Human dengue viruses emerged from primate reservoirs, yet paradoxically dengue does not reach high titers in primate models. This presents a unique opportunity to examine the genetics of spillover ...versus reservoir hosts. The dengue virus 2 (DENV2) - encoded protease cleaves human STING, reducing type I interferon production and boosting viral titers in humans. We find that both human and sylvatic (reservoir) dengue viruses universally cleave human STING, but not the STING of primates implicated as reservoir species. The special ability of dengue to cleave STING is thus specific to humans and a few closely related ape species. Conversion of residues 78/79 to the human-encoded 'RG' renders all primate (and mouse) STINGs sensitive to viral cleavage. Dengue viruses may have evolved to increase viral titers in the dense and vast human population, while maintaining decreased titers and pathogenicity in the more rare animals that serve as their sustaining reservoir in nature.
Abstract Purpose Racial/ethnic differences in children's self-reports of being a frequent victim of bullying were assessed via two commonly used strategies: a definition-based single-item measure and ...behavior-based multiresponse measure. Methods Logistic regression analyses were conducted on survey data from 24,345 youth to examine ethnic differences in youths' responses to definition-based and behavior-based measures of victimization. Separate analyses were conducted for boys and girls at different school levels. Results Prevalence estimates were higher using the behavior-based measure than definition-based measure. Several ethnic differences emerged, such that African American youth tended to be less likely than their white counterparts to indicate that they were bullied using the definition-based measure. African American girls and African American and Asian middle-school boys who reported being a victim via the behavior-based measure were less likely to report being a frequent victim of “bullying” via the definition-based measure. Conclusion Prevalence estimates vary considerably by the way in which victimization is assessed. African American youth who were victimized tended to under-report being a victim of “bullying.” Self-report studies of bullying should carefully consider the measures used to assess victimization.
Summary
The majority of people with psoriasis have localized disease, where topical therapy forms the cornerstone of treatment. We set out to summarize evidence on the relative efficacy, safety and ...tolerability of different topical treatments used in plaque psoriasis. We undertook a systematic review and meta‐analyses of randomized trial data of U.K.‐licensed topical therapies. The primary outcome was clear or nearly clear status stratified for (i) trunk and limbs; and (ii) scalp. Network meta‐analyses allowed ranking of treatment efficacy. In total, 48 studies were available for trunk and limb psoriasis, and 17 for scalp psoriasis (22 028 patients in total); the majority included people with at least moderate severity psoriasis. Strategies containing potent corticosteroids (alone or in combination with a vitamin D analogue) or very potent corticosteroids dominated the treatment hierarchy at both sites (trunk and limbs, scalp); coal tar and retinoids were no better than placebo. No significant differences in achievement of clear or nearly clear status were observed between twice‐ and once‐daily application of the same intervention or between any of the following: combined vitamin D analogue and potent corticosteroid (applied separately or in a single product), very potent corticosteroids, or potent corticosteroids (applied twice daily). Investigator and patient assessment of response differed significantly for some interventions (response rates to very potent corticosteroids: 78% and 39%, respectively). No significant differences were noted for tolerability or steroid atrophy, but data were limited. In conclusion, corticosteroids are highly effective in psoriasis when used continuously for up to 8 weeks and intermittently for up to 52 weeks. Coal tar and retinoids are of limited benefit. There is a lack of long‐term efficacy and safety data available on topical interventions used for psoriasis.
What's already known about this topic?
Topical treatments are widely available and prescribed for plaque‐type psoriasis.
What does this study add?
Explicit rank order of efficacy, showing that treatment strategies containing potent or very potent corticosteroids are the most effective.
Investigator and patient evaluation of efficacy may differ.
Twice‐daily application of the same intervention offers no important benefit over once‐daily application for most treatments.
We analyze data from the fall 2020 pandemic response efforts at the University of Colorado Boulder, where more than 72,500 saliva samples were tested for severe acute respiratory syndrome coronavirus ...2 (SARS-CoV-2) using qRT-PCR. All samples were collected from individuals who reported no symptoms associated with COVID-19 on the day of collection. From these, 1,405 positive cases were identified. The distribution of viral loads within these asymptomatic individuals was indistinguishable from what has been previously observed in symptomatic individuals. Regardless of symptomatic status, ∼50% of individuals who test positive for SARS-CoV-2 seem to be in noninfectious phases of the disease, based on having low viral loads in a range from which live virus has rarely been isolated. We find that, at any given time, just 2% of individuals carry 90% of the virions circulating within communities, serving as viral "supercarriers" and possibly also superspreaders.
The COVID-19 pandemic demonstrated the poor ability of body temperature to reliably identify SARS-CoV-2-infected individuals, an observation that has been made before in the context of other ...infectious diseases. While acute infection does not always cause fever, it does reliably drive host transcriptional responses as the body responds at the site of infection. These transcriptional changes can occur both in cells that are directly harboring replicating pathogens and in cells elsewhere that receive a molecular signal that infection is occurring. Here, we identify a core set of approximately 70 human genes that are together upregulated in cultured human cells infected by a broad array of viral, bacterial, and fungal pathogens. We have named these "core response" genes. In theory, transcripts from these genes could serve as biomarkers of infection in the human body, in a way that is agnostic to the specific pathogen causing infection. As such, we perform human studies to show that these infection-induced human transcripts can be measured in the saliva of people harboring different types of infections. The number of these transcripts in saliva can correctly classify infection status (whether a person harbors an infection) 91% of the time. Furthermore, in the case of SARS-CoV-2 specifically, the number of core response transcripts in saliva correctly identifies infectious individuals even when enrollees, themselves, are asymptomatic and do not know they are infected.IMPORTANCEThere are a variety of clinical and laboratory criteria available to clinicians in controlled healthcare settings to help them identify whether an infectious disease is present. However, in situations such as a new epidemic caused by an unknown infectious agent, in health screening contexts performed within communities and outside of healthcare facilities or in battlefield or potential biowarfare situations, this gets more difficult. Pathogen-agnostic methods for rapid screening and triage of large numbers of people for infection status are needed, in particular methods that might work on an easily accessible biospecimen like saliva. Here, we identify a small, core set of approximately 70 human genes whose transcripts serve as saliva-based biomarkers of infection in the human body, in a way that is agnostic to the specific pathogen causing infection.
HIV-1 arose as the result of spillover of simian immunodeficiency viruses (SIVs) from great apes in Africa, namely from chimpanzees and gorillas. Chimpanzees and gorillas were, themselves, infected ...with SIV after virus spillover from African monkeys. During spillover events, SIV is thought to require adaptation to the new host species. The host barriers that drive viral adaptation have predominantly been attributed to restriction factors, rather than cofactors (host proteins exploited to promote viral replication). Here, we consider the role of one cofactor, RanBP2, in providing a barrier that drove viral genome evolution during SIV spillover events. RanBP2 (also known as Nup358) is a component of the nuclear pore complex known to facilitate nuclear entry of HIV-1. Our data suggest that transmission of SIV from monkeys to chimpanzees, and then from chimpanzees to gorillas, both coincided with changes in the viral capsid that allowed interaction with RanBP2 of the new host species. However, human RanBP2 subsequently provided no barrier to the zoonotic transmission of SIV from chimpanzees or gorillas, indicating that chimpanzee- and gorilla-adapted SIVs are pre-adapted to humans in this regard. Our observations are in agreement with RanBP2 driving virus evolution during cross-species transmissions of SIV, particularly in the transmissions to and between great ape species.
Parvoviruses exploit transferrin receptor type-1 (TfR) for cellular entry in carnivores, and specific interactions are key to control of host range. We show that several key mutations acquired by TfR ...during the evolution of Caniforms (dogs and related species) modified the interactions with parvovirus capsids by reducing the level of binding. These data, along with signatures of positive selection in the TFRC gene, are consistent with an evolutionary arms race between the TfR of the Caniform clade and parvoviruses. As well as the modifications of amino acid sequence which modify binding, we found that a glycosylation site mutation in the TfR of dogs which provided resistance to the carnivore parvoviruses which were in circulation prior to about 1975 predates the speciation of coyotes and dogs. Because the closely-related black-backed jackal has a TfR similar to their common ancestor and lacks the glycosylation site, reconstructing this mutation into the jackal TfR shows the potency of that site in blocking binding and infection and explains the resistance of dogs until recent times. This alters our understanding of this well-known example of viral emergence by indicating that canine parvovirus emergence likely resulted from the re-adaptation of a parvovirus to the resistant receptor of a former host.
Biological factors that influence the host range and spillover of Ebola virus (EBOV) and other filoviruses remain enigmatic. While filoviruses infect diverse mammalian cell lines, we report that ...cells from African straw-colored fruit bats (Eidolon helvum) are refractory to EBOV infection. This could be explained by a single amino acid change in the filovirus receptor, NPC1, which greatly reduces the affinity of EBOV-NPC1 interaction. We found signatures of positive selection in bat NPC1 concentrated at the virus-receptor interface, with the strongest signal at the same residue that controls EBOV infection in Eidolon helvum cells. Our work identifies NPC1 as a genetic determinant of filovirus susceptibility in bats, and suggests that some NPC1 variations reflect host adaptations to reduce filovirus replication and virulence. A single viral mutation afforded escape from receptor control, revealing a pathway for compensatory viral evolution and a potential avenue for expansion of filovirus host range in nature.
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