ABSTRACT
BACKGROUND: Patients with Coronavirus Disease 2019 (COVID-19) may present high risk features during hospitalization, including cardiovascular manifestations. However, less is known about the factors that may further increase the risk of death in these patients. METHODS: We included patients with COVID-19 and high risk features according to clinical and/or laboratory criteria at 21 sites in Brazil from June 10th to October 23rd of 2020. All variables were collected until hospital discharge or in-hospital death. RESULTS: A total of 2546 participants were included (mean age 65 years; 60.3% male). Overall, 70.8% were admitted to intensive care units and 54.2% had elevated troponin levels. In-hospital mortality was 41.7%. An interaction among sex, age and mortality was found (p = 0.007). Younger women presented higher rates of death than men (30.0% vs 22.9%), while older men presented higher rates of death than women (57.6% vs 49.2%). The strongest factors associated with in-hospital mortality were need for mechanical ventilation (odds ratio [OR] 8.2, 95% confidence interval [CI] 5.4-12.7), elevated C-reactive protein (OR 2.3, 95% CI 1.7-2.9), cancer (OR 1.8, 95 %CI 1.2-2.9), and elevated troponin levels (OR 1.8, 95% CI 1.4-2.3). A risk score was developed for risk assessment of in-hospital mortality. CONCLUSIONS: This cohort showed that patients with COVID-19 and high risk features have an elevated rate of in-hospital mortality with differences according to age and sex. These results highlight unique aspects of this population and might help identifying patients who may benefit from more careful initial surveillance and potential subsequent interventional therapies.
ABSTRACT
The first reported receptor for SARS-CoV-2 on host cells was the angiotensin-converting enzyme 2 (ACE2). However, the viral spike protein also has an RGD motif, suggesting that cell surface integrins may be co-receptors. We examined the sequences of ACE2 and integrins with the Eukaryotic Linear Motif (ELM) resource and identified candidate short linear motifs (SLiMs) in their short, unstructured, cytosolic tails with potential roles in endocytosis, membrane dynamics, autophagy, cytoskeleton, and cell signaling. These SLiM candidates are highly conserved in vertebrates and may interact with the µ2 subunit of the endocytosis-associated AP2 adaptor complex, as well as with various protein domains (namely, I-BAR, LC3, PDZ, PTB, and SH2) found in human signaling and regulatory proteins. Several motifs overlap in the tail sequences, suggesting that they may act as molecular switches, such as in response to tyrosine phosphorylation status. Candidate LC3-interacting region (LIR) motifs are present in the tails of integrin ß3 and ACE2, suggesting that these proteins could directly recruit autophagy components. Our findings identify several molecular links and testable hypotheses that could uncover mechanisms of SARS-CoV-2 attachment, entry, and replication against which it may be possible to develop host-directed therapies that dampen viral infection and disease progression. Several of these SLiMs have now been validated to mediate the predicted peptide interactions.