Therapeutic Potential of Annexins in Sepsis and COVID-19

Abstract

Sepsis is a continuing problem in modern healthcare, with a relatively high prevalence, and a significant mortality rate worldwide. Currently, no specific anti-sepsis treatment exists despite decades of research on developing potential therapies. Annexins are molecules that show efficacy in preclinical models of sepsis but have not been investigated as a potential therapy in patients with sepsis. Human annexins play important roles in cell membrane dynamics, as well as mediation of systemic effects. Most notably, annexins are highly involved in anti-inflammatory processes, adaptive immunity, modulation of coagulation and fibrinolysis, as well as protective shielding of cells from phagocytosis. These discoveries led to the development of analogous peptides which mimic their physiological function, and investigation into the potential of using the annexins and their analogous peptides as therapeutic agents in conditions where inflammation and coagulation play a large role in the pathophysiology. In numerous studies, treatment with recombinant human annexins and annexin analogue peptides have consistently found positive outcomes in animal models of sepsis, myocardial infarction, and ischemia reperfusion injury. Annexins A1 and A5 improve organ function and reduce mortality in animal sepsis models, inhibit inflammatory processes, reduce inflammatory mediator release, and protect against ischemic injury. The mechanisms of action and demonstrated efficacy of annexins in animal models support development of annexins and their analogues for the treatment of sepsis. The effects of annexin A5 on inflammation and platelet activation may be particularly beneficial in disease caused by SARS-CoV-2 infection. Safety and efficacy of recombinant human annexin A5 are currently being studied in clinical trials in sepsis and severe COVID-19 patients.

Integrated Single Cell and Bulk RNA-Seq Analysis Revealed Immunomodulatory Effects of Ulinastatin in Sepsis: A Multicenter Cohort Study

“…The signaling pathways such as ANNEXIN, ITGB2, and RESISTIN were found to be reduced in the UTI group. ANNEXIN may play a detrimental role in sepsis, by prolonging neutrophil survival, which is known to contribute to sepsis-mediated organ damage ( 48 , 49 ). RESISTIN signaling was suppressed in both MDSC and M2 macrophage by the use of UTI, supporting the therapeutic effects of the UTI.…”

SARS‐CoV‐2 nucleocapsid protein interacts with immunoregulators and stress granules and phase separates to form liquid droplets

“…Interestingly, many immunoregulatory factors, including proteins involved in SARS-CoV-2 infection, were identified as NCAP interactors in our study (Table 1). A selected number of these proteins include IMPDH2 (regulates NF-jB activation and supports SARS-CoV infection) [75], VCP (involved in the maturation of virus-loaded endosomes) [76], TRIM56 (direct antiviral actions against positive-sense singlestranded RNA viruses and positive regulator of innate immune response) [77,78]), ANXA1 (suppression of inflammation by limiting the production of neutrophil and pro-inflammatory cytokines) [79][80][81], AP3B1 (significantly enriched in COVID-19 patients experiencing severe cytokine storms) [82][83][84], HSP90B1 (TLR signalling) [85], PPP1CA (antiviral IFNB production) [86], YY1 (interacts with STAT1 and activates of IFN-1 signalling) [87], EFTUD2 (immune regulator that restricts viral infection) [88], PCBP1 (regulates MAVS degradation and fine-tune antiviral immunity) [89], HSPA1A (protective antiviral immunity and highly upregulated at the maternal-fetal interface during maternal COVID-19) [90,91], PRKRA (governs the effects of IFN in response to viral infection), SQSTM1 (key intracellular target of innate defence regulator-1 (RIG-1), ASCC3 (inhibits IFN signalling) [92], BAIP2L1 (MAVS degradation leading to downregulation of antiviral response) [93], YBX1 (YB-1) (supports viral replication) [94,95], ADAR (a negative regulator of type 1 interferon-mediated signalling) [96] and PCBP2 (a negative regulator of MAVS-mediated antiviral signalling) [89,97]. The inter-relationship between different NCAP interactors and regulation of associated pathways in response to an actual infection with the SARS-CoV-2 virus is likely complex, with the victor (virus or cell) decided by factors including NCAP expression level, viral load, the interplay between the positive and negative immunoregulators, impact on protein translation machinery and physiological state of the cell.…”

Therapeutic potential for targeting Annexin A1 in fibrotic diseases

“…In contrast to annexin A1 protein, which is difficult to manufacture in large quantities, a small peptide derived from the N-terminal region that retains much of biological activity of annexin A1 particularly attractive for pharmacologist. 103 So far, there are three analogues of N-terminal derived peptide reported in literature, termed Ac2-26, Ac2-12, and Ac9-25. Among them, Ac2-26 has sparked great interest and intense investigation in pathological conditions, 103 , 104 such as cerebral ischemia-reperfusion injury, 105 diabetic nephropathy, 106 and pneumococcal meningitis.…”