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The emergence of a new type of COVID-19 patients, who were retested positive after hospital discharge with long-term persistent SARS-CoV-2 infection but without COVID-19 clinical symptoms (hereinafter, LTPPs), poses novel challenges to COVID-19 treatment and prevention. Why was there such a contradictory phenomenon in LTPPs? To explore the mechanism underlying this phenomenon, we performed quantitative proteomic analyses using the sera of 12 LTPPs (Wuhan Pulmonary Hospital), with the longest carrying history of 132 days, and mainly focused on 7 LTPPs without hypertension (LTPPs-NH). The results showed differential serum protein profiles between LTPPs/LTPPs-NH and health controls. Further analysis identified 174 differentially-expressed-proteins (DEPs) for LTPPs, and 165 DEPs for LTPPs-NH, most of which were shared. GO and KEGG analyses for these DEPs revealed significant enrichment of "coagulation" and "immune response" in both LTPPs and LTPPs-NH. A unity of contradictory genotypes in the 2 aspects were then observed: some DEPs showed the same dysregulated expressed trend as that previously reported for patients in the acute phase of COVID-19, which might be caused by long-term stimulation of persistent SARS-CoV-2 infection in LTPPs, further preventing them from complete elimination; in contrast, some DEPs showed the opposite expression trend in expression, so as to retain control of COVID-19 clinical symptoms in LTPPs. Overall, the contrary effects of these DEPs worked together to maintain the balance of LTPPs, further endowing their contradictory steady-state with long-term persistent SARS-CoV-2 infection but without symptoms. Additionally, our study revealed some potential therapeutic targets of COVID-19. Further studies on these are warranted. This study reported a new type of COVID-19 patients and explored the underlying molecular mechanism by quantitative proteomic analyses. DEPs were significantly enriched in "coagulation" and "immune response". Importantly, we identified 7 "coagulation system"- and 9 "immune response"-related DEPs, the expression levels of which were consistent with those previously reported for patients in the acute phase of COVID-19, which appeared to play a role in avoiding the complete elimination of SARS-CoV-2 in LTPPs. On the contrary, 6 "coagulation system"- and 5 "immune response"-related DEPs showed the opposite trend in expression. The 11 inconsistent serum proteins seem to play a key role in the fight against long-term persistent SARS-CoV-2 infection, further retaining control of COVID-19 clinical symptom of LTPPs. The 26 proteins can serve as potential therapeutic targets and are thus valuable for the treatment of LTPPs; further studies on them are warranted.
