The process of human parturition involves inflammation at the interface where fetal chorion trophoblast cells interact with maternal decidual stromal (DS) cells and maternal immune cells in the decidua (endometrium of pregnancy). This study tested the hypothesis that inflammation at the chorion–decidua interface (CDI) induces labor by negating the capacity for progesterone (P4) to block labor and that this is mediated by inactivation of P4 in DS cells by aldo-keto reductase family 1 member C1 (AKR1C1). In human, Rhesus macaque, and mouse CDI, AKR1C1 expression increased in association with term and preterm labor. In a human DS cell line and in explant cultures of term human fetal membranes containing the CDI, the prolabor inflammatory cytokine, interleukin-1ß (IL-1ß), and media conditioned by LPS-stimulated macrophages increased AKR1C1 expression and coordinately reduced nuclear P4 levels and P4 responsiveness. Loss of P4 responsiveness was overcome by inhibition of AKR1C1 activity, inhibition of AKR1C1 expression, and bypassing AKR1C1 activity with a P4 analog that is not metabolized by AKR1C1. Increased P4 activity in response to AKR1C1 inhibition was prevented by the P4 receptor antagonist RU486. Pharmacologic inhibition of AKR1C1 activity prevented parturition in a mouse model of inflammation-induced preterm parturition. The data suggest that inflammatory stimuli at the CDI drive labor by inducing AKR1C1-mediated P4 inactivation in DS cells and that inhibiting and/or bypassing of AKR1C1-mediated P4 inactivation is a plausible therapeutic strategy to mitigate the risk of inflammation-associated preterm birth.

There remains a general misconception that the immune status of the fetus and neonate is immature or insufficient. However, emerging research in immune ontogeny prompts reconsideration of this orthodoxy, reframing this period instead as one of unique opportunity. Vaccine responses (qualitative and quantitative) vary between individuals, and across demographic cohorts. Elements of baseline immune status and function predict vaccine response – some of these factors are well described, others remain a subject of ongoing research, especially with the rapidly expanding field of ‘omics’ research, enabled by development of highly granular immune profiling techniques and increasing computational capacity. Age is one of the strongest predictive factors associated with variability in the response to vaccination; and predictable variation in response to vaccination is a key to identify the crucial underlying mechanisms. Specifically, circulating maternal antibody in the young infant can modulate immune response to vaccination, acting as an ‘undercover adjuvant’ that, counter to current dogma, may offer a pathway to longer lasting, higher quality immune response to vaccination. Exciting avenues for novel research in this area have the potential to dramatically alter how we protect the world's most vulnerable population – the very young.

A recent study shows that the commensal fungus Candida albicans is an inducer of differentiation of human CD4(+) Th17 cells that harbor heterologous specificity for other fungi, which may explain evolutionary benefits of C. albicans as a commensal microbe (Bacher et al. Cell 2019;176;1340-1355). However, Th17 cells that are crossreactive to Aspergillus fumigatus antigens can also drive exaggerated airway inflammation in humans.

Candida albicans is the leading cause of systemic candidiasis, a fungal disease associated with high mortality and poor treatment options. The kidney is the target organ during infection and whose control is largely dependent on innate immunity, because lymphocytes appear redundant for protection. In this article, we show that this apparent redundancy stems from a failure of Ag-specific CD4 + T cells to migrate into infected kidneys. In contrast, Ag-specific CD8 + T cells are recruited normally. Using Ag-loaded immunoliposomes to artificially reverse this defective migration, we show that recruited Ag-specific CD4 + T cells polar-ize toward a Th17 phenotype in the kidney and are protective during fungal infection. Therefore, our data explain the redundancy of CD4 + T cells for defense against systemic infection with C. albicans and have important implications for our understanding of antifungal immunity and the control of renal infections. The Journal of Immunology , 2014, 193: 5381–5385.

Although the increased morbidity and mortality of influenza during pregnancy provide a compelling reason to vaccinate pregnant women, pregnancy is associated with a decreased hemagglutination inhibition (HAI) response to influenza vaccine. We hypothesized that in addition to this quantitative reduction, pregnancy-associated increases in IL-4, IL-10 and IL-13 secretion might promote production of IgG4 over the better complement- and Fc receptor-activating isotypes, IgG1 and IgG3; such a change might decrease antibody-dependent killing of virus. To begin to evaluate this hypothesis, we compared IgG1, IgG3 and IgG4 anti-H1N1 titers by ELISA in sera obtained from 50 pregnant and non-pregnant 18-39 year old women 24-31 days after vaccination. The IgG1:IgG4 ratio was significantly decreased in pregnant vs. non-pregnant women (29.0±35.0 vs. 69.3±94.1 (mean ± SD), p=0.04). Both HAI (p=0.017) and IgG1 (p=0.047) titers were decreased in trimesters 2 and 3 vs. trimester 1. These changes could be quite marked: 28% of women immunized during trimesters 2 and 3 had a combination of high IgG4/low IgG1 titers that was not seen in any non-pregnant or first trimester vaccinated women. Our results suggest that cytokine-mediated qualitative and quantitative changes in the anti-influenza antibody response may decrease protection in a considerable percentage of women vaccinated during the last 2/3 of pregnancy, which, in turn, suggests a need to consider changes in vaccination for this population.

Chromobacterium violaceum is an unusual cause of infection, typically associated with rapid dissemination and a high mortality rate. We describe a case of a young immune-competent patient with sepsis associated with a large focal leg ulcer due to C. violaceum. This case highlights several typical features of infection with C. violaceum, including summertime exposure and presence of liver abscesses; it is atypical in terms of the specific dermatologic findings. We discuss the case itself and briefly review the medical literature on this unusual organism.

ABSTRACT ESAT-6 is a virulence determinant in Mycobacterium tuberculosis and a member of a conserved group of proteins in a variety of other bacteria. A targeted deletion of the homologous gene in Listeria was generated, and in contrast to that observed for mycobacteria, this locus was not required for Listeria virulence.

ABSTRACT The innate host response to lipopolysaccharide (LPS) obtained from Porphyromonas gingivalis is unusual in that different studies have reported that it can be an agonist for Toll-like receptor 2 (TLR2) as well as an antagonist or agonist for TLR4. In this report it is shown that P. gingivalis LPS is highly heterogeneous, containing more lipid A species than previously described. In addition, purification of LPS can preferentially fractionate these lipid A species. It is shown that an LPS preparation enriched for lipid A species at m/z 1,435 and 1,450 activates human and mouse TLR2, TLR2 plus TLR1, and TLR4 in transiently transfected HEK 293 cells coexpressing membrane-associated CD14. The HEK cell experiments further demonstrated that cofactor MD-2 was required for functional engagement of TLR4 but not of TLR2 nor TLR2 plus TLR1. In addition, serum-soluble CD14 effectively transferred P. gingivalis LPS to TLR2 plus TLR1, but poorly to TLR4. Importantly, bone marrow cells obtained from TLR2 −/− and TLR4 −/− mice also responded to P. gingivalis LPS in a manor consistent with the HEK results, demonstrating that P. gingivalis LPS can utilize both TLR2 and TLR4. No response was observed from bone marrow cells obtained from TLR2 and TLR4 double-knockout mice, demonstrating that P. gingivalis LPS activation occurred exclusively through either TLR2 or TLR4. Although the biological significance of the different lipid A species found in P. gingivalis LPS preparations is not currently understood, it is proposed that the presence of multiple lipid A species contributes to cell activation through both TLR2 and TLR4.

Flagellin is the structural component of flagella produced by many pathogenic bacteria and is a potent proinflammatory molecule that mediates these effects through Toll-like receptor (TLR) 5. In Listeria monocytogenes (LM), flagellin expression is regulated by temperature and has been described as being shut off at 37degreesC. In this study, we demonstrate that TLR5-mediated cell activation and flagellin expression is maintained at 37degreesC in some laboratory-adapted strains and in approximate to 20% of LM clinical isolates. To determine the role of flagellin in LM infection, a targeted mutation in the structural gene for flagellin (flaA) was generated in a parental LM strain that expressed flagellin under all conditions examined. In vitro studies demonstrated that this DeltaflaA mutant was (i) non-motile; (ii) not able to activate TLR5-transfected HeLa cells; and (iii) induced tumour necrosis factor (TNF)-alpha production in approximate to50% fewer CD11b(+) cells in splenocytes from normal mice compared with the parental strain. However, there was no significant alteration in virulence of the DeltaflaA mutant after either intravenous or oral murine infection. Similarly, there was no difference in the generation of LM-specific CD8 or CD4 T cells after intravenous or oral infection. These data indicate that flagellin is not essential for LM pathogenesis or for the induction of LM-specific adaptive immune responses in normal mice.

Neonates respond suboptimally to many vaccines. The reasons for this defect are unclear, but suboptimal antigen presentation by dendritic cells has been suggested as one possibility. In this report we describe an in vitro system that allows the generation of large numbers of resting murine neonatal dendritic cells facilitating their study. Using this system, we show a clear reduction in the ability of neonatal dendritic cells to present soluble ovalbumin, while the capacity to present ovalbumin peptide is intact. This suggests a specific defect in cross-presentation of exogenous antigen via the major histocompatibility complex (MHC) class I pathway. Deficient cross-presentation may contribute to the suboptimal CD8 T-cell response to vaccines in neonates.