The 3C-like protease (3CLpro) of SARS-CoV-2 is an attractive drug target for developing antivirals against SARS-CoV-2. A few small molecule inhibitors of 3CLpro are in clinical trials for COVID-19 treatments and more inhibitors are being developed. One limiting factor for 3CLpro inhibitors development is that the cellular activities of such inhibitors have to be evaluated in a Biosafety Level 3 (BSL-3) or BSL-4 laboratory. Here, we design genetically encoded biosensors that can be used in BSL-2 laboratories to set up cell-based assays for 3CLpro inhibitor discovery. The biosensors were constructed by linking a green fluorescent protein (GFP2) to the N-terminus and a Renilla luciferase (RLuc8) to the C-terminus of SARS-CoV-2 3CLpro, with the linkers derived from the cleavage sequences of 3CLpro. After over-expression of the biosensors in HEK293 cells, 3CLpro can be released from GFP2 and RLuc by self-cleavage, resulting in a decrease of the bioluminescence resonance energy transfer (BRET) signal. Using one of these biosensors, pBRET-10, we evaluated the cellular activities of several 3CLpro inhibitors. These inhibitors restored the BRET signal by blocking the proteolysis of pBRET-10, and their relative activities measured using pBRET-10 were consistent with their anti-SARS-CoV-2 activities reported previously. We conclude that the biosensor pBRET-10 is a useful tool for SARS-CoV-2 3CLpro inhibitor discovery. Furthermore, our strategy can be used to design biosensors for other viral proteases that share the same activation mechanism as 3CLpro, such as HIV protease PR and HCV protease NS3. HighlightsO_LISensitive cell-based biosensors for 3CLpro inhibitor discovery in BSL-2 laboratories. C_LIO_LIThe BRET-based self-cleaving biosensors mimic the in vivo autoproteolytic activation of 3CLpro. C_LIO_LISimilar biosensors can be designed for other self-cleaving proteases, such as HIV protease PR and HCV protease NS3. C_LI

Microbial components and the endogenous molecules released from damaged cells can stimulate germ-line-encoded pattern recognition receptors (PRRs) to transduce signals to the hub of the innate immune signaling network-the adaptor proteins MyD88/TRIF/MAVS/STING/Caspase-1, where integrated signals relay to the relevant transcription factors IRF3/IRF7/NF-B/ AP-1 and the signal transducer and activator of transcription 6 (STAT6) to trigger the expression of type I interferons and inflammatory cytokines or the assembly of inflammasomes. Most pleiotropic cytokines are secreted and bind to specific receptors, activating the signaling pathways including JAK-STAT for the proliferation, differentiation and functional capacity of immune cells. This review focuses on several critical adaptors in innate immune signaling cascades and recent progress in their molecular mechanisms.

INTRODUCTION: Severe acute respiratory syndrome coronavirus-2 may escape the inactivation by gastric acid because of hypochlorhydria caused by proton pump inhibitors (PPIs), which could predispose the patients to severe COVID-19. METHODS: We studied the association between prehospitalization PPI exposure and clinical outcomes among hospitalized COVID-19 patients. RESULTS: A total of 295 hospitalized COVID-19 patients were included in the study. 15.6% of hospitalized COVID-19 patients were on PPIs at home. Mortality among PPI-users was 2.3 times higher than non-users, along with 2.3 times higher risk of acute respiratory distress syndrome after adjusting for confounding variables. CONCLUSION: We found that prehospitalization PPI-exposure is independently associated with worse clinical outcomes, including mortality in COVID-19 patients, regardless of the presence of cardiovascular comorbidities.

Background: With the spreading global pandemic of coronavirus disease 2019 (Covid-19) there has been disruption to normal clinical activity in response to the increased demand on health services. There are reports of a reduction in non-Covid-19 emergency presentations. Consequentially, there are concerns that deaths from non-Covid-19 causes could increase. We examined recent reported population-based mortality rates, compared with expected rates, and compared any excess in deaths with the number of deaths attributed to Covid-19. Methods: National agency and death registration reports were searched for numbers of deaths attributed to Covid-19 and overall mortality that had been publicly reported by 16 April 2020. Data on the number of deaths attributed to Covid-19, the total number of deaths registered in the population and the historical average over at least 3 years were collected. Data were available for 3 Northern European countries (England & Wales, Scotland and the Netherlands) and New York State, United States of America. Results: There was an increase in observed, compared with expected, mortality in Scotland (+27%), England and Wales (+35%), the Netherlands (+60%) and New York state (+26%). Of these deaths, only 43% in Scotland and England and Wales, 49% in the Netherlands and 30% in New York state were attributed to Covid-19 leaving a number of excess deaths not attributed to Covid-19. Conclusions: A substantial proportion of excess deaths observed during the current COVID-19 pandemic are not attributed to COVID-19 and may represent an excess of deaths due to other causes.

BackgroundInvasive pneumococcal disease (IPD) declined during the COVID-19 pandemic. Previous studies hypothesized that this was due to reduced pneumococcal transmission resulting from non-pharmacological interventions. We used multiple ongoing cohort surveillance projects in children <5 years to test this hypothesis. MethodsThe first SARS-CoV-2 cases were detected in February-2020, resulting in a full lockdown, followed by several partial restrictions. Data from ongoing surveillance projects captured the incidence dynamics of community-acquired alveolar pneumonia (CAAP), non-alveolar lower respiratory infections necessitating chest X-rays (NA-LRI), nasopharyngeal pneumococcal carriage in non-respiratory visits, nasopharyngeal respiratory virus detection (by PCR), and nationwide invasive pneumococcal disease (IPD). Monthly rates (January-2020 through February-2021 vs. mean monthly rates 2016-2019 [expected rates]) adjusted for age and ethnicity, were compared. FindingsCAAP and bacteremic pneumococcal pneumonia were strongly reduced (incidence rate ratios, [IRRs] 0{eta}07 and 0{eta}19, respectively); NA-LRI and non-pneumonia IPD were also reduced, with a lesser magnitude (IRRs, 0{eta}46 and 0{eta}42, respectively). In contrast, pneumococcal carriage prevalence was only slightly reduced and density of colonization and pneumococcal serotype distributions were similar to previous years. The pneumococcus-associated disease decline was temporally associated with a full suppression of RSV, influenza viruses, and hMPV, often implicated as co-pathogens with pneumococcus. In contrast, adenovirus, rhinovirus, and parainfluenza activities were within or above expected levels. InterpretationReductions in pneumococcal and pneumococcus-associated diseases occurring during the COVID-19 pandemic were not predominantly related to reduced pneumococcal transmission and carriage but were strongly associated with the complete disappearance of specific respiratory viruses. FundingPartially funded by Pfizer, Inc.

Severe Acute Respiratory Syndrome- Coronavirus 2 (SARS-Cov-2) has caused over 5,000,000 cases of Coronavirus disease (COVID-19) with significant fatality rate Due to the urgency of this global pandemic, numerous therapeutic and vaccine trials have begun without customary safety and efficacy studies Laboratory mice have been the stalwart of these types of studies;however, they do not support infection by SARS-CoV-2 due to the inability of its spike (S) protein to engage the mouse ortholog of its human entry receptor angiotensin-converting enzyme 2 (hACE2) While hACE2 transgenic mice support infection and pathogenesis, these mice are currently limited in availability and are restricted to a single genetic background Here we report the development of a mouse model of SARS-CoV-2 based on adeno associated virus (AAV)-mediated expression of hACE2 These mice support viral replication and antibody production and exhibit pathologic findings found in COVID-19 patients as well as non-human primate models Moreover, we show that type I interferons are unable to control SARS-CoV2 replication and drive pathologic responses Thus, the hACE2-AAV mouse model enables rapid deployment for in-depth analysis following robust SARS-CoV-2 infection with authentic patient-derived virus in mice of diverse genetic backgrounds This represents a much-needed platform for rapidly testing prophylactic and therapeutic strategies to combat COVID-19 Funding: This study was supported by awards from National Institute of Health grants, 2T32AI007517-16 (to BI), T32GM007205 and F30CA239444 (to ES), AI054359 and AI127429 (to AI), T32AI007019 (to TM),K08 AI128043 (to CBW), as well as Women's Health Research at Yale Pilot Project Program (AI, AR), Fast Grant from Emergent Ventures at the Mercatus Center (AI, ES), Mathers Foundation (AR, CBW, AI), and the Ludwig Family Foundation (AI, AR, CBW) A I is an investigator of the Howard Hughes Medical Institute Conflict of Interest: None of the authors declare interests related to the manuscript Ethical Approval: All procedures were performed in a BSL-3 facility (for SARS-CoV-2 infected mice) with approval from the Yale Environmental Health and Safety office

BACKGROUND: The present pandemic situation due to coronavirus has led to the search for newer prevention, diagnostic, and treatment methods The onset of the corona infection in a human results in acute respiratory illness followed by death if not diagnosed and treated with suitable antiretroviral drugs With the unavailability of the targeted drug treatment, several repurposed drugs are being used for treatment However, the side-effects of the drugs urges us to move to a search for newer synthetic- or phytochemical-based drugs The present study investigates the use of various phytochemicals virtually screened from various plant sources in Western Ghats, India, and subsequently molecular docking studies were performed to identify the efficacy of the drug in retroviral infection particularly coronavirus infection RESULTS: Out of 57 phytochemicals screened initially based on the structural and physicochemical properties, 39 were effectively used for the docking analysis Finally, 5 lead compounds with highest hydrophobic interaction and number of H-bonds were screened Results from the interaction analysis suggest Piperolactam A to be pocketed well with good hydrophobic interaction with the residues in the binding region R1 ADME and toxicity profiling also reveals Piperolactam A with higher LogS values indicating higher permeation and hydrophilicity Toxicity profiling suggests that the 5 screened compounds to be relatively safe CONCLUSION: The in silico methods used in this study suggests that the compound Piperolactam A to be the most effective inhibitor of S-protein from binding to the GRP78 receptor By blocking the binding of the S-protein to the CS-GRP78 cell surface receptor, they can inhibit the binding of the virus to the host SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10 1186/s43088-021-00095-x

OBJECTIVES/HYPOTHESIS: The overall aim of this study was to evaluate personal protective equipment (PPE) that may facilitate the safe recommencement of cochlear implantation in the COVID-19 era, with the broader goal of minimizing the period of auditory deprivation in prelingually deaf children and reducing the risk of cochlear ossification in individuals following meningitis. METHODS: The study design comprised 1) an objective assessment of mastoid drilling-induced droplet spread conducted during simulated cochlear implant (CI) surgery and its mitigation via the use of a protective drape tent and 2) an evaluation of three PPE configurations by otologists while performing mastoid drilling on ex vivo temporal bones. The various PPE solutions were assessed in terms of their impact on communication, vital physiological parameters, visual acuity and fields, and acceptability to surgeons using a systematic risk-based approach. RESULTS: Droplet spread during simulated CI surgery extended over 2 m, a distance greater than previously reported. A drape tent significantly reduced droplet spread. The ensemble of a half-face mask and safety spoggles (foam lined safety goggles) had consistently superior performance across all aspects of clinical usability. All other PPE options were found to substantially restrict the visual field, making them unsafe for microsurgery. CONCLUSIONS: The results of this preclinical study indicate that the most viable solution to enable the safe conduct of CI and other mastoid surgery is a combination of a filtering facepiece (FFP)3 mask or half-face respirator with safety spoggles as PPE. Prescription spoggles are an option for surgeons who need to wear corrective glasses to operate. A drape tent reduces droplet spread. A multicenter clinical trial to evaluate the effectiveness of PPE should be the next step toward safely performing CI surgery during the COVID-19 era. LEVEL OF EVIDENCE: 4 Laryngoscope, 2020.

Six percent of Americans, including 3 million high schoolers, use e-cigarettes, which contain potentially toxic substances, volatile organic compounds, and metals. We present the first human study on the effects of e-cigarette exposure in the oral cavity. By interrogating both immunoinflammatory responses and microbial functional dynamics, we discovered pathogen overrepresentation, higher virulence signatures, and a brisk proinflammatory signal in clinically healthy e-cigarette users, equivalent to patients with severe periodontitis. Using RNA sequencing and confocal and electron microscopy to validate these findings, we demonstrate that the carbon-rich glycol/glycerol vehicle is an important catalyst in transforming biofilm architecture within 24 hours of exposure. Last, a machine-learning classifier trained on the metagenomic signatures of e-cigarettes identified as e-cigarette users both those individuals who used e-cigarettes to quit smoking, and those who use both e-cigarettes and cigarettes. The present study questions the safety of e-cigarettes and the harm reduction narrative promoted by advertising campaigns.

We present a new interface for controlling a navigation robot in novel environments using coordinated gesture and language. We use a TurtleBot3 robot with a LIDAR and a camera, an embodied simulation of what the robot has encountered while exploring, and a cross-platform bridge facilitating generic communication. A human partner can deliver instructions to the robot using spoken English and gestures relative to the simulated environment, to guide the robot through navigation tasks.

The effects of a period without physical training on the civilian population are well established. However, no studies show the effects of a period without mandatory physical training on maximum oxygen uptake (VO(2) max) and anthropometric parameters in naval cadets. This study aimed to investigate changes in VO(2) max and anthropometric parameters after 12 weeks without mandatory physical training in naval cadets. The sample was 38 healthy and physically active naval cadets. The measured variables, including VO(2) max and anthropometric parameters, were evaluated through the 12-minute race test (12MRT) and the somatotype. Both variables had a separation of 12 weeks without mandatory physical training. A t-test for related samples was used to evidence changes between the test and post-test; effect size was calculated through Cohens d-test. Distance in 12MRT and VO(2) max showed significant decreases at the end of 12 weeks without mandatory physical training (p < 0.001). Likewise, the tricipital skinfold thickness and the endomorphic component showed significant increases (p < 0.05). 12 weeks without mandatory physical training significantly reduces the VO(2) max in naval cadets. Simultaneously, the same period without physical training increases both the tricipital skinfold thickness and the endomorphic component in this population.

This paper addresses the economic impact of the COVID-19 pandemic by providing timely and accurate information on the impact of the current pandemic on income and poverty to inform the targeting of resources to those most affected and assess the success of current efforts. We construct new measures of the income distribution and poverty with a lag of only a few weeks using high frequency data from the Basic Monthly Current Population Survey (CPS), which collects income information for a large, representative sample of U.S. families. Because the family income data for this project are rarely used, we validate this timely measure of income by comparing historical estimates that rely on these data to estimates from data on income and consumption that have been used much more broadly. Our results indicate that at the start of the pandemic, government policy effectively countered its effects on incomes, leading poverty to fall and low percentiles of income to rise across a range of demographic groups and geographies. Simulations that rely on the detailed CPS data and that closely match total government payments made show that the entire decline in poverty that we find can be accounted for by the rise in government assistance, including unemployment insurance benefits and the Economic Impact Payments. Our simulations further indicate that of those losing employment the vast majority received unemployment insurance, though this was less true early on in the pandemic and receipt was uneven across the states, with some states not reaching a large share of their out of work residents. Updated information on the summary measures presented in this paper, using the latest data available, may be found at povertymeasurement.org.

BACKGROUND Choledochal cyst (CDC) is a rare biliary disorder. Surgical treatment consists of CDC excision and biliary-enteric reconstruction. Recently, some institutions have reported successful CDC excision by using minimally invasive techniques. In this study, we report our experience with the laparoscopic management of CDC, with a focus on key operative maneuvers that enhance the likelihood of successful excision. METHODS Following institutional review board approval, we performed a retrospective review of patients who underwent the laparoscopic excision of CDC and Roux-en-Y hepaticojejunostomy. Between October 2003 and November 2007, we performed laparoscopic CDC excision in 9 patients (8 female and 1 male). Median age was 4 years (range, 8 months to 16 years). There were 7 type I and 2 type IV cysts, according to Todani's classification. Average cyst size was 4.4 cm (range, 1.3-8.5). The procedures were performed by utilizing four or five trochars. RESULTS Six of 9 children presented with preoperative pancreatitis, 1 with abdominal pain, 1 with jaundice, and 1 was found incidentally. Three patients required the conversion to laparotomy due to dense adhesions, secondary to pancreatitis. Six patients underwent successful laparoscopic procedures, 5 had complete cyst excisions, and 1 underwent a proximal excision with distal mucosectomy. Of the 3 patients who required conversion, 2 underwent complete excisions; the other underwent a proximal excision, distal mucosectomy. There were no intraoperative complications. One patient had a postoperative bile leak that required an open hepaticojejunostomy revision. Eight patients had an uneventful recovery. Oral feedings were resumed within an average of 3.4 days (range, 2-9). Average time to discharge was 6.1 days (range, 5-12). Average follow-up time was 18 months (range, 4-48). No further laboratory abnormalities were detected in any of the patients. CONCLUSIONS Laparoscopic resection of CDC and Roux-en-Y hepaticojejunostomy in children is an excellent treatment option. Preoperative pancreatitis may cause increased technical difficulty, necessitating a conversion. Proximal excision with distal mucosectomy

Autologous bone transplantation which is a common treatment method for bone defects needs a large quantity of bone cells. In order to develop new treatments to regenerating bone tissues, this research aimed at identifying the key genes and finding their mechanism in human adipose-derived stem cells (hADSCs) osteogenesis. GSE63754, GSE89330 and GSE72429 were downloaded to perform GO functional and KEGG pathway analyses, construct a competing endogenous RNA (ceRNA) network, construct a PPI network and identify hub genes. The expression level of LMO3 during the osteogenesis of hADSCs was examined by quantitative reverse transcription polymerase chain reaction and western blot. Lentivirus transfection was used to knock down or overexpress LMO3, which enabled us to investigate the effect of LMO3 on osteogenic differentiation of hADSCs. Wortmannin were used to identify the mechanism of the LMO3/PI3K/Akt axis in regulating osteogenic differentiation of hADSCs. Moreover, ectopic bone formation in nude mice was used to investigate the effect of LMO3 on osteogenesis in vivo. In this study, we found the expression of LMO3 was significantly upregulated during the osteogenic differentiation of hADSCs. LMO3 knockdown remarkably suppressed osteogenic differentiation of hADSCs, while LMO3 overexpression promoted osteogenic differentiation of hADSCs both in vitro and in vivo. Moreover, we discovered that the enhancing effect of LMO3 overexpression on osteogenic differentiation was related to the activation of PI3K/Akt signaling pathway. Inhibition of PI3K/Akt signaling pathway with wortmannin effectively blocked the stimulation of osteogenic differentiation induced by LMO3 overexpression. In conclusion, based on transcriptomic analysis, we identified key genes involved in regulating the osteogenic differentiation of hADSCs. In addition, we found that LMO3 might act as a positive modulator of hADSC osteogenic differentiation by mediating PI3K/Akt signaling pathway. Manipulating the expression of LMO3 and its associated pathways might contribute to advances in bone regeneration and tissue engineering.

COVID-19 has had a devastating impact on people worldwide. We conducted an international survey (n = 3646) examining the degree to which people's appraisals and coping activities around the pandemic predicted their health and well-being. We obtained subsamples from 12 countries-Bangladesh, Bulgaria, China, Colombia, India, Israel, the Netherlands, Norway, Peru, Portugal, Turkey and the United States. For each, we assessed appraisals and coping strategies as well as indicators of physical and mental health and well-being. Results indicated that, despite mean-level societal differences in outcomes, the pattern of appraisals and coping strategies predicting health and well-being was consistent across countries. Use of disengagement coping (particularly behavioural disengagement and self-isolation) was associated with relatively negative outcomes. In contrast, optimistic appraisals (particularly of high accommodation-focused coping potential and the ability to meet one's physical needs), use of problem-focused coping strategies (especially problem-solving) and accommodative coping strategies (especially positive reappraisal and self-encouragement) were associated with relatively positive outcomes. Our study highlights the critical importance of considering accommodative coping in stress and coping research. It also provides important information on how people have been dealing with the pandemic, the predictors of well-being under pandemic conditions and the generality of such relations.

BACKGROUND: The COVID-19 pandemic has disrupted vaccination services and raised the risk of a global resurgence of preventable diseases. We assessed the extent of and reasons for missed or delayed vaccinations (hereafter missed) in middle- and high-income countries in the early months of the pandemic. METHODS: Participants were 28,429 adults from 26 middle- and high-income countries. From May to June 2020, participants completed an online survey on missed vaccination. Analyses separated missed childhood and adult vaccination in middle-and high-income countries. RESULTS: Respondents were 28,429 adults from 26 middle- and high-income countries. Overall, 9% of households had missed a vaccine, and 13% were unsure. More households in middle- than high-income countries reported missed childhood vaccination (7.6% vs. 3.0%) and missed adult vaccination (9.6% vs. 3.4%, both p<.05). Correlates of missed childhood vaccination in middle-income countries included COVID-19 risk factors (respiratory and cardiovascular disease), younger age, male sex, employment, distress, larger household size, and more children. In high-income countries, correlates of missed childhood vaccination also included immunodeficiency disorders, but did not include sex or household size. Fewer correlates were associated with missed adult vaccination other than COVID-19 risk factors and distress. Common reasons for missed vaccinations were worry about getting COVID-19 at the vaccination clinic (15%) or when leaving the house (11%). Other reasons included no healthcare provider recommendation, clinic closure, and wanting to save services for others. Interpretation Missed vaccination was common and more prevalent in middle- than high-income countries. Missed vaccination could be mitigated by emphasizing COVID-19 safety measures in vaccination clinics, ensuring free and accessible immunization, and clear healthcare provider recommendations

COVID-19, a disease caused by a new strain of coronavirus (SARS-CoV-2) originating from Wuhan, China, has now spread around the world, triggering a global pandemic, leaving the public eagerly awaiting the development of a specific medicine and vaccine. In response, aggressive efforts are underway around the world to overcome COVID-19. In this study, referencing the data published on the Protein Data Bank (PDB ID: 7BV2) on April 22, we conducted a detailed analysis of the interaction between the complex structures of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and Remdesivir, an antiviral drug, from the quantum chemical perspective based on the fragment molecular orbital (FMO) method. In addition to the hydrogen bonding and intra-strand stacking between complementary strands as seen in normal base pairs, Remdesivir bound to the terminus of an primer-RNA strand was further stabilized by diagonal - stacking with the -1A base of the complementary strand and an additional hydrogen bond with an intra-strand base, due to the effect of chemically modified functional group. Moreover, stable OH/ interaction is also formed with Thr687 of the RdRp. We quantitatively revealed the exhaustive interaction within the complex among Remdesivir, template-primer-RNA, RdRp and co-factors, and published the results in the FMODB database.

The SARS-epidemic of 2002/2003 with worldwide 8.096 cases and 774 fatalities was the first pandemia of the 21(st) century. SARS, the severe acute respiratory syndrome, arose in southern China and spread from Southeast-Asia finally over all five continents. It caused heavy pneumonia with pulmonal failure and enteric involvement in man. The causative agent was a novel coronavirus (SARS-CoV), which was transmitted from bats to small carnivores and from them to man. The mutations of the viral receptor gene thus allowed the infection of man and the transmission from man to man. The SARS-pandemia can therefore be regarded as a model of an emerging disease.

PURPOSE: The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or COVID-19 pandemic first arrived in Nashville, Tennessee, in early March 2020. Soon after, stay-at-home orders were initiated. The purpose of this study is to evaluate the impact of a 7-week lockdown on maxillofacial trauma volume at TriStar Skyline Medical Center, a level II trauma center in Nashville, Tennessee. PATIENTS AND METHODS: The investigator designed a retrospective cohort study and enrolled a sample of patients who presented for evaluation of maxillofacial trauma between March 23 and May 11 in the years 2019 and 2020. The primary predictor variable was evaluation of injures during the 2020 lockdown period or the same control period in 2019. The primary outcome variable was injury volume. Additional variables including demographic information, etiology, anatomic location, and initial disposition were evaluated. Descriptive and bivariate statistics were computed, with statistical significance set at P < .05. RESULTS: The study sample showed a 35.6% reduction in patients seen during the 2020 lockdown (n = 38) compared with 2019 (n = 59, P = .15). The proportion of male to female trauma patients increased during the lockdown period from 6.6:1 (n = 33 male, n = 5 female) in 2020 compared with 2.3:1 (n = 41 male, n = 18 female) in 2019 (P = .049). The number of assaults decreased by 65.2% (P = .22). The percentage of patients seen on an outpatient basis decreased from 27.1% (n = 16) to 5.3% (n = 2, P = .007) during the lockdown period. CONCLUSIONS: The initial 7-week lockdown during the COVID-19 pandemic was associated with a decrease in patients with maxillofacial trauma. The effect of the stay-at-home orders with resultant social distancing, has shown a decrease in maxillofacial trauma due to interpersonal violence.

Severe influenza is characterized by a cytokine storm, and the influenza virusCcytokineCtrypsin cycle is one of the important mechanisms of viral multiplication and multiple organ failure. The aim of this study was to define the key cytokine(s) responsible for trypsin upregulation. Mice were infected with influenza virus strain A/Puerto Rico/8/34 (H1N1) or treated individually or with a combination of interleukin-1, interleukin-6, and tumor necrosis factor . The levels of these cytokines and trypsin in the lungs were monitored. The neutralizing effects of anti-IL-1 antibodies on cytokine and trypsin expression in human A549 cells and lung inflammation in the infected mice were examined. Infection induced interleukin-1, interleukin-6, tumor necrosis factor , and ectopic trypsin in mouse lungs in a dose- and time-dependent manner. Intraperitoneal administration of interleukin-1 combined with other cytokines tended to upregulate trypsin and cytokine expression in the lungs, but the combination without interleukin-1 did not induce trypsin. In contrast, incubation of A549 cells with interleukin-1 alone induced both cytokines and trypsin, and anti-interleukin-1 antibody treatment abrogated these effects. Administration of the antibody in the infected mice reduced lung inflammation area. These findings suggest that IL-1 plays a key role in trypsin upregulation and has a pathological role in multiple organ failure.