Circulating acetylated polyamines correlate with Covid-19 severity in cancer patients

Abstract

Cancer patients are particularly susceptible to the development of severe Covid-19, prompting us to investigate the serum metabolome of 204 cancer patients enrolled in the ONCOVID trial. We previously described that the immunosuppressive tryptophan/kynurenine metabolite anthranilic acid correlates with poor prognosis in non-cancer patients. In cancer patients, we observed an elevation of anthranilic acid at baseline (without Covid-19 diagnosis) and no further increase with mild or severe Covid-19. We found that, in cancer patients, Covid-19 severity was associated with the depletion of two bacterial metabolites, indole-3-proprionate and 3-phenylproprionate, that both positively correlated with the levels of several inflammatory cytokines. Most importantly, we observed that the levels of acetylated polyamines (in particular N 1 -acetylspermidine, N 1 ,N 8 -diacetylspermidine and N 1 ,N 12 -diacetylspermine), alone or in aggregate, were elevated in severe Covid-19 cancer patients requiring hospitalization as compared to uninfected cancer patients or cancer patients with mild Covid-19. N 1 -acetylspermidine and N 1 ,N 8 -diacetylspermidine were also increased in patients exhibiting prolonged viral shedding (>40 days). An abundant literature indicates that such acetylated polyamines increase in the serum from patients with cancer, cardiovascular disease or neurodegeneration, associated with poor prognosis. Our present work supports the contention that acetylated polyamines are associated with severe Covid-19, both in the general population and in patients with malignant disease. Severe Covid-19 is characterized by a specific metabolomic signature suggestive of the overactivation of spermine/spermidine N 1 -acetyl transferase-1 (SAT1), which catalyzes the first step of polyamine catabolism.

Diagnostic, Prognostic and Mechanistic Biomarkers of COVID-19 Identified by Mass Spectrometric Metabolomics

“…The clinical definition of health, disease and disease stages is amongst the features that affect metabolomics workflow ( Figure 1 ) [ 22 ]. Multiple studies have explored the COVID-19 metabolome based on a variety of criteria indicating disease progression, such as the severity of pathology (i.e., mild versus severe), outcome (i.e., discharge versus decease), risk factors for severe disease (i.e., comorbidities and cancer), longitudinal assessments of individuals with SARS-CoV-2 infection (i.e., from asymptomatic infection to symptomatic disease, resolution or death), and different types of treatment (e.g., ambulatory versus hospitalization) [ 35 , 36 , 37 , 38 , 39 , 40 ]. These criteria are so heterogeneous as to compromise comparisons among studies.…”

“…In both targeted and non-targeted metabolomics, different methods of chromatography are coupled to an array of mass spectrometers. Typical combinations are liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), gas chromatography–mass spectrometry (GC-MS), and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), which may involve simple to multi-quadrupole mass analyzers (QMS), triple-quadrupole ion trap (QTrap), triple quadrupole (TQ), or quadrupole-TOF (Q-TOF) [ 37 , 38 , 52 ]. However, there are hurdles to the chromatographic separation of metabolites.…”

“…Tryptophan metabolism was also confirmed to be perturbed in several studies, and two immunosuppressive tryptophan metabolites, kynurenine and anthranilic acid, were found to be associated with disease severity [ 41 , 67 , 69 ]. Elevations in such tryptophan metabolites were also found in patients with long-COVID or with cancer [ 37 , 71 ]. It is interesting to note that elevations of kynurenate accompany clinical deterioration in male (but not female) COVID-19 patients [ 66 ].…”

“…A set of metabolomic studies demonstrated that circulating polyamines and their precursor L-ornithine are overabundant in sera of COVID-19 patients. In particular, acetylated polyamine derivatives (N1-acetylputrescine, N1-acetylspermidine, N1,N8-diacetylspermidine and N1,N12-diacetylspermine) were found to be elevated in COVID-19 samples as compared to controls [ 37 , 39 , 64 ]. Interestingly, serum levels of N1-acetylspermidine and N8-acetylspermidine are particularly high in long-term SARS-CoV-2 carriers [ 37 ].…”

“…In particular, acetylated polyamine derivatives (N1-acetylputrescine, N1-acetylspermidine, N1,N8-diacetylspermidine and N1,N12-diacetylspermine) were found to be elevated in COVID-19 samples as compared to controls [ 37 , 39 , 64 ]. Interestingly, serum levels of N1-acetylspermidine and N8-acetylspermidine are particularly high in long-term SARS-CoV-2 carriers [ 37 ]. Recent preclinical work indicates that SARS-CoV-2 infection causes the accumulation of key metabolites in infected cells, including the deregulation of putrescine and N-acetylspermidine by hijacking autophagy to facilitate their own viral replication [ 114 ].…”