BREAKING! Hong Kong Scientists Discover That The Metabolite Glycylproline Is Responsible For Waning Antibodies In Recovered COVID-19 Patients

COVID-19 News: In what can be regarded as a breakthrough study, scientists from Hong Kong Baptist University (HKBU) along with researchers from various research institutions in China have discovered that the plasma metabolite glycylproline (gly-pro) is responsible for the wanning antibodies in recovered COVID-19 patients.


 
The breakthrough study findings can help formulate strategies to main a steady protective level of antibodies in the body against the SARS-CoV-2 virus.
 
The anti-diabetic drug, sitagliptin was also found to be able to counteract the gly-pro–down-regulated SARS-CoV-2-specific antibodies.
 
The current ongoing COVID-19 pandemic has already infected more than 629.4 million people globally and killed more than 6.57 million people according to reported data. (In reality, actual figures could eb as high as 5 to 6-fold not including excess deaths.)
 
In coming months, due to the emergence of a huge variety of new SARS-CoV-2 variants and sub-lineages that are supposedly more transmissive and immune-evasive, the numbers of people getting infected or reinfected or even coinfected are expected to be exponential coupled with increase deaths.
 
The levels of COVID-19 antibodies among individuals in a community are crucial for herd immunity against the virus. In general, recovered COVID-19 patients have high antibody levels as a result of their natural immune reactions. However, antibody levels in some recovered COVID-19 patients have been seen to drop rapidly over the course of a few weeks, and the underlying mechanism of this phenomenon remains poorly understood.
 
The association between neutralizing antibody levels and metabolic alterations in convalescent patients with COVID-19 is still poorly understood.
 
The study team conducted absolutely quantitative profiling to compare the plasma cytokines and metabolome of ordinary convalescent patients with antibodies (CA), convalescents with rapidly faded antibodies (CO), and healthy subjects.
 
The study team initially identified that cytokines such as M-CSF and IL-12p40 and plasma metabolites such as glycylproline (gly-pro) and long-chain acylcarnitines could be associated with antibody fading in COVID-19 convalescent patients.
 
The study team built machine-learning–based classification models using 17 features (six cytokines and 11 metabolites) following feature selection.
 
Accuracies of more than 90% were attained in at least six machine-learning models.
 
Significantly, it was found that the dipeptide gly-pro, a product of enzymatic peptide cleavage catalyzed by dipeptidyl peptidase 4 (DPP4), strongly accumulated in CO individuals compared with the CA group.
 
Subsequent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination experiments in healthy mice demonstrated that supplementation of gly-pro down-regulates SARS-CoV-2–specific receptor-binding domain antibody levels and suppresses immune responses, whereas the DPP4 inhibitor sitagliptin can counteract the inhibitory effects of gly-pro upon SARS-CoV-2 vaccination.
 
The study findings not only reveal the important role of gly-pro in the immune responses to SARS-CoV-2 infection but also indic ate a possible mechanism underlying the beneficial outcomes of treatment with DPP4 inhibitors in convalescent COVID-19 patients, shedding light on therapeutic and vaccination strategies against COVID-19.
 
The study findings were published in the peer reviewed journal: Proceedings of the National Academy of Sciences (PNAS).
https://www.pnas.org/doi/full/10.1073/pnas.2117089119
 
This is the first study to identify the association between rapidly fading antibody levels in some recovered COVID-19 patients and a high plasma concentration of a metabolite called glycylproline (gly-pro) and its producing enzyme.
 
The study team also found that the application of an inhibiting agent can counteract the activities of gly-pro and its producing enzyme, and this helped to maintain COVID-19 antibody levels in a mouse model.
 
The study findings offer important insights that could aid the development of novel therapeutic and vaccination strategies against the virus.
 
The commonly used FDA approved diabetic drug sitagliptin sold under the brand name Januvia could emerge as a potential drug to help overcome the issue of wanning antibodies.
 
It is already recognized that the levels of COVID-19 antibodies among individuals in a community are crucial for herd immunity against the virus.
 
In most cases, recovered COVID-19 patients have high antibody levels as a result of their natural immune reactions.
 
But it has been found that antibody levels in some recovered COVID-19 patients have been seen to drop rapidly over the course of a few weeks, and the underlying mechanism of this phenomenon remains poorly understood.
 
Numerous past studies have revealed changes in plasma cytokine and metabolite levels in COVID-19 patients.
 
As a result of some of these past findings, the study team led by Professor Dr Cai Zongwei, Chair Professor of the Department of Chemistry and Director of the State Key Laboratory of Environmental and Biological Analysis at HKB investigated how plasma cytokines and metabolites are associated with antibody levels in recovered COVID-19 patients.
 
The study team analyzed the cytokine and metabolite profiles in the plasma samples of three subject groups. The first group included 17 recovered COVID-19 patients with steady COVID-19 antibody levels; the second group included 30 recovered COVID-19 patients with rapidly fading COVID-19 antibody levels; the third one was a control group comprising 35 individuals who had not been infected with COVID-19.
 
A detailed series of quantitative computational analyses that involved the use of machine learning techniques were used to compare the levels of different plasma cytokines and metabolites in the three subject groups in relation to their COVID-19 antibody levels.
 
The study team then compared the two recovered patient groups with the control group, and any cytokines and metabolites with significantly different levels between the two groups and the control group were shortlisted. Among the shortlisted targets, the levels of seven cytokines and 20 metabolites were seen to differ significantly between the two groups of recovered COVID-19 patients.
 
The study team then analyzed the association between the selected cytokines and metabolites and COVID-19 antibody levels in recovered patients. From the collected data, they concluded that the plasma concentration of the metabolite gly-pro had increased the most in the two recovered patient groups compared with the control group.
 
The study findings importantly showed that the levels of gly-pro in the recovered patient group with rapidly fading antibody levels were four times higher than the control group, while the levels of gly-pro in the recovered patient group with steady COVID-19 antibody levels were two-and-a-half times higher than the control group.
 
The study team based on these findings further investigated the relationship between COVID-19 antibody levels in recovered patients and gly-pro, as well as the producing enzyme of gly-pro which is named dipeptidyl peptidase-4 (DPP4).
Inhibiting gly-pro maintains steady antibody levels
 
Interestingly, the study team also set up a four-week mouse model experiment to test the hypothesis that high gly-pro levels are associated with a rapid drop in COVID-19 antibody levels in recovered COVID-19 patients.
 
For this experiment, four groups of 12 mice were injected with the spike protein of the COVID-19 virus. The groups were then respectively treated with: (1) exogenous gly-pro; (2) an inhibitor that blocks the degradation of endogenous gly-pro; (3) exogenous gly-pro and a DPP4 inhibitor (Sitagliptin, which is also an anti-diabetic drug); and (4) saline.
 
Initially, the serum COVID-19 antibody levels in all groups were similar in the first week of the experiment.
 
However, the antibody levels of the mice in the first group declined after the second week, suggesting that increased gly-pro levels are associated with a decline in COVID-19 antibody levels.
 
Meanwhile, the antibody levels of the mice in the second group, who had relatively steady gly-pro levels, also began to decline in the third week. The slower decline in antibody levels in the second group of mice compared to the first group shows that varying amounts of gly-pro are associated with the amount of time a steady antibody level can be maintained.
 
Significant, the antibody levels of the mice in the third group given Sitagliptin remained stable throughout the experiment. This shows that when the activities of DPP4 are inhibited, the negative effects of gly-pro can be neutralized, and a steady level of COVID-19 antibodies can be maintained.
 
Professor Cai Zongwei told COVID-19 News section reporters from Thailand Medical News, “The study findings suggest that DPP4 inhibitors can effectively maintain steady antibody levels in COVID-19-infected mice. As a result, our study offers important insights into how we can develop a similar medical approach to maintain COVID-19 antibody levels in humans, which will contribute to the global fight against the pandemic.”
 
First author, Dr Zhu Yang an Assistant Professor at Hong Kong Baptist University (HKBU)added, “Further studies based on our study findings are warranted to explore the potential in other areas of therapeutic and disease control, especially in terms of other applications. For example, novel strategies may be developed to enhance the efficiency of vaccination in boosting antibody levels in humans, particularly in diabetic patients, a well-known high-risk population for COVID-19.”
 
This is the first study to date that has found that gly-pro contributes to the rapid fading of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific antibodies, whereas the inhibitor of its producing enzyme dipeptidyl peptidase 4, sitagliptin - an antidiabetic drug, can counteract the gly-pro–down-regulated SARS-CoV-2-specific antibodies under physiological conditions.
 
The study findings point to a novel mechanism for gly-pro–suppressed immune responses upon SARS-CoV-2 infection and provide therapeutic potentials for maintaining neutralizing antibody levels.
 
The study also involved researchers from the Xiamen University, Fujian-China, Wuhan Institute of Virology at the Center for Biosafety Mega-Science that is part of the Chinese Academy of Sciences, Wuhan-China and the Joint Laboratory of Infectious Diseases and Health at Wuhan Jinyintan Hospital, Wuhan-China.
 
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