsets of NK cells and CD4lo CD8hi doubly positive (DP) lymphocytes at late stage infiltrate granuloma-like structures and could correlate with the IL-10 and TNF-α production. These data offer a base frame to explain cellular events that guide infection control or fungal persistence.

Download Full-text

Leptin, insulin like growth factor-I levels and histology-diagnosed placental malaria in an area characterized by unstable malaria transmission in central Sudan

F1000Research ◽

10.12688/f1000research.10641.1 ◽

2017 ◽

Vol 6 ◽

pp. 736

Author(s):

Hagir Elsheikh ◽

Ishag Adam ◽

Elhassan M. Elhassan ◽

Ahmed A. Mohammed ◽

Ammar H. Khamis ◽

...

Keyword(s):

Birth Weight ◽

Growth Factor ◽

Low Birth Weight ◽

Umbilical Cord ◽

Placental Malaria ◽

Enzyme Linked Immunosorbent Assay ◽

Published Data ◽

Insulin Like Growth Factor ◽

Significant Difference ◽

Malaria During Pregnancy

Background: There are few published data on the association between leptin, insulin like growth factor-1 (IGF-1) and malaria during pregnancy. This study aimed to investigate maternal and umbilical cord leptin and IGF-1 levels and malaria during pregnancy, and their association - if any - with birth weight. Methods: A cross-sectional study was conducted at Medani, Sudan. Medical and obstetrics history was gathered from each parturient woman (n=175) and malaria was investigated by blood film and placental histology. Maternal and umbilical cord leptin and IGF-1 levels were measured using ELISA. Results: Upon histological examination, 48 women were infected with placental malaria, and 127 were found free from the disease. Out of the 48, 2 of the patients showed signs of active infection, 3 of chronic infection and 43 of previous infection. Placental malaria and preterm delivery were associated with low birth weight (< 2500 g). Younger mothers and primigravidae had a higher risk for placental malaria infection. There was no significant difference in maternal and umbilical cord leptin and IGF-1 levels between women infected with placental malaria and those free from the disease. Conclusions: The current study showed that low birth weight was significantly associated with placental malaria. Young mothers and primigravidae had a higher risk to develop the infection. There was no significant difference in the levels of maternal and umbilical cord leptin and IGF-1 levels between women infected with placental malaria and those free from the disease. Both the levels of maternal and cord leptin and IGF-1were found not to be associated with birth weight. Abbreviations: IGF-1: Insulin like growth factor-1; LBW: Low birth weight; ELISA: Enzyme-linked immunosorbent assay; PM: Placental malaria.

Download Full-text

MyD88 Signaling Is Directly Involved in the Development of Murine Placental Malaria

Infection and Immunity ◽

10.1128/iai.01288-13 ◽

2013 ◽

Vol 82 (2) ◽

pp. 830-838 ◽

Cited By ~ 11

Author(s):

Renato Barboza ◽

Aramys Silva Reis ◽

Leandro Gustavo da Silva ◽

Lutero Hasenkamp ◽

Keitty Raquel Benevides Pereira ◽

...

Keyword(s):

Malaria Infection ◽

Placental Malaria ◽

Placental Tissue ◽

Therapeutic Interventions ◽

Histopathological Analysis ◽

Necrosis Factor Alpha ◽

Content Type ◽

Tnf Α ◽

Factor Alpha ◽

Myd88 Signaling

ABSTRACTMalaria is a widespread infectious disease caused by the parasitePlasmodium. During pregnancy, malaria infection leads to a range of complications that can affect both the mother and fetus, including stillbirth, infant mortality, and low birth weight. In this study, we utilized a mouse model of placental malaria (PM) infection to determine the importance of the protein MyD88 in the host immune response toPlasmodiumduring pregnancy. Initially, we demonstrated thatPlasmodium bergheiNK65GFP adhered to placental tissue via chondroitin sulfate A and induced PM in mice with a C57BL/6 genetic background. To evaluate the involvement of MyD88 in the pathology of PM, we performed a histopathological analysis of placentas obtained from MyD88−/−and wild-type (WT) mice following infection on the 19th gestational day. Our data demonstrated that the detrimental placental alterations observed in the infected mice were correlated with the expression of MyD88. Moreover, in the absence of this protein, production of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) was significantly reduced in the infected mice. More importantly, in contrast to fetuses from infected WT mice, which exhibited a reduction in body weight, the fetuses from infected MyD88−/−mice did not display significant weight loss compared to their noninfected littermates. In addition, we observed a decrement of maternal care associated with malaria infection, which was attenuated in the MyD88-deficient mice. Collectively, the results of this study illustrate the pivotal importance of the MyD88 signaling pathway in the pathogenesis of placental malaria, thus presenting new possibilities for targeting MyD88 in therapeutic interventions.

Download Full-text