# A Double-Edged Sword: Extracellular Serine Proteases as Facilitators of Infection and Mediators of Immunity **Authors:** Alua Shagirova, Maiya Allayarova, Aiya Makhanova, Amanbek Bekturgan, Timo Burster PMC · DOI: 10.3390/molecules31040670 · Molecules · 2026-02-15 ## TL;DR This paper explores how serine proteases can both help viruses infect and help the body fight infections. ## Contribution The paper introduces the dual roles of exogenous serine proteases in both promoting infection and supporting immunity. ## Key findings - Extracellular serine proteases can be hijacked by viruses to aid infection. - Neutrophil serine proteases contribute to both disease progression and antiviral defense. - Modulating serine protease activity presents new therapeutic opportunities. ## Abstract Serine proteases are a class of enzymes that orchestrate an immune response. These proteases can be hijacked by viruses to facilitate entry and spread, while simultaneously supporting the innate immune system in neutralizing pathogens. This review highlights the dual roles of exogenous serine proteases, emphasizing neutrophil serine proteases (NSPs) that facilitate viral entry and promote disease progression while also contributing to antiviral defense by degrading viral glycoproteins. Additionally, the potential to modulate serine protease activity to boost host defenses will be discussed, offering both significant challenges and new opportunities for therapeutic intervention. ## Full-text entities - **Genes:** CCL5 (C-C motif chemokine ligand 5) [NCBI Gene 6352] {aka D17S136E, RANTES, SCYA5, SIS-delta, SISd, TCP228}, ACE2 (angiotensin converting enzyme 2) [NCBI Gene 59272] {aka ACEH}, S (surface glycoprotein) [NCBI Gene 43740568] {aka spike glycoprotein}, TMPRSS2 (transmembrane serine protease 2) [NCBI Gene 7113] {aka PRSS10}, FLNC (filamin C) [NCBI Gene 2318] {aka ABP-280, ABP280A, ABPA, ABPL, ARVC15, CMD1PP}, HPN (hepsin) [NCBI Gene 3249] {aka TMPRSS1}, ST14 (ST14 transmembrane serine protease matriptase) [NCBI Gene 6768] {aka ARCI11, CAP3, HAI, MT-SP1, MTSP1, PRSS14}, CD81 (CD81 molecule) [NCBI Gene 975] {aka CVID6, S5.7, TAPA1, TSPAN28}, VTN (vitronectin) [NCBI Gene 7448] {aka V75, VN, VNT}, S100B (S100 calcium binding protein B) [NCBI Gene 6285] {aka NEF, S100, S100-B, S100beta}, TMPRSS13 (transmembrane serine protease 13) [NCBI Gene 84000] {aka MSP, MSPL, MSPS, TMPRSS11}, OCLN (occludin) [NCBI Gene 100506658] {aka BLCPMG, PPP1R115, PTORCH1}, SERPINA3 (serpin family A member 3) [NCBI Gene 12] {aka AACT, ACT, GIG24, GIG25}, FURIN (furin, paired basic amino acid cleaving enzyme) [NCBI Gene 5045] {aka FUR, PACE, PCSK3, SPC1}, CTSG (cathepsin G) [NCBI Gene 1511] {aka CATG, CG}, TMPRSS11D (transmembrane serine protease 11D) [NCBI Gene 9407] {aka ASP, HAT}, SERPINE1 (serpin family E member 1) [NCBI Gene 5054] {aka PAI, PAI-1, PAI1, PLANH1}, CTRL (chymotrypsin like) [NCBI Gene 1506] {aka CTRL1}, CD4 (CD4 molecule) [NCBI Gene 920] {aka CD4mut, IMD79, Leu-3, OKT4D, T4}, RNASE3 (ribonuclease A family member 3) [NCBI Gene 6037] {aka ECP, RAF1, RNS3}, ELANE (elastase, neutrophil expressed) [NCBI Gene 1991] {aka ELA2, GE, HLE, HNE, NE, PMN-E}, F2 (coagulation factor II, thrombin) [NCBI Gene 2147] {aka PT, RPRGL2, THPH1}, SERPINA1 (serpin family A member 1) [NCBI Gene 5265] {aka A1A, A1AT, AAT, PI, PI1, PRO2275}, MPO (myeloperoxidase) [NCBI Gene 4353], ITIH4 (inter-alpha-trypsin inhibitor heavy chain 4) [NCBI Gene 3700] {aka GP120, H4P, IHRP, ITI-HC4, ITIHL1, PK-120}, CTSL (cathepsin L) [NCBI Gene 1514] {aka CATL, CTSL1, MEP}, CD8A (CD8 subunit alpha) [NCBI Gene 925] {aka CD8, CD8alpha, IMD116, Leu2, p32}, CLDN1 (claudin 1) [NCBI Gene 9076] {aka CLD1, ILVASC, SEMP1}, F2R (coagulation factor II thrombin receptor) [NCBI Gene 2149] {aka CF2R, HTR, PAR-1, PAR1, TR}, TMPRSS4 (transmembrane serine protease 4) [NCBI Gene 56649] {aka CAP2, CAPH2, MT-SP2, TMPRSS3}, PRSS57 (serine protease 57) [NCBI Gene 400668] {aka NSP4, PRSSL1, UNQ782}, PRTN3 (proteinase 3) [NCBI Gene 5657] {aka ACPA, AGP7, C-ANCA, CANCA, MBN, MBT}, ORF1ab (ORF1a polyprotein;ORF1ab polyprotein) [NCBI Gene 43740578], ENPEP (glutamyl aminopeptidase) [NCBI Gene 2028] {aka APA, CD249, gp160} - **Diseases:** myalgic encephalomyelitis/chronic fatigue syndrome (MESH:D015673), autoimmunity (MESH:D001327), respiratory dysfunction (MESH:D012131), hypercoagulability (MESH:D019851), lung inflammation (MESH:D011014), lung (MESH:D008171), lung tissue damage (MESH:D055370), injury to (MESH:D014947), inflammation (MESH:D007249), influenza infection (MESH:D007251), immune dysregulation (OMIM:614878), HIV infection (MESH:D015658), Long COVID (MESH:D000094024), tissue injury (MESH:D017695), COVID-19 (MESH:D000086382), Infection (MESH:D007239), cardiovascular, thrombotic, and cerebrovascular disease (MESH:D002318), weight loss (MESH:D015431), thrombotic (MESH:D013927), postural orthostatic tachycardia syndrome (MESH:D054972), influenza A virus disease (MESH:D014777) - **Chemicals:** sivelestat (MESH:C069195), nafamostat (MESH:C032855), Camostat (MESH:C034532), oxygen (MESH:D010100), phosphatidylserine (MESH:D010718), Serine (MESH:D012694), D (MESH:D003903), A1AT (-), heparan sulfate (MESH:D006497) - **Species:** Human immunodeficiency virus 1 (no rank) [taxon 11676], Severe acute respiratory syndrome-related coronavirus (no rank) [taxon 694009], H1N1 subtype (serotype) [taxon 114727], Severe acute respiratory syndrome coronavirus 2 (no rank) [taxon 2697049], Gammacoronavirus (genus) [taxon 694013], Mus musculus (house mouse, species) [taxon 10090], Hepatitis C Virus [taxon 11103], Influenza A virus (no rank) [taxon 11320], Human betaherpesvirus 6 (species) [taxon 10368], Bacillus sp. AT (species) [taxon 1196779], Bos taurus (bovine, species) [taxon 9913], human gammaherpesvirus 4 (Epstein Barr virus, no rank) [taxon 10376], Homo sapiens (human, species) [taxon 9606], Cricetinae (hamsters, subfamily) [taxon 10026], H7N9 subtype (serotype) [taxon 333278], Viruses (acellular root) [taxon 10239] - **Mutations:** P681H, rs2227692, rs2227667, N679K, rs75603675, CatG - **Cell lines:** H1299 — Homo sapiens (Human), Lung large cell carcinoma, Cancer cell line (CVCL_0060), A549 — Homo sapiens (Human), Lung adenocarcinoma, Cancer cell line (CVCL_0023), U-937 — Homo sapiens (Human), Adult acute monocytic leukemia, Cancer cell line (CVCL_0007), Vero — Chlorocebus sabaeus (Green monkey), Spontaneously immortalized cell line (CVCL_0059), RaTG13 — Homo sapiens (Human), Childhood T acute lymphoblastic leukemia, Cancer cell line (CVCL_1081), Jurkat — Homo sapiens (Human), Childhood T acute lymphoblastic leukemia, Cancer cell line (CVCL_0065) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12943037/full.md ## Figures 3 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12943037/full.md ## References 100 references — full list in the complete paper: https://tomesphere.com/paper/PMC12943037/full.md --- Source: https://tomesphere.com/paper/PMC12943037