Pesquisador responsável: Otávio Cabral Marques (ICB-USP)
Abstract: The coronavirus disease 2019 (COVID-19) fatality rate varies in different patient groups. However, the underlying mechanisms that explain this variation are poorly understood. Here, we reanalyzed and integrated public RNAseq datasets of nasopharyngeal swabs and peripheral blood leukocytes from patients with SARS-CoV-2, comparing transcription patterns according to sex, age, and viral load. We found that female and young patients infected by SARS-CoV-2 exhibited a similar transcriptomic pattern with a larger number of total (up- and downregulated) differentially expressed genes (DEGs) compared to males and elderly patients. The transcriptional analysis showed a sex-specific profile with a higher transcriptional modulation of immune response-associated genes in female and young subjects against SARS-CoV-2. The functional clustering was characterized by a highly correlated interferome network of cytokine/chemokine- and neutrophil-associated genes that were enriched both in nasopharyngeal cells and peripheral blood of COVID-19 patients. Females exhibited reduced transcriptional levels of key pro-inflammatory/neutrophil-related genes such as CXCL8 receptors (CXCR1/CXCR2), IL-1β, S100A9, ITGAM, and DBNL compared to males, which correlate with a protective gene expression profile against inflammatory damage. Our data indicate specific immune-regulatory pathways associated with sex and age of patients infected with SARS-CoV-2. These results point out therapeutic targets to reduce morbidity and mortality of COVID-19.
COVID-19 and Nutritional Status: The Missing Link?
Pesquisadora responsável: Marilia Seelaender (ICB-USP)
Abstract: Coronavirus disease 2019 (COVID-19) is an emerging disease that has reached pandemic status by rapidly spreading worldwide. Elderly individuals and patients with comorbidities such as obesity, diabetes, and hypertension show a higher risk of hospitalization, severe disease, and mortality by acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These patients frequently show exacerbated secretion of proinflammatory cytokines associated with an overreaction of the immune system, the so-called cytokine storm. Host nutritional status plays a pivotal role in the outcome of a variety of different infectious diseases. It is known that the immune system is highly affected by malnutrition, leading to decreased immune responses with consequent augmented risk of infection and disease severity. Body composition, especially low lean mass and high adiposity, has consistently been linked to worsened prognosis in many different diseases. In this review, evidence concerning the impact of nutritional status on viral infection outcomes is discussed.
Pesquisadores responsáveis: Jean Pierre Schatzmann Peron (ICB-USP) e Helder Nakaya (FCF-USP)
Abstract: The pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has resulted in several thousand deaths worldwide in just a few months. Patients who died from Coronavirus disease 2019 (COVID-19) often had comorbidities, such as hypertension, diabetes, and chronic obstructive lung disease. The angiotensin-converting enzyme 2 (ACE2) was identified as a crucial factor that facilitates SARS-CoV2 to bind and enter host cells. To date, no study has assessed the ACE2 expression in the lungs of patients with these diseases. Here, we analyzed over 700 lung transcriptome samples of patients with comorbidities associated with severe COVID-19 and found that ACE2 was highly expressed in these patients, compared to control individuals. This finding suggests that patients with such comorbidities may have higher chances of developing severe COVID-19. We also found other genes, such as RAB1A, that can be important for SARS-CoV-2 infection in the lung. Correlation and network analyses revealed many potential regulators of ACE2 in the human lung, including genes related to histone modifications, such as HAT1, HDAC2, and KDM5B. In fact, epigenetic marks found in ACE2 locus were compatible to with those promoted by KDM5B. Our systems biology approach offers a possible explanation for increase of COVID-19 severity in patients with certain comorbidities.
Pesquisador responsável: Jean Pierre Schatzmann Peron (ICB-USP)
Abstract: The world is currently facing a serious SARS-CoV-2 infection pandemic. </mac_aq>This virus is a new isolate of coronavirus, and the current infection crisis has surpassed the SARS and MERS epidemics</mac_aq> that occurred in 2002 and 2013, respectively. SARS-CoV-2 has currently infected more than 142,000 people, causing </mac_aq>5,000 deaths and spreading across more than 130 </mac_aq>countries worldwide. The spreading capacity of the virus clearly demonstrates the potential threat </mac_aq>of respiratory viruses to human health, thereby reiterating to the governments around the world that preventive </mac_aq>health policies and scientific research are pivotal to overcoming the crisis. Coronavirus disease (COVID-19) causes flu-like symptoms in most cases. However, approximately 15% of the patients need hospitalization, and 5% require assisted ventilation, depending on the cohorts studied. What is intriguing, however, is the higher susceptibility of the elderly, especially individuals who are older than 60 years of age, and have comorbidities, including hypertension, diabetes, and heart disease. In fact, the death rate in this group may be up to 10-12%. Interestingly, children are somehow less susceptible and are not considered as a risk group.
Therefore, in this review, we discuss some possible molecular and cellular mechanisms by virtue of which the elderly subjects may be more susceptible to severe COVID-19. Toward this, we raise two main </mac_aq>points, i) increased ACE-2 expression in pulmonary and heart tissues in users of chronic angiotensin 1 </mac_aq>receptor (AT1R) blockers; and ii) antibody-dependent enhancement (ADE) after previous exposure to other circulating coronaviruses. We believe that these points are pivotal for a better understanding of the pathogenesis of severe COVID-19, and must be carefully addressed by physicians and scientists in the field.
Neurological Complications of Pandemic COVID-19: What Have We Got So Far?
Pesquisador responsável: Jean Pierre Schatzmann Peron (ICB-USP)
Abstract: The recently emerged coronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS- CoV-2) is the newest threat to human health. It has already infected more than half a million people worldwide, leading to a lot of deaths. Although it causes mild flu-like disease in most patients, lethality may increase to more than 20% in elderly subjects, especially those with comorbidities, like hypertension, diabetes or lung and cardiac disease, and the mechanisms are still elusive. Common symptoms at the onset of illness are fever, cough, myalgia or fatigue, headache, and diarrhea or constipation. Interestingly, respiratory viruses have also placed themselves as relevant agents for CNS pathologies. Here we discuss several CNS related features, referred by several patients, especially at the beginning of the disease. Thus, we also discuss the possibility by which SARS-CoV-2 may affect the olfactive system of patients, either directly or indirectly.
Diacerein: A potential multi-target therapeutic drug for COVID-19
Pesquisadores responsáveis: Pedro Gonçalves de Oliveira (FM-USP), Lara Terminic (FM-USP), Edison Luiz Durigon (ICB-USP), Ana Paula Lepique (ICB-USP), Andrei C Sposito (Unicamp), Enrique Boccardo (ICB-USP)
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 19 (COVID-19), was declared pandemic by the World Health Organization in March 2020. SARS-CoV-2 binds its host cell receptor, angiotensin-converting enzyme 2 (ACE2), through the viral spike (S) protein. The mortality related to severe acute respiratory distress syndrome (ARDS) and multi-organ failure in COVID-19 patients has been suggested to be connected with cytokine storm syndrome (CSS), an excessive immune response that severely damages healthy lung tissue. In addition, cardiac symptoms, including fulminant myocarditis, are frequent in patients in a severe state of illness. Diacerein (DAR) is an anthraquinone derivative drug whose active metabolite is rhein. Different studies have shown that this compound inhibits the IL-1, IL-2, IL-6, IL-8, IL-12, IL-18, TNF-α, NF-κB and NALP3 inflammasome pathways. The antiviral activity of rhein has also been documented. This metabolite prevents hepatitis B virus (HBV) replication and influenza A virus (IAV) adsorption and replication through mechanisms involving regulation of oxidative stress and alterations of the TLR4, Akt, MAPK, and NF-κB signalling pathways. Importantly, rhein inhibits the interaction between the SARS-CoV S protein and ACE2 in a dose-dependent manner, suggesting rhein as a potential therapeutic agent for the treatment of SARS-CoV infection. Based on these findings, we hypothesize that DAR is a multi-target drug useful for COVID-19 treatment. This anthraquinone may control hyperinflammatory conditions by multi-faceted cytokine inhibition and by reducing viral infection.
Pesquisador responsável: Edison Luiz Durigon (ICB-USP)
