From the Cover: PNAS Plus: Comprehensive analysis of dengue virus-specific responses supports an HLA-linked protective role for CD8+ T cells

The role of CD8⁺ T cells in dengue virus infection and subsequent disease manifestations is not fully understood. According to the original antigenic sin theory, skewing of T-cell responses induced by primary infection with one serotype causes less effective response upon secondary infection with a different serotype, predisposing individuals to severe disease. A comprehensive analysis of CD8⁺ responses in the general population from the Sri Lankan hyperendemic area, involving the measurement of ex vivo IFNγ responses associated with more than 400 epitopes, challenges the original antigenic sin theory. Although skewing of responses toward primary infecting viruses was detected, this was not associated with impairment of responses either qualitatively or quantitatively. Furthermore, we demonstrate higher magnitude and more polyfunctional responses for HLA alleles associated with decreased susceptibility to severe disease, suggesting that a vigorous response by multifunctional CD8⁺ T cells is associated with protection from dengue virus disease.Dengue virus (DENV) is the etiologic agent of dengue fever (DF), the most significant mosquito-borne viral disease in humans. Disease can be caused by any of the four DENV serotypes (DENV1 to -4), which share 67–75% sequence homology with one another (1). DENV transmission occurs in more than 100 countries and is an increasing public health problem in tropical and subtropical regions (2). Demographic changes, urbanization, and international travel contribute to the expansion of geographical areas where transmission occurs, and all four DENV serotypes are now circulating in Asia, Africa, and the Americas (3, 4). Up to 100 million DENV infections occur every year (5), and severity can range from asymptomatic to an acute self-limiting febrile illness (DF). In a small proportion of patients, the disease can exacerbate and progress to dengue hemorrhagic fever (DHF) and/or dengue shock syndrome (DSS), characterized by severe vascular leakage, thrombocytopenia, and hemorrhagic manifestations (4).Although natural infection by any of the four DENV serotypes (primary infection) produces a lasting protective immunity against reinfection by the same serotype, it does not protect against infections with other serotypes (secondary infections) (6, 7). Epidemiologic studies have shown that the majority of individuals that develop DHF/DSS had been previously infected with a different serotype (8). Consequently, the development of DENV vaccines has been hampered by the potential risk of vaccine-related adverse events and the requirement to induce long-lasting protective immune responses against all four DENV serotypes simultaneously (9). The cause for the increased frequency of DHF following secondary infections has not been fully elucidated. One hypothesis is that serotype cross-reactive antibodies exacerbate disease by increasing infection of cells bearing Fcγ receptors, resulting in higher viral loads and more severe disease via this antibody-dependent enhancement (ADE) of infection (10, 11). Indeed, nonhuman primate and murine models have demonstrated that antibodies can lead to enhancement of DENV infection and disease in vivo (12–15).Another hypothesis postulates that T cells raised against the first infecting serotype dominate during a secondary heterologous infection in a phenomenon termed “original antigenic sin” (16, 17). This term was first applied to the humoral response to influenza epidemics (18) but has also been observed in CD8⁺ T-cell responses against lymphocytic choriomeningitis virus (19). This hypothesis postulates that, during secondary infection, expansion of preexisting lower avidity cross-reactive memory T cells dominate the responses over that of naïve T cells that are of higher avidity for the new DENV serotype. This expansion of low avidity T cells results in less efficient elimination of DENV-infected cells.A role for T cells in control of DENV infection is suggested by several studies that implicate HLA associations as a genetic component to variable susceptibility to DENV disease (20–26). However, it has not been addressed whether these associations might indicate a positive or detrimental role for T-cell responses. One major obstacle to the elucidation of the function of T cells is the lack of a comprehensive characterization of HLA-restricted DENV responses in the context of natural infection.Herein, we present a comprehensive analysis of functional T-cell memory against DENV and are able to correlate this with HLA alleles expressed in the very same donors. Collectively, the data suggest an HLA-linked protective role of CD8⁺ T-cell responses and do not support a causative role for CD8⁺ T cells in the induction of severe disease following secondary heterologous infection.     

Chondrosarcoma of the hyoid.

Two cases of chondrosarcoma of the hyoid bone are described. They were managed with surgical resection and postoperative radiotherapy. These patients are disease free at 26 months and 15 months respectively.     

A test of nonrandom segregation

Within a family, associations between a disease and a marker locus are often inferred when affected offspring share marker alleles more often than is expected by chance. Generally, this is due to nonrandom parental transmission of marker alleles and specifically could be due to linkage, epistatic gene action, or segregation distortion at the marker locus. In this paper, we discuss the statistical properties of a general test of nonrandom segregation of a marker gene. The exact probability distribution of the test under the null hypothesis of random segregation is derived, as is the distribution under the alternative hypothesis of genetic linkage. We compute the mean and variance of these distributions as a means of judging the adequacy of random segregation to explain disease-marker data but also provide a method for computing the exact significance value under the null hypothesis. These methods have been utilized for studying HLA segregation in families with tuberculoid leprosy. On the assumption that this type of leprosy is autosomal recessive, we find evidence that a gene controlling susceptibility to infection by Mycobacterium leprae resides on human chromosome 6, approximately 13 map units away from the HLA locus in males.     

Antibodies targeting dengue virus envelope domain III are not required for serotype-specific protection or prevention of enhancement in vivo

The envelope (E) protein of dengue virus (DENV) is composed of three domains (EDI, EDII, EDIII) and is the main target of neutralizing antibodies. Many monoclonal antibodies that bind EDIII strongly neutralize DENV. However in vitro studies indicate that anti-EDIII antibodies contribute little to the neutralizing potency of human DENV-immune serum. In this study, we assess the role of anti-EDIII antibodies in mouse and human DENV-immune serum in neutralizing or enhancing DENV infection in mice. We demonstrate that EDIII-depleted human DENV-immune serum was protective against homologous DENV infection in vivo. Although EDIII-depleted DENV-immune mouse serum demonstrated decreased neutralization potency in vitro, reduced protection in some organs, and enhanced disease in vivo, administration of increased volumes of EDIII-depleted serum abrogated these effects. These data indicate that anti-EDIII antibodies contribute to protection and minimize enhancement when present, but can be replaced by neutralizing antibodies targeting other epitopes on the dengue virion.     

Human embryonic stem cells have a unique epigenetic signature

Human embryonic stem (hES) cells originate during an embryonic period of active epigenetic remodeling. DNA methylation patterns are likely to be critical for their self-renewal and pluripotence. We compared the DNA methylation status of 1536 CpG sites (from 371 genes) in 14 independently isolated hES cell lines with five other cell types: 24 cancer cell lines, four adult stem cell populations, four lymphoblastoid cell lines, five normal human tissues, and an embryonal carcinoma cell line. We found that the DNA methylation profile clearly distinguished the hES cells from all of the other cell types. A subset of 49 CpG sites from 40 genes contributed most to the differences among cell types. Another set of 25 sites from 23 genes distinguished hES cells from normal differentiated cells and can be used as biomarkers to monitor differentiation. Our results indicate that hES cells have a unique epigenetic signature that may contribute to their developmental potential.     

Discovery of Tetrahydropyrazolopyrimidine Carboxamide Derivatives As Potent and Orally Active Antitubercular Agents

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Transvascular Pacing of Aorticorenal Ganglia Provides a Testable Procedural Endpoint for Renal Artery Denervation

ObjectivesThis study sought to develop a method to assess renal sympathetic nerve function through localization and pacing of aorticorenal ganglia (ARG).BackgroundTranscatheter renal denervation procedures often fail to produce complete renal denervation because of the lack of a physiological procedural endpoint.MethodsHigh-frequency pacing was performed in the inferior vena cava and aorta in sheep (n = 19) to identify ARG pace-capture sites. Group A (n = 5) underwent injection at the ARG pace-capture site for histological verification, group B (n = 6) underwent unilateral irrigated radiofrequency ablation of ARG pace-capture sites and assessment of renal innervation at 1 week post-procedure; and group C (n = 8) underwent ARG pacing before and 2 to 3 weeks after unilateral microwave renal denervation.ResultsARG pace-capture responses were observed at paired discrete sites above the ipsilateral renal artery eliciting a change in mean arterial blood pressure of 22.2 (interquartile range [IQR]: 15.5 to 34.3 mm Hg; p < 0.001) with concurrent ipsilateral renal arterial vasoconstriction, change in main renal artery diameter of ?0.42 mm (IQR: ?0.64 to ?0.24 mm; p < 0.0001), and without consistent contralateral renal vasoconstriction. Sympathetic ganglionic tissue was observed at ARG pace-capture sites, and ganglion ablation led to significant ipsilateral renal denervation. Circumferential renal denervation resulted in immediate and sustained abolition of ARP pacing-induced renal vasoconstriction and significant ipsilateral renal denervation.ConclusionsTransvascular ARG pace-capture is feasible and recognized by concurrent hypertensive and ipsilateral renal arterial vasoconstrictive responses. Abolition of ARG pacing-induced vasoconstriction may indicate successful renal sympathetic denervation and serve as a physiological procedural endpoint to guide transcatheter renal denervation.