SARS-CoV-2 mediated dysregulation in cell signaling events drives the severity of COVID-19.

A balance in immune response against an unfamiliar pathogen is crucial to eliminate the infection. A cascade of cell signaling events is immediately activated upon sensing the presence of SARS-CoV-2 by cellular toll like receptors in a natural host response manner against the invading virus. The ultimate aim of such innate immune signaling pathways is to provide a required level of protection to our bodies by interfering with the invader. However, if there is any loss in such balance, an impairment in immune system emerge that fails to control the regulated transcription and translation of signaling components. Consequently, excessive level of proinflammatory mediators release into the circulatory systems that ultimately cause "cytokine storm" and COVID-19 pathological syndromes. The limited production of interferons (IFNs), while excessive yield of pro-inflammatory cytokines followed by SARS-CoV-2 infection suggests an abnormal cell signaling event and explains the reasons of increased immunopathology and severity in COVID-19.

ATF1 Restricts Human Herpesvirus 6A Replication via Beta Interferon Induction.

The stimulus-induced cAMP response element (CRE)-binding protein (CREB) family of transcription factors bind to CREs to regulate diverse cellular responses, including proliferation, survival, and differentiation. Human herpesvirus 6A (HHV-6A), which belongs to the Betaherpesvirinae subfamily, is a lymphotropic herpesvirus frequently found in patients with neuroinflammatory diseases. Previous reports implicated the importance of CREs in the HHV-6A life cycle, although the effects of the binding of transcription factors to CREs in viral replication have not been fully elucidated. In this study, we analyzed the role of the CREB family of transcription factors during HHV-6A replication. We found that HHV-6A infection enhanced phosphorylation of the CREB family members CREB1 and activating transcription factor 1 (ATF1). Knockout (KO) of CREB1 or ATF1 enhanced viral gene expression and viral replication. The increase in viral yields in supernatants from ATF1-KO cells was greater than that in supernatants from CREB1-KO cells. Transcriptome sequencing (RNA-seq) analysis showed that sensors of the innate immune system were downregulated in ATF1-KO cells, and mRNAs of beta interferon (IFN-ß) and IFN-regulated genes were reduced in these cells infected with HHV-6A. IFN-ß treatment of ATF1-KO cells reduced progeny viral yields significantly, suggesting that the enhancement of viral replication was caused by a reduction of IFN-ß. Taken together, our results suggest that ATF1 is activated during HHV-6A infection and restricts viral replication via IFN-ß induction. IMPORTANCE Human herpesvirus 6A (HHV-6A) is a ubiquitous herpesvirus implicated in Alzheimer's disease, although its role in its pathogenesis has not been confirmed. Here, we showed that the transcription factor ATF1 restricts HHV-6A replication, mediated by IFN-ß induction. Our study provides new insights into the role of ATF1 in innate viral immunity and reveals the importance of IFN-ß for regulation of HHV-6A replication, which possibly impairs HHV-6A pathogenesis.

NLRP3 inflammasome activation in COVID-19: an interlink between risk factors and disease severity.

NLRP3 inflammasome is a critical immune component that plays a crucial role in mounting innate immune responses. The deleterious effects of inflammasome activation have been correlated with the COVID-19 disease severity. In the presence of several underlying disorders, the immune components of our bodies are dysregulated, creating conditions that could adversely affect us other than providing a required level of protection. In this review, we focused on the occurrence of NLRP3 inflammasome activation in response to SARS-COV-2 infection, dysregulation of NLRP3 activation events in the presence of several comorbidities, the contribution of activated NLRP3 inflammasome to the severity of COVID-19, and available therapeutics for the treatment of such NLRP3 inflammasome related diseases based on current knowledge. The primed state of immunity in individuals with comorbidities (risk factors) could accelerate many deaths and severe COVID-19 cases via activation of NLRP3 inflammasome and the release of downstream inflammatory molecules. Therefore, a detailed understanding of the host-pathogen interaction is needed to clarify the pathophysiology and select a potential therapeutic approach.

Human Herpesvirus 6A Tegument Protein U14 Induces NF-κB Signaling by Interacting with p65.

Viral infection induces host cells to mount a variety of immune responses, which may either limit viral propagation or create conditions conducive to virus replication in some instances. In this regard, activation of the NF-κB transcription factor is known to modulate virus replication. Human herpesvirus 6A (HHV-6A), which belongs to the Betaherpesvirinae subfamily, is frequently found in patients with neuroinflammatory diseases, although its role in disease pathogenesis has not been elucidated. In this study, we found that the HHV-6A-encoded U14 protein activates NF-κB signaling following interaction with the NF-κB complex protein, p65. Through induction of nuclear translocation of p65, U14 increases the expression of interleukin-6 (IL-6), IL-8, and monocyte chemoattractant protein 1 transcripts. We also demonstrated that activation of NF-κB signaling is important for HHV-6A replication, since inhibition of this pathway reduced virus protein accumulation and viral genome copy number. Taken together, our results suggest that HHV-6A infection activates the NF-κB pathway and promotes viral gene expression via late gene products, including U14. IMPORTANCE Human herpesvirus 6A (HHV-6A) is frequently found in patients with neuro-inflammation, although its role in the pathogenesis of this disease has not been elucidated. Most viral infections activate the NF-κB pathway, which causes the transactivation of various genes, including those encoding proinflammatory cytokines. Our results indicate that HHV-6A U14 activates the NF-κB pathway, leading to upregulation of proinflammatory cytokines. We also found that activation of the NF-κB transcription factor is important for efficient viral replication. This study provides new insight into HHV-6A U14 function in host cell signaling and identifies potential cellular targets involved in HHV-6A pathogenesis and replication.

Evaluation of knowledge, awareness and attitudes towards breast cancer risk factors and early detection among females in Bangladesh: A hospital based cross-sectional study.

BACKGROUND: Breast cancer (BCa) is a leading cause of mortality among women in Bangladesh. Many young women in Bangladesh have poor knowledge about breast cancer screening, including risk factors, warning signs/symptoms, diagnosis and early detection. We investigated awareness about breast cancer risk factors as a screening tool among women at the Sheikh Hasina Medical College (SHMC) of Tangail district in Bangladesh. METHODS: A cross sectional survey was conducted to collect data via a structured questionnaire from SHMC during the period of February to December 2019. A total of 1,007 participants (aged 33.47 (±12.37 years)) was considered for data analysis. RESULTS: Of the 1,007 women, about 50% were knowledgeable about the risk factors. Pain in the breast was identified as the most commonly warning sign/symptom of breast cancer. Only 32.2% of respondents knew at least one breast cancer screening method. The mean knowledge was scored 3.43 ± 2.25 out of a total possible score of 8. Awareness of BCa was associated with residence, family history of breast cancer, marital, literacy and socio-economic status (p <0.05). Only 14.7% of women who knew about BSE said they were conducting regular breast self-examination. Unmarried women (aOR: 2.971; 95% CI: 1.108-7.968) were more likely to have performed BSE compared to married women (p <0.05). CONCLUSION: Although most participants were aware of breast cancer; knowledge about risk factors, warning signs/symptoms, early diagnosis and detection was relatively poor. Knowledge about performing BSE was particularly low. This highlights the importance of increasing awareness about breast cancer risk factors and early detection among young women in Bangladesh.

Knowledge, awareness and preventive practices of dengue outbreak in Bangladesh: A countrywide study.

BACKGROUND: Dengue, the mosquito borne disease has become a growing public health threat in Bangladesh due to its gradual increasing morbidity and mortality since 2000. In 2019, the country witnessed the worst ever dengue outbreak. The present study was conducted to characterize the socio-economic factors and knowledge, attitude and practice (KAP) status towards dengue among the people of Bangladesh. METHOD: A cross-sectional study was conducted with 1,010 randomly selected respondents from nine different administrative regions of Bangladesh between July and November 2019. A structured questionnaire was used covering socio-demographic characteristics of the participants including their knowledge, awareness, treatment and practices regarding dengue fever. Factors associated with the knowledge and awareness of dengue were investigated separately, using multivariable logistic regression. RESULTS: Although majority (93.8%) of the respondents had heard about dengue, however, they had still misconceptions about Aedes breeding habitat. Around half of the study population (45.7%) had mistaken belief that Aedes can breed in dirty water and 43.1% knew that Aedes mosquito usually bites around sunrise and sunset. Fever indication was found in 36.6% of people which is the most common symptom of dengue. Among the socio-demographic variables, the level of education of the respondents was identified as an independent predictor for both knowledge (p<0.05) and awareness (p<0.05) of dengue. The preventive practice level was moderately less than the knowledge level though there was a significant association (p<0.05) existed between knowledge and preventive practices. Our study noted that TV/Radio is an effective predominant source of information about dengue fever. CONCLUSION: As dengue is emerging in Bangladesh, there is an urgent need to increase health promotion activities through campaigns for eliminating the misconception and considerable knowledge gaps about dengue.

Seroepidemiological Survey of the Antibody for Severe Acute Respiratory Syndrome Coronavirus 2 with Neutralizing Activity at Hospitals: A Cross-sectional Study in Hyogo Prefecture, Japan.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic is spreading rapidly all over the world. The Japanese government lifted the state of emergency, announced in April 2020, on May 25, but there are still sporadic clusters. Asymptomatic patients who can transmit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause some of these clusters. It is thus urgent to investigate the seroprevalence of antibodies against SARS-CoV-2 and their neutralizing activity. We conducted a cross-sectional study of >10,000 samples at hospitals in Hyogo Prefecture, Japan. METHODS: Between August 6 and October 1, 2020, we collected samples of residual blood from the patients who visited or were admitted to five hospitals and a foundation in Hyogo. We tested the samples for antibodies against SARS-CoV-2 by electrochemiluminescence immunoassay (ECLIA) and chemiluminescent enzyme immunoassay (CLEIA). Sera that were positive by ECLIA or CLEIA were analyzed by an immunochromatographic (IC) test and neutralizing activity assay. RESULTS: We tested 10,377 samples from patients aged between 0 and 99 years old; 27 cases (0.26%) were positive on the ECLIA, and 51 cases (0.49%) were positive on CLEIA. In the 14 cases that tested positive on both ECLIA and CLEIA, the positive rates on the IC test and for neutralizing activity were high (85% and 92%, respectively). In 50 cases (0.48%) that were positive by either ECLIA or CLEIA, the corresponding rates were low (20% and 6%, respectively). The positive rate of neutralizing antibody was 0.15%. CONCLUSIONS: These results indicate that most Hyogo Prefecture residents still do not have antibodies and should avoid the risk of incurring a SARS-CoV-2 infection. Two or more antibody tests should be required for seroepidemiological studies of the antibody for SARS-CoV-2, and a neutralizing activity assay is also essential.

Effects of misinformation on COVID-19 individual responses and recommendations for resilience of disastrous consequences of misinformation.

The proliferation of misinformation on social media platforms is faster than the spread of Corona Virus Diseases (COVID-19) and it can generate hefty deleterious consequences on health amid a disaster like COVID-19. Drawing upon research on the stimulus-response theory (hypodermic needle theory) and the resilience theory, this study tested a conceptual framework considering general misinformation belief, conspiracy belief, and religious misinformation belief as the stimulus; and credibility evaluations as resilience strategy; and their effects on COVID-19 individual responses. Using a self-administered online survey during the COVID-19 pandemic, the study obtained 483 useable responses and after test, finds that all-inclusive, the propagation of misinformation on social media undermines the COVID-19 individual responses. Particularly, credibility evaluation of misinformation strongly predicts the COVID-19 individual responses with positive influences and religious misinformation beliefs as well as conspiracy beliefs and general misinformation beliefs come next and influence negatively. The findings and general recommendations will help the public, in general, to be cautious about misinformation, and the respective authority of a country, in particular, for initiating proper safety measures about disastrous misinformation to protect the public health from being exploited.