ABSTRACT
Dysregulated IL-1ß and IL-6 responses have been implicated in the pathogenesis of severe Coronavirus Disease 2019 (COVID-19). Innovative approaches for evaluating the biological activity of these cytokines in vivo are urgently needed to complement clinical trials of therapeutic targeting of IL-1ß and IL-6 in COVID-19. We show that the expression of IL-1ß or IL-6 inducible transcriptional signatures (modules) reflects the bioactivity of these cytokines in immunopathology modelled by juvenile idiopathic arthritis (JIA) and rheumatoid arthritis. In COVID-19, elevated expression of IL-1ß and IL-6 response modules, but not the cytokine transcripts themselves, is a feature of infection in the nasopharynx and blood but is not associated with severity of COVID-19 disease, length of stay, or mortality. We propose that IL-1ß and IL-6 transcriptional response modules provide a dynamic readout of functional cytokine activity in vivo, aiding quantification of the biological effects of immunomodulatory therapies in COVID-19.
ABSTRACT
Viruses deploy genetically encoded strategies to coopt host machinery and support viral replicative cycles. Here, we use protein structure similarity to scan for molecular mimicry, manifested by structural similarity between viral and endogenous host proteins, across thousands of cataloged viruses and hosts spanning broad ecological niches and taxonomic range, including bacteria, plants and fungi, invertebrates, and vertebrates. This survey identified over 6,000,000 instances of structural mimicry; more than 70% of viral mimics cannot be discerned through protein sequence alone. We demonstrate that the manner and degree to which viruses exploit molecular mimicry varies by genome size and nucleic acid type and identify 158 human proteins that are mimicked by coronaviruses, providing clues about cellular processes driving pathogenesis. Our observations point to molecular mimicry as a pervasive strategy employed by viruses and indicate that the protein structure space used by a given virus is dictated by the host proteome. A record of this paper's transparent peer review process is included in the Supplemental Information.
Subject(s)
Coronavirus/genetics , Host-Pathogen Interactions/genetics , Molecular Mimicry/genetics , Viral Proteins/genetics , Virome/genetics , Virus Diseases/genetics , Animals , Coronavirus/chemistry , Culicidae , Databases, Genetic , Humans , Protein Structure, Secondary , Viral Proteins/chemistry , Virus Diseases/epidemiology , Viruses/chemistry , Viruses/geneticsABSTRACT
Understanding the pathophysiology of SARS-CoV-2 infection is critical for therapeutic and public health strategies. Viral-host interactions can guide discovery of disease regulators, and protein structure function analysis points to several immune pathways, including complement and coagulation, as targets of coronaviruses. To determine whether conditions associated with dysregulated complement or coagulation systems impact disease, we performed a retrospective observational study and found that history of macular degeneration (a proxy for complement-activation disorders) and history of coagulation disorders (thrombocytopenia, thrombosis and hemorrhage) are risk factors for SARS-CoV-2-associated morbidity and mortality-effects that are independent of age, sex or history of smoking. Transcriptional profiling of nasopharyngeal swabs demonstrated that in addition to type-I interferon and interleukin-6-dependent inflammatory responses, infection results in robust engagement of the complement and coagulation pathways. Finally, in a candidate-driven genetic association study of severe SARS-CoV-2 disease, we identified putative complement and coagulation-associated loci including missense, eQTL and sQTL variants of critical complement and coagulation regulators. In addition to providing evidence that complement function modulates SARS-CoV-2 infection outcome, the data point to putative transcriptional genetic markers of susceptibility. The results highlight the value of using a multimodal analytical approach to reveal determinants and predictors of immunity, susceptibility and clinical outcome associated with infection.