Clade I-Associated Mpox Cases Associated with Sexual Contact, the Democratic Republic of the Congo.

We report a cluster of clade I monkeypox virus infections linked to sexual contact in the Democratic Republic of the Congo. Case investigations resulted in 5 reverse transcription PCR-confirmed infections; genome sequencing suggest they belonged to the same transmission chain. This finding demonstrates that mpox transmission through sexual contact extends beyond clade IIb.

Stigmatization of Ebola virus disease survivors in 2022: A cross-sectional study of survivors in Sierra Leone.

BACKGROUND: Evidence has demonstrated a high proportion of Ebola virus disease (EVD) survivors experienced stigma due to the disease. This study sought to understand the longer-term effects of stigma encountered by survivors of the 2014-2016 EVD epidemic living in Sierra Leone. METHODS: This was a cross-sectional study of 595 EVD survivors and 403 close contacts (n = 998) from Sierra Leone. Assessments were conducted using a three-part survey between November 2021 to March 2022. We explored the socio-demographic factors associated with stigma experienced by EVD survivors. FINDINGS: 50·6 % (n = 301) of EVD survivors reported that they continued to experience at least one aspect of stigma. Females were disproportionately affected by stigma, with 45·2 % of females reporting isolation from friends and family compared to 33·9 % of men (p = 0·005). Multivariable logistic regression models revealed those aged 40-44, living rurally, and reporting an acute infection longer than seven days was associated with EVD-related stigma at the time of survey. INTERPRETATION: This study demonstrates stigma is still prevalent among people who survived EVD in 2022. It also identified socio-demographic factors associated with stigma that can be used for targeting interventions. Importantly, this highlights the continued need for EVD survivors to access mental healthcare and social support systems well after disease recovery. FUNDING: This study was funded by the Canadian Institutes for Health Research (Grant no. PJT-175098. JK is funded by a Tier 2 Canada Research Chair in the Molecular Pathogenesis of Emerging and Re-Emerging Viruses. SS is funded by a Tier 2 Canada Research Chair in Program Science and Global Public Health.

Variola virus and clade I monkeypox virus differentially modulate cellular responses longitudinally in monocytes during infection.

Variola virus (VARV), the etiological agent of smallpox, had enormous impacts on global health prior to its eradication. In the absence of global vaccination programs, monkeypox virus (MPXV) has become a growing public health threat that includes endemic regions of Sub-Saharan Africa and, more recently, non-endemic regions following the identification of clade IIb MPXV in many global regions. While human mpox resembles smallpox in clinical presentation, there are considerable knowledge gaps regarding conservation of molecular mechanisms of pathogenesis between these two human orthopoxviruses. Given this paucity of knowledge, we sought to compare MPXV and VARV infections in human monocytes through kinome analysis. We performed a longitudinal analysis of host cellular responses to VARV infection in human monocytes as well as a comparative analysis to clade I MPXV-mediated responses. While infection with either virus resulted in greater activation of cellular responses early in the course of infection as compared to later time points, several key differences in specific cell signaling events were identified and validated through the analysis of inhibition of kinases and cell signaling pathways on viral infection. These observations will help in the design and development of pan-orthopoxvirus therapeutics. To our knowledge, this is the first assessment of host cell signaling responses during VARV infection and comparison of host cell signaling response modulation by VARV and clade I MPXV.

Emergence of mpox in the post-smallpox era-a narrative review on mpox epidemiology.

BACKGROUND: The 2022 mpox outbreak drew global attention to this neglected pathogen. While most of the world was taken by surprise, some countries have seen this pathogen emerge and become endemic several decades prior to this epidemic. OBJECTIVES: This narrative review provides an overview of mpox epidemiology since its discovery through the 2022 global outbreak. SOURCES: We searched PubMed for relevant literature about mpox epidemiology and transmission through 28 February 2023. CONTENT: The emergence of human mpox is intertwined with the eradication of smallpox and the cessation of the global smallpox vaccination campaign. The first human clade I and II monkeypox virus (MPXV) infections were reported as zoonoses in Central and West Africa, respectively, around 1970 with sporadic infections reported throughout the rest of the decade. Over the next five decades, Clade I MPXV was more common and caused outbreaks of increasing size and frequency, mainly in the Democratic Republic of the Congo. Clade II MPXV was rarely observed, until its re-emergence and ongoing transmission in Nigeria, since 2017. Both clades showed a shift from zoonotic to human-to-human transmission, with potential transmission through sexual contact being observed in Nigeria. In 2022, clade II MPXV caused a large human outbreak which to date has caused over 86,000 cases in 110 countries, with strong evidence of transmission during sexual contact. By February 2023, the global epidemic has waned in most countries, but endemic regions continue to suffer from mpox. IMPLICATIONS: The changing epidemiology of mpox demonstrates how neglected zoonosis turned into a global health threat within a few decades. Thus, mpox pathophysiology and transmission dynamics need to be further investigated, and preventive and therapeutic interventions need to be evaluated. Outbreak response systems need to be strengthened and sustained in endemic regions to reduce the global threat of mpox.

Ebola virus shed glycoprotein is toxic to human T, B, and natural killer lymphocytes.

Lymphocyte depletion is a distinctive feature of Ebola virus (EBOV) disease. The ectodomain of EBOV glycoprotein (GP) is cleaved off the surface of infected cells into circulation as shed GP. To test the hypothesis that shed GP induces lymphocyte death, we cultured primary human B, NK, or T cells with shed GP in vitro. We found that shed GP dependably decreased B, NK, and T cell viability across donors. B and NK cells exhibited higher susceptibility than T cells. Continuous monitoring revealed shed GP began to kill B and NK cells by 4 h and T cells by 5 h. We also demonstrated that shed GP-induced lymphocyte death can be both caspase dependent and caspase independent. Our data are evidence that the cytotoxic effect of shed GP on lymphocytes may contribute to EBOV disease and highlight the need for further research to clarify mechanisms of shed GP-induced death.

A contemporary review of clade-specific virological differences in monkeypox viruses.

BACKGROUND: Monkeypox virus (MPXV) is an emerging zoonotic virus that has had on-going public health impacts in endemic regions of Central and West Africa for over a half-century. Historically, the MPXV clade endemic in regions of Central Africa is associated with higher morbidity and mortality as compared with the clade endemic in West Africa. OBJECTIVES: Here, we review the virological characteristics of MPXV and discuss potential relationships between virulence factors and clade- (and subclade-) specific differences in virulence and transmission patterns. SOURCES: Targeted search was conducted in PubMed using ((monkeypox virus) OR (Orthopoxvirus)) AND (zoonosis)) OR ((monkeypox) OR (human mpox). CONTENT: Forty-seven references were considered that included three publicly available data reports and/or press releases, one book chapter, and 44 published manuscripts. IMPLICATIONS: Although zoonosis has been historically linked to emergence events in humans, epidemiological analyses of more recent outbreaks have identified increasing frequencies of human-to-human transmission. Furthermore, viral transmission during the 2022 global human mpox outbreak, caused by a recently identified MPXV subclade, has relied exclusively on human-to-human contact with no known zoonotic link.

A Personalized Avatar-Based Web Application to Help People Understand How Social Distancing Can Reduce the Spread of COVID-19: Cross-sectional, Observational, Pre-Post Study.

BACKGROUND: To reduce the transmission of SARS-CoV-2 and the associated spread of COVID-19, many jurisdictions around the world imposed mandatory or recommended social or physical distancing. As a result, at the beginning of the pandemic, various communication materials appeared online to promote distancing. Explanations of the science underlying these mandates or recommendations were either highly technical or highly simplified. OBJECTIVE: This study aimed to understand the effects of a dynamic visualization on distancing. Our overall aim was to help people understand the dynamics of the spread of COVID-19 in their community and the implications of their own behavior for themselves, those around them, the health care system, and society. METHODS: Using Scrum, which is an agile framework; JavaScript (Vue.js framework); and code already developed for risk communication in another context of infectious disease transmission, we rapidly developed a new personalized web application. In our application, people make avatars that represent themselves and the people around them. These avatars are integrated into a 3-minute animation illustrating an epidemiological model for COVID-19 transmission, showing the differences in transmission with and without distancing. During the animation, the narration explains the science of how distancing reduces the transmission of COVID-19 in plain language in English or French. The application offers full captions to complement the narration and a descriptive transcript for people using screen readers. We used Google Analytics to collect standard usage statistics. A brief, anonymous, optional survey also collected self-reported distancing behaviors and intentions in the previous and coming weeks, respectively. We launched and disseminated the application on Twitter and Facebook on April 8, 2020, and April 9, 2020. RESULTS: After 26 days, the application received 3588 unique hits from 82 countries. The optional survey at the end of the application collected 182 responses. Among this small subsample of users, survey respondents were nearly (170/177, 96%) already practicing distancing and indicated that they intended to practice distancing in the coming week (172/177, 97.2%). Among the small minority of people (n=7) who indicated that they had not been previously practicing distancing, 2 (29%) reported that they would practice distancing in the week to come. CONCLUSIONS: We developed a web application to help people understand the relationship between individual-level behavior and population-level effects in the context of an infectious disease spread. This study also demonstrates how agile development can be used to quickly create personalized risk messages for public health issues like a pandemic. The nonrandomized design of this rapid study prevents us from concluding the application's effectiveness; however, results thus far suggest that avatar-based visualizations may help people understand their role in infectious disease transmission.

The descriptive epidemiology of pre-omicron SARS-CoV-2 breakthrough infections and severe outcomes in Manitoba, Canada.

Introduction: Vaccination plays a key role in curbing severe outcomes resulting from COVID-19 disease. With the Omicron variant and the relaxing of public health protections breakthrough infections are increasingly common, and certain groups remain at higher risk for severe outcomes from breakthrough infections. We analysed population-based public health data from Manitoba, Canada to understand characteristics of those experiencing breakthrough infections and severe outcomes from breakthrough infections. Data from previous pandemic stages can provide valuable information regarding severe outcomes associated with breakthrough infection in the Omicron and future phases. Methods: Positive SARS-CoV-2 PCR tests from Cadham Provincial Laboratory were linked to case information from the population-based Public Health Information Management System. A retrospective design was used with time-to-event analyses to examine severe outcomes among those experiencing breakthrough infection. Results: Breakthrough cases were more likely to have 2 + chronic conditions, compared to age-, sex-, and time-period matched unvaccinated cases (24% vs. 17%), with hypertension (30%), diabetes (17%), and asthma (14%) being the most prevalent chronic conditions amongst breakthrough cases. Severe outcomes resulting from breakthrough infection was associated with age and chronic conditions, with those with 2 + chronic conditions at higher risk of severe outcomes (adjusted hazard ratio: 3.6, 95% confidence intervals: 2.0-6.4). Risk of severe outcomes varied by age group, with those 70 + years at over 13 times the risk of severe outcomes (95% CI: 4.5-39.8), compared to those 18-29 years of age. Discussion: Our results demonstrate the impact of chronic conditions on the likelihood of, and severity of outcomes from breakthrough infections. These findings underscore the importance of vaccination programs prioritizing vulnerable populations.

Monkeypox emergency: Urgent questions and perspectives.

Amidst the COVID-19 pandemic, we now face another public health emergency in the form of monkeypox virus. As of August 1, the Centers for Disease Control and Prevention report over 23,000 cases in 80 countries. An inclusive and global collaborative effort to understand the biology, evolution, and spread of the virus as well as commitment to vaccine equity will be critical toward containing this outbreak. We share the voices of leading experts in this space on what they see as the most pressing questions and directions for the community.

The future of zoonotic risk prediction.

In the light of the urgency raised by the COVID-19 pandemic, global investment in wildlife virology is likely to increase, and new surveillance programmes will identify hundreds of novel viruses that might someday pose a threat to humans. To support the extensive task of laboratory characterization, scientists may increasingly rely on data-driven rubrics or machine learning models that learn from known zoonoses to identify which animal pathogens could someday pose a threat to global health. We synthesize the findings of an interdisciplinary workshop on zoonotic risk technologies to answer the following questions. What are the prerequisites, in terms of open data, equity and interdisciplinary collaboration, to the development and application of those tools? What effect could the technology have on global health? Who would control that technology, who would have access to it and who would benefit from it? Would it improve pandemic prevention? Could it create new challenges? This article is part of the theme issue 'Infectious disease macroecology: parasite diversity and dynamics across the globe'.

COVID-19 false dichotomies and a comprehensive review of the evidence regarding public health, COVID-19 symptomatology, SARS-CoV-2 transmission, mask wearing, and reinfection.

Scientists across disciplines, policymakers, and journalists have voiced frustration at the unprecedented polarization and misinformation around coronavirus disease 2019 (COVID-19) pandemic. Several false dichotomies have been used to polarize debates while oversimplifying complex issues. In this comprehensive narrative review, we deconstruct six common COVID-19 false dichotomies, address the evidence on these topics, identify insights relevant to effective pandemic responses, and highlight knowledge gaps and uncertainties. The topics of this review are: 1) Health and lives vs. economy and livelihoods, 2) Indefinite lockdown vs. unlimited reopening, 3) Symptomatic vs. asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, 4) Droplet vs. aerosol transmission of SARS-CoV-2, 5) Masks for all vs. no masking, and 6) SARS-CoV-2 reinfection vs. no reinfection. We discuss the importance of multidisciplinary integration (health, social, and physical sciences), multilayered approaches to reducing risk ("Emmentaler cheese model"), harm reduction, smart masking, relaxation of interventions, and context-sensitive policymaking for COVID-19 response plans. We also address the challenges in understanding the broad clinical presentation of COVID-19, SARS-CoV-2 transmission, and SARS-CoV-2 reinfection. These key issues of science and public health policy have been presented as false dichotomies during the pandemic. However, they are hardly binary, simple, or uniform, and therefore should not be framed as polar extremes. We urge a nuanced understanding of the science and caution against black-or-white messaging, all-or-nothing guidance, and one-size-fits-all approaches. There is a need for meaningful public health communication and science-informed policies that recognize shades of gray, uncertainties, local context, and social determinants of health.

Sex and age bias viral burden and interferon responses during SARS-CoV-2 infection in ferrets.

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) hospitalizations and deaths disportionally affect males and older ages. Here we investigated the impact of male sex and age comparing sex-matched or age-matched ferrets infected with SARS-CoV-2. Differences in temperature regulation was identified for male ferrets which was accompanied by prolonged viral replication in the upper respiratory tract after infection. Gene expression analysis of the nasal turbinates indicated that 1-year-old female ferrets had significant increases in interferon response genes post infection which were delayed in males. These results provide insight into COVID-19 and suggests that older males may play a role in viral transmission due to decreased antiviral responses.

SARS-CoV-2 infection in the Syrian hamster model causes inflammation as well as type I interferon dysregulation in both respiratory and non-respiratory tissues including the heart and kidney.

COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is a disease affecting several organ systems. A model that captures all clinical symptoms of COVID-19 as well as long-haulers disease is needed. We investigated the host responses associated with infection in several major organ systems including the respiratory tract, the heart, and the kidneys after SARS-CoV-2 infection in Syrian hamsters. We found significant increases in inflammatory cytokines (IL-6, IL-1beta, and TNF) and type II interferons whereas type I interferons were inhibited. Examination of extrapulmonary tissue indicated inflammation in the kidney, liver, and heart which also lacked type I interferon upregulation. Histologically, the heart had evidence of myocarditis and microthrombi while the kidney had tubular inflammation. These results give insight into the multiorgan disease experienced by people with COVID-19 and possibly the prolonged disease in people with post-acute sequelae of SARS-CoV-2 (PASC).

Male sex and age biases viral burden, viral shedding, and type 1 and 2 interferon responses during SARS-CoV-2 infection in ferrets.

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) hospitalizations and deaths disportionally affect males and the elderly. Here we investigated the impact of male sex and age by infecting adult male, aged male, and adult female ferrets with SARS-CoV-2. Aged male ferrets had a decrease in temperature which was accompanied by prolonged viral replication with increased pathology in the upper respiratory tract after infection. Transcriptome analysis of the nasal turbinates and lungs indicated that female ferrets had significant increases in interferon response genes (OASL, MX1, ISG15, etc.) on day 2 post infection which was delayed in aged males. In addition, genes associated with taste and smell such as RTP1, CHGA, and CHGA1 at later time points were upregulated in males but not in females. These results provide insight into COVID-19 and suggests that older males may play a role in viral transmission due to decreased antiviral responses.

Allergen inhalation generates pro-inflammatory oxidised phosphatidylcholine associated with airway dysfunction.

Oxidised phosphatidylcholines (OxPCs) are produced under conditions of elevated oxidative stress and can contribute to human disease pathobiology. However, their role in allergic asthma is unexplored. The aim of this study was to characterise the OxPC profile in the airways after allergen challenge of people with airway hyperresponsiveness (AHR) or mild asthma. The capacity of OxPCs to contribute to pathobiology associated with asthma was also to be determined.Using bronchoalveolar lavage fluid from two human cohorts, OxPC species were quantified using ultra-high performance liquid chromatography-tandem mass spectrometry. Murine thin-cut lung slices were used to measure airway narrowing caused by OxPCs. Human airway smooth muscle (HASM) cells were exposed to OxPCs to assess concentration-associated changes in inflammatory phenotype and activation of signalling networks.OxPC profiles in the airways were different between people with and without AHR and correlated with methacholine responsiveness. Exposing patients with mild asthma to allergens produced unique OxPC signatures that associated with the severity of the late asthma response. OxPCs dose-dependently induced 15% airway narrowing in murine thin-cut lung slices. In HASM cells, OxPCs dose-dependently increased the biosynthesis of cyclooxygenase-2, interleukin (IL)-6, IL-8, granulocyte-macrophage colony-stimulating factor and the production of oxylipins via protein kinase C-dependent pathways.Data from human cohorts and primary HASM cell culture show that OxPCs are present in the airways, increase after allergen challenge and correlate with metrics of airway dysfunction. Furthermore, OxPCs may contribute to asthma pathobiology by promoting airway narrowing and inducing a pro-inflammatory phenotype and contraction of airway smooth muscle. OxPCs represent a potential novel target for treating oxidative stress-associated pathobiology in asthma.

Integrating Proteomics for Facilitating Drug Identification and Repurposing During an Emerging Virus Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has disrupted global healthcare and economic systems throughout 2020 with no clear end in sight. While the pandemic continues to have deleterious effects across the globe, mechanisms for disrupting disease transmission have relied on behavioral controls (e.g., social distancing, masks, and hygiene) as there are currently no vaccines approved for use and limited therapeutic options. As this pandemic has demonstrated our vulnerability to newly emerging viruses, there has been strong interest in utilizing proteomics approaches to identify targets for repurposed drugs as novel therapeutic candidates that could be fast-tracked for human use. Building on a previous discussion on the combination of proteomics technologies with clinical data for combating emerging viruses, we discuss how these technologies are being employed for COVID-19 and the current state of knowledge regarding repurposed drugs in these efforts.

Dysregulated Host Responses Underlie 2009 Pandemic Influenza-Methicillin Resistant Staphylococcus aureus Coinfection Pathogenesis at the Alveolar-Capillary Barrier.

Influenza viruses are a continual public health concern resulting in 3-5 million severe infections annually despite intense vaccination campaigns and messaging. Secondary bacterial infections, including Staphylococcus aureus, result in increased morbidity and mortality during seasonal epidemics and pandemics. While coinfections can result in deleterious pathologic consequences, including alveolar-capillary barrier disruption, the underlying mechanisms are poorly understood. We have characterized host- and pathogen-centric mechanisms contributing to influenza-bacterial coinfections in a primary cell coculture model of the alveolar-capillary barrier. Using 2009 pandemic influenza (pH1N1) and methicillin-resistant S. aureus (MRSA), we demonstrate that coinfection resulted in dysregulated barrier function. Preinfection with pH1N1 resulted in modulation of adhesion- and invasion-associated MRSA virulence factors during lag phase bacterial replication. Host response modulation in coinfected alveolar epithelial cells were primarily related to TLR- and inflammatory response-mediated cell signaling events. While less extensive in cocultured endothelial cells, coinfection resulted in changes to cellular stress response- and TLR-related signaling events. Analysis of cytokine expression suggested that cytokine secretion might play an important role in coinfection pathogenesis. Taken together, we demonstrate that coinfection pathogenesis is related to complex host- and pathogen-mediated events impacting both epithelial and endothelial cell regulation at the alveolar-capillary barrier.

Nonhuman primates exposed to Zika virus in utero are not protected against reinfection at 1 year postpartum.

There is limited information about the impact of Zika virus (ZIKV) exposure in utero on the anti-ZIKV immune responses of offspring. We infected six rhesus macaque dams with ZIKV early or late in pregnancy and studied four of their offspring over the course of a year postpartum. Despite evidence of ZIKV exposure in utero, we observed no structural brain abnormalities in the offspring. We detected infant-derived ZIKV-specific immunoglobulin A antibody responses and T cell memory responses during the first year postpartum in the two offspring born to dams infected with ZIKV early in pregnancy. Critically, although the infants had acquired some immunological memory of ZIKV, it was not sufficient to protect them against reinfection with ZIKV at 1 year postpartum. The four offspring reexposed to ZIKV at 1 year postpartum all survived but exhibited acute viremia and viral tropism to lymphoid tissues; three of four reexposed offspring exhibited spinal cord pathology. These data suggest that macaque infants born to dams infected with ZIKV during pregnancy remain susceptible to postnatal infection and consequent neuropathology.