The immune system in the female reproductive tract (FRT) does not mount an attack against HIV or other sexually transmitted infections (STI) with a single endogenously produced microbicide or with a single arm of the immune system. Instead, the body deploys dozens of innate antimicrobials to the secretions of the female reproductive tract. Working together, these antimicrobials along with mucosal antibodies attack many different viral, bacterial and fungal targets. Within the FRT, the unique challenges of protection against sexually transmitted pathogens coupled with the need to sustain the development of an allogeneic fetus have evolved in such a way that sex hormones precisely regulate immune function to accomplish both tasks. The studies presented in this review demonstrate that estradiol and progesterone secreted during the menstrual cycle act both directly and indirectly on epithelial cells and other immune cells in the reproductive tract to modify immune function in a way that is unique to specific sites throughout the FRT. As presented in this review, studies from our laboratory and others demonstrate that the innate immune response is under hormonal control, varies with the stage of the menstrual cycle, and as such is suppressed at mid-cycle to optimize conditions for successful fertilization and pregnancy. In doing so, a window of STI vulnerability is created during which potential pathogens including HIV enter the reproductive tract to infect host targets.

Malarial anemia (MA) is a multifactorial disease for which the complex etiological basis is only partially defined. The association of clinical, nutritional, demographic, and socioeconomic factors with parasitemia, anemia, and MA was determined for children presenting at a hospital in a holoendemic area of Plasmodium falciparum transmission in western Kenya. Parasitemia was not associated with malaria disease severity. In univariate logistic regression, fever was significantly associated with parasitemia, and wasting was associated with increased presentation of MA. Caretaker's level of education and occupation were significantly correlated with parasitemia, anemia, and MA. Housing structure was also significantly associated with parasitemia and anemia. Bed net use was protective against parasitemia but not anemia or MA. Multivariate logistic regression models demonstrated that fever, mother's occupation, and bed net use were associated with parasitemia. In the current study, none of the factors were associated with anemia or MA in the multivariate models.

Chemokines regulate the host immune response to a variety of infectious pathogens. Since the role of chemokines in regulating host immunity in children with Plasmodium falciparum malaria has not previously been reported, circulating levels of ␤-chemokines (MIP-1␣, MIP-1␤, and RANTES) and their respective transcriptional profiles in ex vivo peripheral blood mononuclear cells (PBMCs) were investigated. Peripheral blood MIP-1␣ and MIP-1␤ levels were significantly elevated in mild and severe malaria, while RANTES levels decreased with increasing disease severity. ␤-Chemokine gene expression profiles in blood mononuclear cells closely matched those of circulating ␤-chemokines, illustrating that PBMCs are a primary source for the observed pattern of ␤-chemokine production during acute malaria. Statistical modeling revealed that none of the chemokines was significantly associated with either parasitemia or anemia. Additional investigations in healthy children with a known history of malaria showed that children with prior severe malaria had significantly lower baseline RANTES production than children with a history of mild malaria, suggesting inherent differences in the ability to produce RANTES in these two groups. Baseline MIP-1␣ and MIP-1␤ did not significantly differ between children with prior severe malaria and those with mild malaria. Additional in vitro experiments in PBMCs from healthy, malaria-naïve donors revealed that P. falciparum-derived hemozoin (Hz; malarial pigment) and synthetic Hz (␤-hematin) promote a similar pattern of ␤-chemokine gene expression. Taken together, the results presented here demonstrate that children with severe malaria have a distinct profile of ␤-chemokines characterized by increased circulating levels of MIP-1␣ and MIP-1␤ and decreased RANTES. Altered patterns of circulating ␤-chemokines result, at least in part, from Hz-induced changes in ␤-chemokine gene expression in blood mononuclear cells.

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The mucosal immune system in the upper female reproductive tract is uniquely prepared to maintain a balance between the presence of commensal bacteria, sexually transmitted bacterial and viral pathogens, allogeneic spermatozoa, and an immunologically distinct fetus. At the center of this dynamic system are the epithelial cells that line the Fallopian tubes, uterus, cervix and vagina. Epithelial cells provide a first line of defense that confers continuous protection, by providing a physical barrier as well as secretions containing bactericidal and virucidal agents. In addition to maintaining a state of ongoing protection, these cells have evolved to respond to pathogens, in part through Toll-like receptors (TLRs), to enhance innate immune protection and, when necessary, to contribute to the initiation of an adaptive immune response. Against this backdrop, epithelial cell innate and adaptive immune function is modulated to meet the constraints of procreation. The overall goal of this review is to focus on the dynamic role of epithelial cells in the upper reproductive tract, with special emphasis on the uterus, to define the unique properties of these cells as they maintain homeostasis in preparation for successful fertilization and pregnancy while at the same time confer protection against sexually transmitted infections, which threaten to compromise women's reproductive health and survival. By understanding the nature of this protection and the ways in which innate and adaptive immunity are regulated by sex hormones, these studies provide the opportunity to contribute to the foundation of information essential for ensuring reproductive health.

BackgroundSexual transmission accounts for the majority of HIV-1 infections. In over 75% of cases, infection is initiated by a single variant (transmitted/founder virus). However, the determinants of virus selection during transmission are unknown. Host cell-cell interactions in the mucosa may be critical in regulating susceptibility to infection. We hypothesized in this study that specific immune modulators secreted by uterine epithelial cells modulate susceptibility of dendritic cells (DC) to infection with HIV-1.Methodology/Principal FindingsHere we report that uterine epithelial cell secretions (i.e. conditioned medium, CM) decreased DC-SIGN expression on immature dendritic cells via a transforming growth factor beta (TGF-β) mechanism. Further, CM inhibited dendritic cell-mediated trans infection of HIV-1 expressing envelope proteins of prototypic reference. Similarly, CM inhibited trans infection of HIV-1 constructs expressing envelopes of transmitted/founder viruses, variants that are selected during sexual transmission. In contrast, whereas recombinant TGF- β1 inhibited trans infection of prototypic reference HIV-1 by dendritic cells, TGF-β1 had a minimal effect on trans infection of transmitted/founder variants irrespective of the reporter system used to measure trans infection.Conclusions/SignificanceOur results provide the first direct evidence for uterine epithelial cell regulation of dendritic cell transmission of infection with reference and transmitted/founder HIV-1 variants. These findings have immediate implications for designing strategies to prevent sexual transmission of HIV-1.

One of the commonest complications of Plasmodium falciparum malaria is the development of severe malarial anemia (SMA), which is, at least in part, due to malaria-induced suppression of erythropoiesis. Factors associated with suppression of erythropoiesis and development of SMA include accumulation of malarial pigment (hemozoin, PfHz) in bone marrow and altered production of inflammatory mediators, such as tumor necrosis factor (TNF)-α, and nitric oxide (NO). However, studies investigating the specific mechanisms responsible for inhibition of red blood cell development have been hampered by difficulties in obtaining bone marrow aspirates from infants and young children, and the lack of reliable models for examining erythroid development. As such, an in vitro model of erythropoiesis was developed using CD34+ stem cells derived from peripheral blood to examine the effects of PfHz, PfHz-stimulated peripheral blood mononuclear cell (PBMC)-conditioned media (CM-PfHz), TNF-α, and NO on erythroid cell development. PfHz only slightly suppressed erythroid cell proliferation and maturation marked by decreased expression of glycophorin A (GPA). On the other hand, CM-PfHz, TNF-α, and NO significantly inhibited erythroid cell proliferation. Furthermore, decreased proliferation in cells treated with CM-PfHz and NO was accompanied by increased apoptosis of erythropoietin-stimulated CD34+ cells. In addition, NO significantly inhibited erythroid cell maturation, whereas TNF-α did not appear to be detrimental to maturation. Collectively, our results demonstrate that PfHz suppresses erythropoiesis by acting both directly on erythroid cells, and indirectly via inflammatory mediators produced from PfHz-stimulated PBMC, including TNF-α and NO.

The balance between immunity and tolerance in the endometrium is governed by dynamic interactions of UEC and immune cells including DC. In this study, we tested the hypothesis that soluble immune mediators secreted by UEC modulate the differentiation and functions of human DC. We found that DC differentiated with CM from polarized UEC (i.e., CM-DC) expressed significantly lower surface CD86. Upon activation with LPS or PIC, the expression of CD80, CD86, and CD83 was decreased significantly on CM-DC relative to Con-DC. Further, mRNA for TLR3, TLR4, and TLR5 was decreased significantly in CM-DC relative to Con-DC. As a functional read-out of the effect of CM on DC, we determined the following parameters: First, analysis of cytokine production showed that when compared with Con-DC, CM-DC responded to LPS or PIC stimulation with enhanced IL-10 production but undetectable IL-12p70 secretion. Second, RT-PCR analysis showed that CM-DC significantly expressed higher mRNA for IDO, an immune tolerance-promoting enzyme. Lastly, in a MLR assay, CM-DC induced significantly lower allogeneic proliferative responses compared with Con-DC. These findings indicate collectively that epithelial cells confer a tolerogenic phenotype to DC in the endometrium. Our results suggest novel cellular and molecular mechanisms for the regulation of adaptive immunity within the FRT.