Estimating disease risk using the microbiome: the Microbial Risk Score (preprint)

Our microbiome has profound impacts on our health, and technological advances have allowed for ever-growing pools of data from microbiome-wide studies. This means that our microbiome could be used to estimate disease risk, but the nature of the data makes the endeavor difficult. Similar issues with using genetics to predict disease risk led to the development of the polygenic risk score. Motivated by the success of that framework, a team of researchers recently developed the microbial risk score (MRS). MRS summarizes the complex microbial profile by first identifying a sub- community consisting of disease-associated microbial taxa and then integrating those microbial taxa into a continuous score based on the alpha diversity of the identified sub-community. MRS can be easily integrated with the other risk scores built upon metatranscriptomics, host genetics, or host transcriptomics, making it useful for 'multi-omics' approaches as well. The researchers validated this new algorithm on three cohort datasets that included data on COVID-19, several gastrointestinal diseases, and type 1 diabetes. While MRS needs to be tested in more populations, it showed promise in this study as a tool to predict disease and could also be applied to microbial ecology research and exploring the microbiome’s clinical potential. 

ACE2-containing defensosomes serve as decoys to inhibit SARS-CoV-2 infection (preprint)

Extracellular vesicles of endosomal origin, exosomes, mediate intercellular communication by transporting substrates with a variety of functions related to tissue homeostasis and disease. Their diagnostic and therapeutic potential has been recognized for diseases such as cancer in which signaling defects are prominent. However, it is unclear to what extent exosomes and their cargo inform the progression of infectious diseases. We recently defined a subset of exosomes termed defensosomes that are mobilized during bacterial infection in a manner dependent on autophagy proteins. Through incorporating protein receptors on their surface, defensosomes mediated host defense by binding and inhibiting pore-forming toxins secreted by bacterial pathogens. Given this capacity to serve as decoys that interfere with surface protein interactions, we investigated the role of defensosomes during infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19. Consistent with a protective function, exosomes containing high levels of the viral receptor ACE2 in bronchioalveolar lavage fluid from critically ill COVID-19 patients was associated with reduced ICU and hospitalization times. We found ACE2+ exosomes were induced by SARS-CoV-2 infection and activation of viral sensors in cell culture, which required the autophagy protein ATG16L1, defining these as defensosomes. We further demonstrate that ACE2+ defensosomes directly bind and block viral entry. These findings suggest that defensosomes may contribute to the antiviral response against SARS-CoV-2 and expand our knowledge on the regulation and effects of extracellular vesicles during infection.

Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome (preprint)

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal (Mycoplasma salivarium), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.