Goss, C. W. | Search bioRxiv

bioRxiv2021

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection.

Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and, if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers. We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza, and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV). We demonstrate that circulating markers of complement activation (i.e., sC5b-9) are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., Ang2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials. SUMMMARYComplement has been implicated in COVID-19. However, whether this is distinctive of COVID-19 remains unanswered. Ma et al report increased complement activation in COVID-19 compared to influenza and non-COVID respiratory failure, and demonstrate alternative pathway activation as a key marker of multiorgan failure and death.

immunology↗

bioRxiv2020

Contribution of noncanonical antigens to virulence and adaptive immunity in human infection with enterotoxigenic E. coli

Enterotoxigenic E. coli (ETEC) contribute significantly to the substantial burden of infectious diarrhea among children living in low and middle income countries. In the absence of a vaccine for ETEC, children succumb to acute dehydration as well as non-diarrheal sequelae related to these infections including malnutrition. The considerable diversity of ETEC genomes has complicated canonical vaccine development approaches focused on a subset of antigens known as colonization factors (CFs). To identify additional conserved immunogens, we mined genomic sequences of 89 ETEC isolates, bioinformatically selected potential surface-exposed pathovar-specific antigens conserved in more than 40% of the genomes (n=118), and assembled the representative proteins onto microarrays, complemented with known or putative colonization factor subunit molecules (n=52), and toxin subunits to interrogate samples from individuals with acute symptomatic ETEC infections. Surprisingly, in this open-aperture approach, we found that immune responses were largely constrained to a small number of antigens including individual colonization factor antigens and EtpA, an extracellular adhesin. In a Bangladeshi cohort of naturally infected children < 2 years of age, both EtpA and a second noncanonical antigen, EatA, elicited significant serologic responses that were associated with protection from symptomatic illness. In addition, children infected with ETEC isolates bearing either etpA or eatA genes were significantly more likely to develop symptomatic disease. These studies support a role for more recently discovered noncanonical antigens in virulence and the development of adaptive immune responses during ETEC infections, findings that may inform vaccine design efforts to complement existing approaches.

microbiology↗