Assessing COVID-19 pandemic policies and behaviours and their economic and educational trade-offs across US states from Jan 1, 2020, to July 31, 2022: an observational analysis.

BACKGROUND: The USA struggled in responding to the COVID-19 pandemic, but not all states struggled equally. Identifying the factors associated with cross-state variation in infection and mortality rates could help to improve responses to this and future pandemics. We sought to answer five key policy-relevant questions regarding the following: 1) what roles social, economic, and racial inequities had in interstate variation in COVID-19 outcomes; 2) whether states with greater health-care and public health capacity had better outcomes; 3) how politics influenced the results; 4) whether states that imposed more policy mandates and sustained them longer had better outcomes; and 5) whether there were trade-offs between a state having fewer cumulative SARS-CoV-2 infections and total COVID-19 deaths and its economic and educational outcomes. METHODS: Data disaggregated by US state were extracted from public databases, including COVID-19 infection and mortality estimates from the Institute for Health Metrics and Evaluation's (IHME) COVID-19 database; Bureau of Economic Analysis data on state gross domestic product (GDP); Federal Reserve economic data on employment rates; National Center for Education Statistics data on student standardised test scores; and US Census Bureau data on race and ethnicity by state. We standardised infection rates for population density and death rates for age and the prevalence of major comorbidities to facilitate comparison of states' successes in mitigating the effects of COVID-19. We regressed these health outcomes on prepandemic state characteristics (such as educational attainment and health spending per capita), policies adopted by states during the pandemic (such as mask mandates and business closures), and population-level behavioural responses (such as vaccine coverage and mobility). We explored potential mechanisms connecting state-level factors to individual-level behaviours using linear regression. We quantified reductions in state GDP, employment, and student test scores during the pandemic to identify policy and behavioural responses associated with these outcomes and to assess trade-offs between these outcomes and COVID-19 outcomes. Significance was defined as p<0·05. FINDINGS: Standardised cumulative COVID-19 death rates for the period from Jan 1, 2020, to July 31, 2022 varied across the USA (national rate 372 deaths per 100 000 population [95% uncertainty interval [UI] 364-379]), with the lowest standardised rates in Hawaii (147 deaths per 100 000 [127-196]) and New Hampshire (215 per 100 000 [183-271]) and the highest in Arizona (581 per 100 000 [509-672]) and Washington, DC (526 per 100 000 [425-631]). A lower poverty rate, higher mean number of years of education, and a greater proportion of people expressing interpersonal trust were statistically associated with lower infection and death rates, and states where larger percentages of the population identify as Black (non-Hispanic) or Hispanic were associated with higher cumulative death rates. Access to quality health care (measured by the IHME's Healthcare Access and Quality Index) was associated with fewer total COVID-19 deaths and SARS-CoV-2 infections, but higher public health spending and more public health personnel per capita were not, at the state level. The political affiliation of the state governor was not associated with lower SARS-CoV-2 infection or COVID-19 death rates, but worse COVID-19 outcomes were associated with the proportion of a state's voters who voted for the 2020 Republican presidential candidate. State governments' uses of protective mandates were associated with lower infection rates, as were mask use, lower mobility, and higher vaccination rate, while vaccination rates were associated with lower death rates. State GDP and student reading test scores were not associated with state COVD-19 policy responses, infection rates, or death rates. Employment, however, had a statistically significant relationship with restaurant closures and greater infections and deaths: on average, 1574 (95% UI 884-7107) additional infections per 10 000 population were associated in states with a one percentage point increase in employment rate. Several policy mandates and protective behaviours were associated with lower fourth-grade mathematics test scores, but our study results did not find a link to state-level estimates of school closures. INTERPRETATION: COVID-19 magnified the polarisation and persistent social, economic, and racial inequities that already existed across US society, but the next pandemic threat need not do the same. US states that mitigated those structural inequalities, deployed science-based interventions such as vaccination and targeted vaccine mandates, and promoted their adoption across society were able to match the best-performing nations in minimising COVID-19 death rates. These findings could contribute to the design and targeting of clinical and policy interventions to facilitate better health outcomes in future crises. FUNDING: Bill & Melinda Gates Foundation, J Stanton, T Gillespie, J and E Nordstrom, and Bloomberg Philanthropies.

A tale of three pandemics: Shining a light on a hidden problem.

An "epidemic" is an event in which a disease, infectious or non-infectious, is actively spreading within a population and designated area. The term "pandemic" is defined as "an epidemic occurring worldwide, or over a very wide area, crossing international boundaries and usually affecting a large number of people". The global response to the COVID-19 pandemic has not been seen since the outbreak of Human Immunodeficiency Virus in the early eighties. But there is another unseen pandemic running alongside the current COVID-19 pandemic, which affects a vast number of people, crossing international boundaries and occurring in every single country worldwide. The pandemic of traumatic injuries. Traumatic injuries account for 11% of the current Global Burden of Disease, resulting in nearly 5 million deaths annually and is the third-leading cause of death worldwide. For every trauma-related death, it is estimated that up to 50 people sustain permanent or temporary disabilities. Furthermore, traumatic injuries occur at disproportionately higher rates in low- and middle-income countries, with approximately 90% of injuries and more than 90% of global deaths from injury occurring these countries. Injuries are increasing worldwide, crossing international boundaries and affecting a large number of people, in the same manner Human Immunodeficiency Virus did in the 1980's and COVID-19 is today. The tremendous global effort to tackle the COVID-19 and Human Immunodeficiency Virus pandemics has occurred whilst ignoring the comparable pandemic of injury. Without change and future engagement with policy makers and international donors this disparity is likely to continue.

Pandemic-Related Challenges and Organizational Support Among Personnel in Canada's Defense Establishment.

In the final week of March 2020, 2.8 million Canadians were away from their usual places of work and engaging in remote and/or telework to mitigate the spread of COVID-19 (Statistics Canada, 2020). The Government of Canada's Department of National Defence (DND) and the Canadian Armed Forces (CAF) were no exception, with most members from the regular force (Reg F), the primary reserve force (P Res), and the DND public service (DND PS) working from home. The COVID-19 Defence Team Survey was administered from April 29th, 2020, and May 22nd, 2020, to gain insight into work, health, and family-related challenges since the onset of the pandemic and change in work arrangements. Responses from five open-ended questions were qualitatively analyzed to determine general themes of concern regarding work, personal, and family related challenges, stress-management and coping strategies, and recommendations for improving the work situation and personal well-being. Given the different roles and conditions of employment, responses of the different groups or "components" of respondents (Reg F, P Res, DND PS) were compared to identify common and unique challenges to inform targeted organizational responses. A total of 26,207 members (Reg F = 13,668, 52.2%; P Res = 5,052, 19.3%; DND PS = 7,487, 28.6%) responded to the survey's five open-ended questions, which yielded a total of 75,000 open-ended responses. When asked about work-related challenges, respondents' most common challenges included dissatisfaction with technology/software, work arrangements, ergonomics, work-life balance, communication within the organization, and the uncertainties regarding career development. In terms of personal and/or family-related challenges, the most common challenges included social isolation, the impact of the pandemic on mental health, school closures and homeschooling, caring for vulnerable family members, and childcare concerns. The most common stress-management and coping strategies included exercise, spending time outdoors, communicating or spending time with family members, household chores/projects, mind-body wellness exercises, and playing games. The most common recommendations made by respondents to improve their work- or personal-related situations included improving technological capabilities, streamlining communication, providing hardware and software necessary to ensure comfortable ergonomics, the provision of flexibility in terms of telework schedules, return-to-work decisions, and the expansion of benefits and access to childcare services. In terms of differences among the components, DND PS personnel were most likely to report dissatisfaction with technological changes and ergonomics, and to recommend improving these technological limitations to maximize productivity. Reg F members, on the other hand, were most likely to recommend increased support and access to childcare, and both Reg F and P Res members were more likely to mention that increased benefits and entitlements in response to the COVID-19 pandemic would be ameliorative. The results of this study highlight several important facts about the impact of the COVID-19 pandemic on personnel working in large, diverse organizations. For example, advancements in organizational technological capabilities were highlighted herein, and these are likely to grow to maintain productivity should remote work come to be used more extensively in the long-term. This study also highlighted the importance of flexibility and accommodation in relation to individual needs - a trend that was already underway but has taken on greater relevance and urgency in light of the pandemic. This is clearly essential to the organization's role in supporting the well-being of personnel and their families. Clear and streamlined communication regarding organizational changes and support services is also essential to minimize uncertainty and to provide useful supports for coping with this and other stressful situations.

Hip fracture mortality in patients co-infected with coronavirus disease 2019: a comparison of the first two waves of the United Kingdom pandemic during the pre-vaccine era.

AIMS: In the UK, deaths associated with COVID-19 have occurred in two waves. Evidence has shown an increase in 30-day mortality for hip fracture patients co-infected with COVID-19. However, there are no studies analysing mortality trends between the first two waves of the UK pandemic. Additionally, hospital versus community acquired COVID-19 infection between the two waves has not been analysed. Furthermore, predictive factors of 30-day mortality have not been fully evaluated. METHODS: Data from two audits conducted by the CHIP collaborative group were used: a published regional audit in England of nine hospitals providing the COVID-19 negative cases and an unpublished UK national audit of 43 hospitals, which provided the COVID-19 positive cases. Data collection for the COVID-19 positive cases was from 23 March to 31 December 2020. September 1, 2020 was used to define the transition between the two waves. RESULTS: There were 517 COVID-19 positive hip fracture patients and 1445 COVID-19 negative hip fracture patients. Overall, 30-day mortality rates were 5.7% in the COVID-19 negative group and 22.4% in the COVID-19 positive patients (p < 0.001). A difference in survival function between the first and second waves was found (p = 0.038). To allow for significant demographic differences, a matched analysis of 185 patients found a 26.5% 30-day mortality in the first wave compared to 21.1% in the second wave (p = 0.222). Within the COVID-19 positive groups, the virus was hospital acquired in 66.7% of cases in the first wave and 72.8% of cases in the second wave (p = 0.130). Independent predictors of mortality were found to include COVID-19 positive status, AMTS ≤ 6, male gender and age. CONCLUSION: There was a reduction in 30-day mortality for hip fracture patients co-infected with COVID-19 between the two UK pandemic waves but this was not statistically significant. There was no reduction in hospital acquired COVID-19 infection between the two waves.

Histological findings of tracheal samples from COVID-19 positive critically ill mechanically ventilated patients.

OBJECTIVES: This study examines the histological findings of tracheal tissue samples obtained from COVID-19 positive mechanically ventilated patients, to assess the degree of tracheal inflammation/ulceration present. DESIGN AND PARTICIPANTS: Retrospective single-centre observational cohort study. All patients admitted to Adult Intensive Care Unit (AICU) with COVID-19 infection, requiring mechanical ventilation and surgical tracheostomy between 1 April and 1 May 2020, were included (Group 1). Tracheal windows excised at tracheostomy underwent histological analysis. Comparison was made with: tracheal windows from COVID-19 positive AICU ventilated patients admitted between 1 January and 1 March 2021 (Group 2); tracheal windows from COVID-19 negative AICU ventilated patients (Group 3); and, tracheal autopsy samples from COVID-19 positive patients that died without undergoing prolonged mechanical ventilation (Group 4). RESULTS: Group 1 demonstrated mild/moderate inflammation (tracheitis) in nearly all samples (15/16, 93.8%), with infrequent micro-ulceration (2/16, 12.5%). Group 2 demonstrated similar mild/moderate inflammation in all samples (17/17, 100%), with no ulceration. Histological findings of Groups 1 and 2 COVID-19 positive patients were similar to Group 3 COVID-19 negative patients, which demonstrated mild/moderate inflammation (5/5, 100%), with uncommon superficial erosion (1/5, 20%). Group 4 demonstrated mild chronic inflammation or no significant inflammation, with uncommon micro-ulceration (1/4, 25%). CONCLUSIONS: Severe tracheal inflammation was not demonstrated in mechanically ventilated COVID-19 positive patients at the level of the second/third tracheal rings, at the stage of disease patients underwent tracheostomy. Histological findings were similar between mechanically ventilated COVID-19 positive and negative patients. Tracheal ulceration may be a feature of early or severe COVID-19 disease.

Immunodominant NP105-113-B*0702 cytotoxic T cell response controls viral replication and is associated with less severe COVID-19 disease (preprint)

NP 105-113 -B*07:02 specific CD8 + T-cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP 105-113 -B*07:02 specific T-cell clones and single cell sequencing were performed concurrently, with functional avidity and anti-viral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with TCR usage, transcriptome signature, and disease severity (acute N=77, convalescent N=52). We demonstrated a beneficial association of NP 105-113 -B*07:02 specific T-cells in COVID-19 disease progression, linked with expansion of T-cell precursors, high functional avidity and anti-viral effector function. Broad immune memory pools were narrowed post-infection but NP 105-113 -B*07:02 specific T-cells were maintained 6 months after infection with preserved anti-viral efficacy to the SARS-CoV-2 Victoria strain, as well as new Alpha, Beta and Gamma variants. Our data shows that NP 105-113 -B*07:02 specific T-cell responses associate with mild disease and high anti-viral efficacy, pointing to inclusion for future vaccine design.

A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19 (preprint)

SARS-CoV-2 remains a global threat to human health particularly as escape mutants emerge. There is an unmet need for effective treatments against COVID-19 for which neutralizing single domain antibodies (nanobodies) have significant potential. Their small size and stability mean that nanobodies are compatible with respiratory administration. We report four nanobodies (C5, H3, C1, F2) engineered as homotrimers with pmolar affinity for the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Crystal structures show C5 and H3 overlap the ACE2 epitope, whilst C1 and F2 bind to a different epitope. Cryo Electron Microscopy shows C5 binding results in an all down arrangement of the Spike protein. C1, H3 and C5 all neutralize the Victoria strain, and the highly transmissible Alpha (B.1.1.7 first identified in Kent, UK) strain and C1 also neutralizes the Beta (B.1.35, first identified in South Africa). Administration of C5-trimer via the respiratory route showed potent therapeutic efficacy in the Syrian hamster model of COVID-19 and separately effective prophylaxis. The molecule was similarly potent by intraperitoneal injection.

Absolute quantitation of individual SARS-CoV-2 RNA molecules: a new paradigm for infection dynamics and variant differences (preprint)

Despite an unprecedented global research effort on SARS-CoV-2, early replication events remain poorly understood. Given the clinical importance of emergent viral variants with increased transmission, there is an urgent need to understand the early stages of viral replication and transcription. We used single molecule fluorescence in situ hybridisation (smFISH) to quantify positive sense RNA genomes with 95% detection efficiency, while simultaneously visualising negative sense genomes, sub-genomic RNAs and viral proteins. Our absolute quantification of viral RNAs and replication factories revealed that SARS-CoV-2 genomic RNA is long-lived after entry, suggesting that it avoids degradation by cellular nucleases. Moreover, we observed that SARS-CoV-2 replication is highly variable between cells, with only a small cell population displaying high burden of viral RNA. Unexpectedly, the Alpha variant, first identified in the UK, exhibits significantly slower replication kinetics than the Victoria strain, suggesting a novel mechanism contributing to its higher transmissibility with important clinical implications.

High-resolution within-sewer SARS-CoV-2 surveillance facilitates informed intervention (preprint)

To assist in the COVID-19 public health guidance on a college campus, daily composite wastewater samples were withdrawn at 20 manhole locations across the University of Colorado Boulder campus. Low-cost autosamplers were fabricated in-house to enable an economical approach to this distributed study. These sample stations operated from August 25th until November 23rd during the fall 2020 semester, with 1,512 samples collected. The concentration of SARS-CoV-2 in each sample was quantified through two comparative reverse transcription quantitative polymerase chain reactions (RT-qPCRs). These methods were distinct in the utilization of technical replicates and normalization to an endogenous control. (1) Higher temporal resolution compensates for supply chain or other constraints that prevent technical or biological replicates. (2) The endogenous control normalized data agreed with the raw concentration data, minimizing the utility of normalization. The raw wastewater concentration values reflected SARS-CoV-2 prevalence on campus as detected by clinical services. Overall, combining the low-cost composite sampler with a method that quantifies the SARS-CoV-2 signal within six hours enabled actionable and time-responsive data delivered to key stakeholders. With daily reporting of the findings, wastewater surveillance assisted in decision making during critical phases of the pandemic on campus, from detecting individual cases within populations ranging from 109 to 2,048 individuals to monitoring the success of on-campus interventions.

Applying changes made during the COVID-19 pandemic to the future: trauma and orthopaedics

The NHS has made significant changes to practice and specialty training in trauma and orthopaedics as a result of the COVID-19 pandemic. This article looks at the positive and innovative changes along with lessons learnt, which could affect policies in a new challenging post-pandemic health service. At a national level, Public Health England, the British Orthopaedic Association and the Royal Colleges have issued a number of guidelines, which have evolved throughout the pandemic. Developing resilient rotas, virtual clinics, teleconsultations, webinar-based training and operating theatre reorganisation are just some examples of how collaborative working has led to positive changes, despite the huge challenges and hardships created by COVID-19. As we emerge from this crisis, the field of trauma and orthopaedics will need to prepare for the challenges of patient backlogs, neglected trauma and long waiting lists. A continuation of the innovative and collaborative working seen during the pandemic will be crucial to cope with the post-COVID-19 world of orthopaedics.

Natural and vaccine-induced antibody and cellular responses against emerging SARS-CoV-2 variants of concern (preprint)

Both natural infection with SARS-CoV-2 and immunization with a number of vaccines induce protective immunity. However, the ability of such immune responses to recognize and therefore protect against emerging variants is a matter of increasing importance. Such variants of concern (VOC) include isolates of lineage B1.1.7, first identified in the UK, and B1.351, first identified in South Africa. Our data confirm that VOC, particularly those with substitutions at residues 484 and 417 escape neutralization by antibodies directed to the ACE2-binding Class 1 and the adjacent Class 2 epitopes but are susceptible to neutralization by the generally less potent antibodies directed to Class 3 and 4 epitopes on the flanks RBD. To address this potential threat, we sampled a SARS-CoV-2 uninfected UK cohort recently vaccinated with BNT162b2 (Pfizer-BioNTech, two doses delivered 18-28 days apart), alongside a cohort naturally infected in the first wave of the epidemic in Spring 2020. We tested antibody and T cell responses against a reference isolate (VIC001) representing the original circulating lineage B and the impact of sequence variation in these two VOCs. We identified a reduction in antibody neutralization against the VOCs which was most evident in the B1.351 variant. However, the majority of the T cell response was directed against epitopes conserved across all three strains. The reduction in antibody neutralization was less marked in post-boost vaccine-induced than in naturally-induced immune responses and could be largely explained by the potency of the homotypic antibody response. However, after a single vaccination, which induced only modestly neutralizing homotypic antibody titres, neutralization against the VOCs was completely abrogated in the majority of vaccinees. These data indicate that VOCs may evade protective neutralising responses induced by prior infection, and to a lesser extent by immunization, particularly after a single vaccine, but the impact of the VOCs on T cell responses appears less marked. The results emphasize the need to generate high potency immune responses through vaccination in order to provide protection against these and other emergent variants. We observed that two doses of vaccine also induced a significant increase in binding antibodies to spike of both SARS-CoV-1 & MERS, in addition to the four common coronaviruses currently circulating in the UK. The impact of antigenic imprinting on the potency of humoral and cellular heterotypic protection generated by the next generation of variant-directed vaccines remains to be determined.

Correlative Multi-scale Cryo-imaging Unveils SARS-CoV-2 Assembly and Egress (preprint)

Since the outbreak of the SARS-CoV-2 pandemic, there have been intense structural studies on purified recombinant viral components and inactivated viruses. However, structural and ultrastructural evidence on how the SARS-CoV-2 infection progresses in the frozen-hydrated native cellular context is scarce, and there is a lack of comprehensive knowledge on the SARS-CoV-2 replicative cycle. To correlate the cytopathic events induced by SARS-CoV-2 with virus replication process under the frozen-hydrated condition, here we established a unique multi-modal, multi-scale cryo-correlative platform to image SARS-CoV-2 infection in Vero cells. This platform combines serial cryoFIB/SEM volume imaging and soft X-ray cryo-tomography with cell lamellae-based cryo-electron tomography (cryoET) and subtomogram averaging. The results place critical SARS-CoV-2 structural events – e.g. viral RNA transport portals on double membrane vesicles, virus assembly and budding intermediates, virus egress pathways, and native virus spike structures from intracellular assembled and extracellular released virus - in the context of whole-cell images. The latter revealed numerous heterogeneous cytoplasmic vesicles, the formation of membrane tunnels through which viruses exit, and the drastic cytoplasm invasion into the nucleus. This integrated approach allows a holistic view of SARS-CoV-2 infection, from the whole cell to individual molecules.

SARS-CoV-2 Assembly and Egress Pathway Revealed by Correlative Multi-Modal Multi-Scale Cryo-Imaging (preprint)

Understanding the genome replication, assembly and egress of SARS-CoV-2, a multistage process that involves different cellular compartments and the activity of many viral and cellular proteins, is critically important as it bears the means of medical intervention to stop infection. However, there is a lack of comprehensive knowledge on SARS-CoV-2 replicative cycle. Here, we investigated SARS-CoV-2 replication in the native cellular context using a unique correlative multi-modal, multi-scale cryo-imaging approach combining soft X-ray cryo-tomography and serial cryoFIB/SEM volume imaging with cryo-electron tomography (cryoET) and subtomogram averaging. Our results reveal not only profound cytopathic effects of SARS-CoV-2 infection at the whole cell level, exemplified by the formation of membrane tunnels through which viruses exit and drastic cytoplasm invasion into nucleus, but also novel processes of SASR-CoV-2 assembly, budding and egress. The integration of multi-scale cryo-imaging data has led us to propose a model for SARS-CoV-2 replication pathway.Funding Statement: This research was supported by the National Institutes of Health grant P50AI150481, the UK Wellcome Trust Investigator Award 206422/Z/17/Z, the UK Biotechnology and Biological Sciences Research Council grant BB/S003339/1, and the grant from the Chinese Academy of Medical Sciences Oxford Institute. Containment level 3 experiments were funded through the generous support of philanthropic donors to the University of Oxford’s COVID-19 Research Response Fund. M.L.K. is supported by the Biotechnology and Biological Sciences Research Council (BBSRC) (grant number BB/M011224/1).Declaration of Interests: The authors declare no competing interests.

Potent SARS-CoV-2 neutralizing antibodies selected from a human antibody library constructed decades ago (preprint)

Combinatorial antibody libraries not only effectively reduce antibody discovery to a numbers game, but enable documentation of the history of antibody responses in an individual. The SARS-CoV-2 pandemic has prompted a wider application of this technology to meet the public health challenge of pandemic threats in the modern era. Herein, we used a combinatorial human antibody library constructed 20 years before the COVID-19 pandemic to discover three highly potent antibodies that selectively bind SARS-CoV-2 spike protein and neutralize authentic SARS-CoV-2 virus. Compared to neutralizing antibodies from COVID-19 patients with generally low somatic hypermutation (SHM), these antibodies contain over 13-22 SHMs, many of which are involved in specific interactions in crystal structures with SARS-CoV-2 spike RBD. The identification of these somatically mutated antibodies in a pre-pandemic library raises intriguing questions about the origin and evolution of human immune responses to SARS-CoV-2.

SARS-CoV-2 Assembly and Egress Pathway Revealed by Correlative Multi-modal Multi-scale Cryo-imaging (preprint)

Since the outbreak of the SARS-CoV-2 pandemic, there have been intense structural studies on purified recombinant viral components and inactivated viruses. However, investigation of the SARS-CoV-2 infection in the native cellular context is scarce, and there is a lack of comprehensive knowledge on SARS-CoV-2 replicative cycle. Understanding the genome replication, assembly and egress of SARS-CoV-2, a multistage process that involves different cellular compartments and the activity of many viral and cellular proteins, is critically important as it bears the means of medical intervention to stop infection. Here, we investigated SARS-CoV-2 replication in Vero cells under the near-native frozen-hydrated condition using a unique correlative multi-modal, multi-scale cryo-imaging approach combining soft X-ray cryo-tomography and serial cryoFIB/SEM volume imaging of the entire SARS-CoV-2 infected cell with cryo-electron tomography (cryoET) of cellular lamellae and cell periphery, as well as structure determination of viral components by subtomogram averaging. Our results reveal at the whole cell level profound cytopathic effects of SARS-CoV-2 infection, exemplified by a large amount of heterogeneous vesicles in the cytoplasm for RNA synthesis and virus assembly, formation of membrane tunnels through which viruses exit, and drastic cytoplasm invasion into nucleus. Furthermore, cryoET of cell lamellae reveals how viral RNAs are transported from double-membrane vesicles where they are synthesized to viral assembly sites; how viral spikes and RNPs assist in virus assembly and budding; and how fully assembled virus particles exit the cell, thus stablishing a model of SARS-CoV-2 genome replication, virus assembly and egress pathways.

SLAMF7 engagement super-activates macrophages in acute and chronic inflammation (preprint)

Macrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation. To identify regulators of vigorous macrophage activation, we analyzed RNA-seq data from synovial macrophages and identified SLAMF7 as a receptor associated with a super-activated macrophage state in rheumatoid arthritis. We implicated IFN-gamma as a key regulator of SLAMF7 expression. Engaging this receptor drove an exuberant wave of inflammatory cytokine expression, and induction of TNF-alpha following SLAMF7 engagement amplified inflammation through an autocrine signaling loop. We observed SLAMF7-induced gene programs not only in macrophages from rheumatoid arthritis patients, but in gut macrophages from active Crohn's disease patients and lung macrophages from severe COVID-19 patients. This suggests a central role for SLAMF7 in macrophage super-activation with broad implications in pathology.