Host and microbiome features of secondary infections in lethal covid-19

ABSTRACT

Secondary infections contribute significantly to covid-19 mortality but host and microbial factors driving this sequel remain poorly understood. We performed an autopsy study of 20 covid-19 cases and 14 controls from the first pandemic wave. Autopsies combined with microbial cultivation and deep RNA sequencing (RNAseq) allowed us to define major organ pathologies and specify secondary infections. Lethal covid-19 segregated into two main death causes separating cases with either dominant diffuse alveolar damage (DAD) or secondary infections of lungs. Lung microbiome changes were profound in covid-19 showing a reduced biodiversity and increased presence of prototypical bacterial and fungal pathogens in cases with secondary infections. Deep RNAseq of lung tissues distinctly mirrored death causes and cellular deconvolution stratified DAD cases into subgroups with different cellular compositions. Myeloid cells, including macrophages, and complement C1q activation were found to be strong stratifying factors suggesting a pathophysiological link possibly leading to tolerance in DAD subgroups. Moreover, several signs of immune-impairment were evident in covid-19 lungs including strong induction of inhibitory immune-checkpoints. Thus, our study highlights profound alterations of the local immunity in covid-19, wherein immune-impairment leads to reduced antimicrobial defense favoring the development of secondary infections on top of SARS-CoV-2 infection.