Chikungunya virus (CHIKV) is a mosquito-borne alphavirus known to cause epidemics resulting in predominantly symptomatic infections, which in rare cases cause long term debilitating arthritis and ...arthralgia. Significant progress has been made in understanding the roles of canonical RNA sensing pathways in the host recognition of CHIKV; however, less is known regarding antagonism of CHIKV by cytosolic DNA sensing pathways like that of cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING). With the use of cGAS or STING null cells we demonstrate that the pathway restricts CHIKV replication in fibroblasts and immune cells. We show that DNA accumulates in the cytoplasm of infected cells and that CHIKV blocks DNA dependent IFN-β transcription. This antagonism of DNA sensing is via an early autophagy-mediated degradation of cGAS and expression of the CHIKV capsid protein is sufficient to induce cGAS degradation. Furthermore, we identify an interaction of CHIKV nsP1 with STING and map the interaction to 23 residues in the cytosolic loop of the adaptor protein. This interaction stabilizes the viral protein and increases the level of palmitoylated nsP1 in cells. Together, this work supports previous publications highlighting the relevance of the cGAS-STING pathway in the early detection of (+)ssRNA viruses and provides direct evidence that CHIKV interacts with and antagonizes cGAS-STING signaling.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The evolutionary origins of Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) are unknown. Current evidence suggests that insectivorous bats are likely to be the original source, as ...several 2c CoVs have been described from various species in the family
Here, we describe a MERS-like CoV identified from a
bat sampled in Uganda (strain PREDICT/PDF-2180), further supporting the hypothesis that bats are the evolutionary source of MERS-CoV. Phylogenetic analysis showed that PREDICT/PDF-2180 is closely related to MERS-CoV across much of its genome, consistent with a common ancestry; however, the spike protein was highly divergent (46% amino acid identity), suggesting that the two viruses may have different receptor binding properties. Indeed, several amino acid substitutions were identified in key binding residues that were predicted to block PREDICT/PDF-2180 from attaching to the MERS-CoV DPP4 receptor. To experimentally test this hypothesis, an infectious MERS-CoV clone expressing the PREDICT/PDF-2180 spike protein was generated. Recombinant viruses derived from the clone were replication competent but unable to spread and establish new infections in Vero cells or primary human airway epithelial cells. Our findings suggest that PREDICT/PDF-2180 is unlikely to pose a zoonotic threat. Recombination in the S1 subunit of the spike gene was identified as the primary mechanism driving variation in the spike phenotype and was likely one of the critical steps in the evolution and emergence of MERS-CoV in humans.
Global surveillance efforts for undiscovered viruses are an important component of pandemic prevention initiatives. These surveys can be useful for finding novel viruses and for gaining insights into the ecological and evolutionary factors driving viral diversity; however, finding a viral sequence is not sufficient to determine whether it can infect people (i.e., poses a zoonotic threat). Here, we investigated the specific zoonotic risk of a MERS-like coronavirus (PREDICT/PDF-2180) identified in a bat from Uganda and showed that, despite being closely related to MERS-CoV, it is unlikely to pose a threat to humans. We suggest that this approach constitutes an appropriate strategy for beginning to determine the zoonotic potential of wildlife viruses. By showing that PREDICT/PDF-2180 does not infect cells that express the functional receptor for MERS-CoV, we further show that recombination was likely to be the critical step that allowed MERS to emerge in humans.
Objective
Fatigue is a common symptom in systemic lupus erythematosus (SLE), and engaging in physical activity may reduce fatigue. We aimed to characterize relationships between fatigue, other health ...status measures assessed with the Patient Reported Outcomes Measurement Information System (PROMIS) instruments, and accelerometer-based physical activity measurements in patients with SLE. The internal consistency of each PROMIS measure in our SLE sample was also evaluated.
Methods
This cross-sectional study analyzed 123 adults with SLE. The primary fatigue outcome was Fatigue Severity Scale score. Secondary outcomes were PROMIS standardized T-scores in seven health status domains. Accelerometers were worn for seven days, and mean daily minutes of light, moderate/vigorous, and bouted (10 minutes) moderate/vigorous physical activity were estimated. Cronbach’s alpha was determined for each PROMIS measure to assess internal consistency. Relationships between Fatigue Severity Scale, PROMIS, and physical activity were summarized with Spearman partial correlation coefficients (r), adjusted for average daily accelerometer wear time.
Results
Mean Fatigue Severity Scale score (4.3, SD 1.6) was consistent with clinically relevant levels of fatigue. Greater daily and bouted moderate/vigorous physical activity minutes correlated with lower Mean Fatigue Severity Scale score (r = −0.20, p = 0.03 and r = −0.30, p = 0.0007, respectively). For PROMIS, bouted moderate/vigorous physical activity minutes correlated with less fatigue (r = −0.20, p = 0.03). PROMIS internal consistency was excellent, with Cronbach’s alpha > 0.90 for each domain. Mean PROMIS T-scores for fatigue, pain interference, anxiety, sleep disturbance, sleep-related impairment, and physical function were worse than reported for the general US population. More moderate/vigorous physical activity minutes were associated with less pain interference (r = −0.22, p = 0.01). Both light physical activity and moderate/vigorous physical activity minutes correlated with better physical function (r = 0.19, p = 0.04 and r = 0.25, p = 0.006, respectively).
Conclusion
More time spent in moderate/vigorous physical activity was associated with less fatigue (Fatigue Severity Scale and PROMIS), less pain interference, and better physical function (PROMIS). PROMIS had excellent internal consistency in our SLE sample, and six of seven PROMIS measures indicated poorer average health status in SLE patients compared with the general US population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
In this essay, we discuss the under-representation of women in leadership positions in global health (GH) and the importance of mentorship to advance women's standing in the field. We then describe ...the mentorship model of GROW, Global Research for Women. We describe the theoretical origins of the model and an adapted theory of change explaining how the GROW model for mentorship advances women's careers in GH. We present testimonials from a range of mentees who participated in a pilot of the GROW model since 2015. These mentees describe the capability-enhancing benefits of their mentorship experience with GROW. Thus, preliminary findings suggest that the GROW mentorship model is a promising strategy to build women's leadership in GH. We discuss supplemental strategies under consideration and next steps to assess the impact of GROW, providing the evidence to inform best practices for curricula elsewhere to build women's leadership in GH.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We evaluate the effects of marital resources and early-life experiences on recent domestic violence and attitudes about wife abuse among 2,074 married Cambodian women. Household standard of living ...was negatively associated with physical domestic violence. Women with 8-13 fewer years of schooling than their husbands more often experienced physical and psychological domestic violence. Women with more living children more often experienced physical domestic violence and justified wife beating. Having surviving parents and siblings was not associated with domestic violence nor with attitudes about wife beating. Women reporting higher paternal schooling, urban childhood residence and domestic violence against their mothers had higher odds of experiencing physical and psychological domestic violence. Findings underscore the effects of marital resources and early-life experiences on domestic violence in Cambodia.
beta-Defensins are microbicidal peptides implicated in host defense functions of phagocytic leukocytes and certain surface epithelial cells. Here we investigated the genetic structures and cellular ...expression of BNBD-4, -12, and -13, three prototypic bovine neutrophil beta-defensins. Characterization of the corresponding cDNAs indicated that BNBD-4 (41 residues) derives from a 63-amino acid prepropeptide and that BNBD-12 (38 residues) and BNBD-13 (42 residues) derive from a common 60-amino acid precursor (BNBD-12/13). The peptides were found to be encoded by two-exon genes that are closely related to bovine epithelial beta-defensin genes. BNBD-4 and BNBD-12/13 mRNAs were most abundant in bone marrow, but were expressed differentially in certain non-myeloid tissues. In situ hybridization and immunohistochemical studies demonstrated that BNBD-4 synthesis is completed early in myelopoiesis. BNBD-12 was localized exclusively to the novel dense granules, organelles that also contain precursors of cathelicidins, antimicrobial peptides that undergo proteolytic processing during phagocytosis. In contrast to cathelicidins, Western blot analyses revealed that mature beta-defensins are the predominant organellar form in myeloid cells. Stimulation of neutrophils with phorbol myristate acetate induced secretion of BNBD-12, indicating that it is co-secreted with pro-cathelicidins. The exocytosis of BNBD-12 by activated neutrophils reveals different mobilization pathways for myeloid alpha- and beta-defensins.
The mode of acquisition and causes for the variable clinical spectrum of coronavirus disease 2019 (COVID-19) remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to ...explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and a luciferase reporter virus to demonstrate sera collected from SARS and COVID-19 patients exhibited limited cross-CoV neutralization. High-sensitivity RNA in situ mapping revealed the highest angiotensin-converting enzyme 2 (ACE2) expression in the nose with decreasing expression throughout the lower respiratory tract, paralleled by a striking gradient of SARS-CoV-2 infection in proximal (high) versus distal (low) pulmonary epithelial cultures. COVID-19 autopsied lung studies identified focal disease and, congruent with culture data, SARS-CoV-2-infected ciliated and type 2 pneumocyte cells in airway and alveolar regions, respectively. These findings highlight the nasal susceptibility to SARS-CoV-2 with likely subsequent aspiration-mediated virus seeding to the lung in SARS-CoV-2 pathogenesis. These reagents provide a foundation for investigations into virus-host interactions in protective immunity, host susceptibility, and virus pathogenesis.
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•A SARS-CoV-2 infectious cDNA clone and reporter viruses are generated•SARS-CoV-2 and SARS-CoV neutralization assays show limited cross neutralization•SARS-CoV-2 shows a gradient infectivity from the proximal to distal respiratory tract•Ciliated airway cells and AT-2 cells are primary targets for SARS-CoV-2 infection
Hou et al. present a reverse genetics system for SARS-CoV-2, which is then used to make reporter viruses to quantify the ability of patient sera and antibodies to neutralize infectious virus and to examine viral tropism along the human respiratory tract.
SARS-like WIV1-CoV poised for human emergence Menachery, Vineet D.; Yount, Boyd L.; Sims, Amy C. ...
Proceedings of the National Academy of Sciences - PNAS,
03/2016, Letnik:
113, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Outbreaks from zoonotic sources represent a threat to both human disease as well as the global economy. Despite a wealth of metagenomics studies,methods to leverage these datasets to identify future ...threats are underdeveloped. In this study, we describe an approach that combines existing metagenomics data with reverse genetics to engineer reagents to evaluate emergence and pathogenic potential of circulating zoonotic viruses. Focusing on the severe acute respiratory syndrome (SARS)-like viruses, the results indicate that the WIV1-coronavirus (CoV) cluster has the ability to directly infect and may undergo limited transmission in human populations. However, in vivo attenuation suggests additional adaptation is required for epidemic disease. Importantly, available SARS monoclonal antibodies offered success in limiting viral infection absent from available vaccine approaches. Together, the data highlight the utility of a platform to identify and prioritize prepandemic strains harbored in animal reservoirs and document the threat posed by WIV1-CoV for emergence in human populations.
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