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.
Funding Information: Supported from the Medical university of Graz and the Austrian Science fund (FWF, DK-MOLIN W1241). The design of the BSL-3 laboratory used for autopsy of covid-19 cases was supported by the EU-funded program "European Research Infrastructure for Highly Pathogenic Agents" (ERINHA-Advance, Grant agreement 824061).
Conflict of Interests: All authors declare no competing interests.
Ethical Approval: The study was approved by the ethics committee of the Medical University of Graz (EK- number: 32–362 ex 19/20).
Zacharias, Martin and Kashofer, Karl and Wurm, Philipp and Regitnig, Peter and Schütte, Moritz and Neger, Margit and Ehmann, Sandra and Marsh, Leigh M. and Kwapiszewska, Grazyna and Loibner, Martina and Birnhuber, Anna and Leitner, Eva and Thüringer, Andrea and Winter, Elke and Sauer, Stefan and Pollheimer, Marion J. and Vagena, Fotini R. and Lackner, Carolin and Jelusic, Barbara and Ogilvie, Lesley and Durdevic, Marija and Timmermann, Bernd and Lehrach, Hans and Zatloukal, Kurt and Gorkiewicz, Gregor, Host and Microbiome Features of Secondary Infections in Lethal COVID-19. Available at SSRN: https://ssrn.com/abstract=4052015 or http://dx.doi.org/10.2139/ssrn.4052015
This version of the paper has not been formally peer reviewed.
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