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Herpes simplex virus (HSV-1) progeny form in the nucleus and must exit to successfully infect other cells. These newly formed viral capsids navigate the complex chromatin architecture of the nucleus to reach the inner nuclear membrane and egress. Here, we demonstrate by transmission electron microscopy (TEM) that HSV-1 capsids traverse dense heterochromatin in the nuclear periphery to reach the inner nuclear membrane. We found that this heterochromatin is dependent on the specific chromatin marks of trimethylation on histone H3 lysine 27 (H3K27me3) and the histone variant macroH2A1. Through chromatin profiling over the course of infection, we revealed massive host genomic regions bound by macroH2A1 and H3K27me3 that correlate with decreased host transcription in active compartments. This indicates the formation of new heterochromatin during infection. We found that loss of these markers resulted in significantly lower viral titers but did not impact viral genome or protein accumulation. Strikingly, we discovered by TEM that loss of macroH2A1 or H3K27me3 resulted in nuclear trapping of viral capsids. Thus, our work demonstrates that HSV-1 takes advantage of the dynamic nature of host heterochromatin formation during infection for efficient viral egress.

IntroductionEstimating COVID-19 cumulative incidence in Africa remains problematic due to challenges in contact tracing, routine surveillance systems and laboratory testing capacities and strategies. We undertook a meta-analysis of population-based seroprevalence studies to estimate SARS-CoV-2 seroprevalence in Africa to inform evidence-based decision making on public health and social measures (PHSM) and vaccine strategy.MethodsWe searched for seroprevalence studies conducted in Africa published 1 January 2020–30 December 2021 in Medline, Embase, Web of Science and Europe PMC (preprints), grey literature, media releases and early results from WHO Unity studies. All studies were screened, extracted, assessed for risk of bias and evaluated for alignment with the WHO Unity seroprevalence protocol. We conducted descriptive analyses of seroprevalence and meta-analysed seroprevalence differences by demographic groups, place and time. We estimated the extent of undetected infections by comparing seroprevalence and cumulative incidence of confirmed cases reported to WHO.PROSPERO: CRD42020183634.ResultsWe identified 56 full texts or early results, reporting 153 distinct seroprevalence studies in Africa. Of these, 97 (63%) were low/moderate risk of bias studies. SARS-CoV-2 seroprevalence rose from 3.0% (95% CI 1.0% to 9.2%) in April–June 2020 to 65.1% (95% CI 56.3% to 73.0%) in July–September 2021. The ratios of seroprevalence from infection to cumulative incidence of confirmed cases was large (overall: 100:1, ranging from 18:1 to 954:1) and steady over time. Seroprevalence was highly heterogeneous both within countries—urban versus rural (lower seroprevalence for rural geographic areas), children versus adults (children aged 0–9 years had the lowest seroprevalence)—and between countries and African subregions.ConclusionWe report high seroprevalence in Africa suggesting greater population exposure to SARS-CoV-2 and potential protection against COVID-19 severe disease than indicated by surveillance data. As seroprevalence was heterogeneous, targeted PHSM and vaccination strategies need to be tailored to local epidemiological situations.

Household transmission investigations (HHTI) contribute timely epidemiologic knowledge in response to emerging pathogens. HHTIs conducted in the context of the COVID-19 pandemic in 2020-21 reported variable methodological approaches, producing epidemiological estimates that vary in meaning, precision, and accuracy. Since specific tools to assist with the optimal design and critical appraisal of HHTIs are not available, the aggregation and pooling of HHTI to inform policy and interventions may be challenging. In this manuscript, we discuss key aspects of the HHTI design, we provide recommendations for the reporting of these studies, and propose an appraisal tool that contributes to the optimal design and critical appraisal of HHTI studies. The appraisal tool consists of 12 questions that explore 10 aspects of HHTIs and can be answered ‘yes’, ‘no’ or ‘unclear’. The manuscript seeks to fill a gap in the epidemiologic literature and contribute to standardise HHTI approaches across settings, to achieve richer and more informative datasets. The manuscript also calls for a periodic revision of HHTI protocols and critical appraisal tools

Virus infection necessarily requires redirecting cellular resources towards viral progeny production. Adenovirus encodes the histone-like protein VII that causes catastrophic global reorganization of host chromatin to promote virus infection. Protein VII recruits the family of high mobility group box (HMGB) proteins to chromatin along with the histone chaperone SET. As a consequence of this recruitment, we find that protein VII causes chromatin-depletion of several linker histone H1 isoforms. The relationship between linker histone H1 and the functionally opposite HMGB proteins is critical for higher order chromatin structure. However, the physiological consequences of perturbing this relationship are largely unknown. Here, we employ complementary systems in Saccharomyces cerevisiae and human cells to demonstrate that adenovirus protein VII disrupts the H1-HMGB balance to obstruct the cell cycle. We find that protein VII causes an accumulation of G2/M cells both in yeast and human systems, underscoring the high conservation of this chromatin vulnerability. In contrast, adenovirus E1A and E1B proteins are well-established to override cell cycle regulation and promote transformation of human cells. Strikingly, we find that protein VII obstructs the cell cycle even in the presence of E1A and E1B, suggesting that protein VII-directed cell cycle disruption ensures host resources are directed towards viral proliferation during infection. Together, our results demonstrate that protein VII targets H1-HMGB1 antagonism to obstruct cell cycle progression, revealing an unexpected chromatin vulnerability exploited for viral benefit.

Virus infection necessarily requires redirecting cellular resources toward viral progeny production. Adenovirus encodes the histone-like protein VII, which causes catastrophic global reorganization of host chromatin to promote virus infection. Protein VII recruits the family of high mobility group box (HMGB) proteins to chromatin along with the histone chaperone SET. As a consequence of this recruitment, we find that protein VII causes chromatin depletion of several linker histone H1 isoforms. The relationship between linker histone H1 and the functionally opposite HMGB proteins is critical for higher-order chromatin structure. However, the physiological consequences of perturbing this relationship are largely unknown. Here, we employ complementary systems in Saccharomyces cerevisiae and human cells to demonstrate that adenovirus protein VII disrupts the H1-HMGB balance to obstruct the cell cycle. We find that protein VII causes an accumulation of G2/M cells both in yeast and human systems, underscoring the high conservation of this chromatin vulnerability. In contrast, adenovirus E1A and E1B proteins are well established to override cell cycle regulation and promote transformation of human cells. Strikingly, we find that protein VII obstructs the cell cycle, even in the presence of E1A and E1B. We further show that, in a protein-VII-deleted infection, several cell cycle markers are regulated differently compared to wild-type infection, supporting our model that protein VII plays an integral role in hijacking cell cycle regulation during infection. Together, our results demonstrate that protein VII targets H1-HMGB1 antagonism to obstruct cell cycle progression, revealing an unexpected chromatin vulnerability exploited for viral benefit.

Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological function by unknown mechanisms. We report here the results of a large metabolomics study showing that people with DS produce elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. We found that immune cells of people with DS overexpress IDO1, the rate-limiting enzyme in the kynurenine pathway (KP) and a known interferon (IFN)-stimulated gene. Furthermore, we found a positive correlation between levels of specific inflammatory cytokines and KP dysregulation. Using metabolic flux assays, we found that IFN stimulation causes IDO1 overexpression and kynurenine overproduction in cells with T21, dependent on overexpression of IFN receptors encoded on chromosome 21. Finally, KP dysregulation is conserved in a mouse model of DS carrying triplication of the IFN receptors. Altogether, these results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS.

Our genetic information is contained within structures called chromosomes. Down syndrome is caused by the genetic condition known as trisomy 21, in which a person is born with an extra copy of chromosome 21. This extra chromosome affects human development in many ways, including causing neurological problems and stunted growth. Trisomy 21 makes individuals more susceptible to certain diseases, such as Alzheimer’s disease and autoimmune disorders – where the immune system attacks healthy cells in the body – while protecting them from tumors and some other conditions. Since cells with trisomy 21 have an extra copy of every single gene on chromosome 21, it is expected that these genes should be more highly expressed – that is, the products of these genes should be present at higher levels inside cells. However, it was not clear which genes on other chromosomes are also affected by trisomy 21. Sullivan et al. aimed to identify which genes are affected by trisomy 21 by studying samples collected from a variety of individuals with, and without, this condition. Four genes in chromosome 21 encode proteins that recognize signal molecules called interferons, which are produced by cells in response to viral or bacterial infection. Interferons act on neighboring cells to regulate genes that prevent the spread of the infection, shut down the production of proteins and activate the immune system. Sullivan et al. show that cells with trisomy 21 produce high levels of genes that are activated by interferons and lower levels of genes required for protein production. In other words, the cells of people with Down syndrome are constantly fighting a viral infection that does not exist. Constant activation of interferon signaling could explain many aspects of Down syndrome, including neurological problems and protection against tumors. The next steps are to fully define the role of interferon signaling in the development of Down syndrome, and to find out whether drugs that block the action of interferons could have therapeutic benefits.

Persons living or working on farms, particularly pig farms, are at increased risk for infection., An emerging subtype of methicillin-resistant Staphylococcus aureus (MRSA), clonal complex (CC) 398, is associated with animals, particularly pigs. We conducted a matched case–control and a case–case study comparing 21 CC398 case-patients with 2 controls randomly selected from the Danish Civil Registry and 2 case-patients infected with MRSA other than CC398. On farms of case-patients, animals were examined for MRSA. Thirteen case-patients reported pig exposure. Living or working on farms with animals was an independent risk factor for CC398 in the case–control (matched odds ratio [MOR] 35.4, 95% confidence interval [CI] 2.7–469.8) and the case–case study (MOR 14.5, 95%CI 2.7–76.7). History of hospitalization was associated with an increased risk only in the case–control study (MOR 11.4, 95% CI 1.4–94.8). A total of 23 of 50 pigs on 4 of 5 farms were positive for CC398. Our results, corroborated by microbiologic testing, demonstrate that pigs are a source of CC398 in Denmark.

Although dengue has been a public health problem for several decades in the Lao People's Democratic Republic, the magnitude of the disease burden and epidemiological trends remain poorly understood. We analysed national dengue surveillance and laboratory data from 2006 to 2012 by person, place and time. Between 2006 and 2012, the annual dengue notification rate ranged between 62 and 367 cases per 100 000 population with an apparent geographical expansion of transmission throughout the country in recent years and concurrent co-circulation of all four dengue virus subtypes. An electronic database, called Lao People's Democratic Republic Early Warning Alert and Response Network, was introduced in 2008 to provide automated early warning for outbreaks and epidemics. Village outbreaks continue to be notified primarily through event-based surveillance, whereas the weekly indicator-based system provides systematic assessment of annual epidemic cycles. The dengue case data indicate a high and increasing burden of disease. Efforts now need to focus on using available data to prompt more effective outbreak response and to guide the design and implementation of intervention strategies.