I have read with great interest the paper by Yang et al. who assessed the plasma metabolome and cytokine profile in the blood obtained from convalescent-phase COVID-19 patients (1). They reported that glycylproline (gly-pro) strongly accumulated in individuals with rapidly declining antibody levels defined as no detectable SARS-CoV-2–specific IgG antibodies 40 to 70 d after the COVID-19 onset (1). Experimental evidence also demonstrated that gly-pro directly suppressed the immune responses upon SARS-CoV-2 infection. Gly-pro is a known product of enzymatic dipeptide cleavage from the N-terminal of different proteins catalyzed by the dipeptidyl peptidase 4 (DPP4) that in many cases results in the biological inactivation of proteins as well (1–3).
We published earlier that the reduction of circulating DPP4 activity was associated with the worsening severity of acute COVID-19 disease and was one of the strongest prognostic biomarkers of mortality, deserving interest for potential future application in the clinical care (4, 5). The serum DPP4 enzyme activity—measured by gly-pro/paranitroaniline (pNA) hydrolysis—was significantly increased in the convalescent phase in individuals who donated plasma after acute SARS-CoV-2 infection compared with those still hospitalized with acute COVID-19 (4, 5). Moreover, we also found an increase in the serum DPP4 activity of plasma donors in the convalescent phase compared with SARS-CoV-2–naive individuals who never had been exposed to this virus (4, 5). The pattern of change in serum DPP4 activities according to the disease course and virus exposure (acute vs convalescent COVID-19 phases and convalescent vs SARS-CoV-2 naive) (Table 1) suggests a rebound increase evolving in the convalescent phase after a significant decrease in the acute phase. Rebound increases above the normal range are known medical phenomena that occur after an acute pathologic condition is resolved. Perhaps the most well-known example for a rebound increase is the posthypoglycemic hyperglycemia, i.e., the Somogyi effect in diabetes care (6, 7).
Table 1.
Circulating sDPP4 enzyme activities in different study groups stratified by SARS-CoV-2 virus exposure and phase of COVID-19 disease
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Plasma donors were at least 14 d after complete recovery from PCR-confirmed SARS-CoV-2 infection and had presence of anti-SARS-CoV-2 antibodies in the testing performed on the day of screening for convalescent plasma donation that was subsequently used for the treatment of severe cases with acute COVID-19 disease.
+Mann–Whitney U test, P < 0.0001, acute (hospitalized) Covid-19 cases vs SARS-CoV-2–naive individuals.
*Mann–Whitney U test, P < 0.0001, convalescent-phase vs acute (hospitalized) Covid-19 cases.
**Mann–Whitney U test, P = 0.0003, convalescent-phase Covid-19 vs SARS-CoV-2–naive individuals.
The significant rebound increase in circulating DPP4 activity in the convalescent phase of COVID-19 explains the strong accumulation of gly-pro in individuals with rapidly fading antibodies and suggests a highly coordinated regulatory process of the immune system that employs the aminopeptidase function of the multifunctional DPP4 protein. It is especially intriguing that DPP4 has also been predicted to have a weak interaction with the receptor-binding domain of SARS-CoV-2 and emerged as a coreceptor candidate in physical proximity to the attachment sites of the spike protein on the host cell membrane (8, 9).
The question, whether this multifaceted interaction between DPP4 and SARS-CoV-2 evolved to help the patients to decrease the virus-specific antibody levels that are no longer sustainable/needed after recovering from an acute coronavirus infection such as COVID-19 (and potentially MERS also ref. 10) urges further studies. Taken together, DPP4 may be involved in a novel regulatory mechanism that drives the fading of the immune response against these particular pathogens after the acute infection.
Acknowledgments
I am grateful for Ákos Nádasdi, M.D., and for Zsolt I. Komlósi, M.D., Ph.D., Semmelweis University, Budapest, Hungary, for their thorough reading of the manuscript, useful comments, and discussions on this material.
Author contributions
G.F. led the prior research project associated to this task; and G.F. wrote the paper.
Competing interest
The authors declare a competing interest, the authors have organizational affiliations to disclose: the author reports paid part-time employment at the Semmelweis University, Budapest, Hungary where his employer did not declare employee conflict of interest for this independently conducted work. The author also received financial support for presentations at diabetes meetings and personal fees from 77 Elektronika Ltd, the Diabetes and Metabolism Foundation, and honoraria from KRKA Hungary for delivering presentations on DPP4 inhibitor drugs. The author has stock ownership to disclose: he has stocks in Ramgen Plc, Hungary and other interests as co-CEO at Ramgen Plc, a private biotech company. The author has a patent filling to disclose, WO2022180415 - Methods for prediction of severity and risk of mortality of COVID-19 disease and pre-screening of acute Sars-Cov-2 infections available at: https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022180415&_cid=P12-LAUV2P-84288-1.
References
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