Viral Sepsis in Children

Gupta, Neha; Richter, Robert; Robert, Stephen; Kong, Michele

Cytokine Release (Figure 1) Pathogen-recognition receptors (PRRs) are cellular sensors that recognize specific molecular structure of a pathogen (28) . Toll-like receptors (TLRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) are two types of PRRs that are involved in viral sensing (28) . TLRs, which are found on the cell surface or within endosomes of monocytes, macrophages, dendritic, epithelial and endothelial cells, encounter pathogenassociated molecular patterns (PAMPs) (29, 30) . Intracellular TLR-7 and TLR-8 recognize single-stranded Ribonucleic Acid (RNA) of viruses like HPeV, the enteroviruses, human metapneumovirus, and influenza; intracellular TLR-9 recognizes double-stranded (ds) DNA of viruses like the herpes viruses (e.g., HSV-1 and -2, EBV), adenovirus, and CMV; and TLR-3 recognizes dsRNA produced during intracellular viral replication (31) . TLR activation culminates in myeloid differentiation primary response 88 (MyD88, through TLR-7,-8, and -9) or Toll/Interleukin (IL)-1 receptor domain-containing adapter protein inducing IFN-β (TRIF, through TLR-3) activation (32). These proteins, in turn, activate nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) and IFN-regulatory factor (IFR)-mediated cytokine transcription (33) (34) (35) . RLRs are cytosolic innate immunity sensors for viral RNA. Three members of RLRs have been identified: RIG-I, melanoma differentiation associated factor 5 (MDA5], and laboratory of genetics and physiology 2 (LGP2) (36) . RIG-I and MDA5 recognize dsRNAs in response to different RNA viruses and signal the production of pro-inflammatory cytokines and type-1 IFNs (37) . Cytokine proliferation instigates a pro-inflammatory cascade that results in complement activation, neutrophil chemotaxis, cytotoxic cluster of differentiation (CD) 8+ T-cell recruitment, and protease release from leukocytes and endothelial cells, particularly trypsin (38) and heparanase (39). Trypsin is upregulated and released by the vascular endothelium (38) and has been shown to cleave circulating pro-matrix metalloproteinase (pro-MMP) released from macrophages to form activated MMPs (40) . MMPs, in conjunction with heparanase, degrade the endothelial glycocalyx (41, 42). Moreover, viral particles induce reactive oxygen species generation by circulating neutrophils, eosinophils, and macrophages (43, 44) that further injure the endothelial glycocalyx (45) and activate NF-κB cell-signaling Systemic viral dissemination appears to be the etiology of viral sepsis. The exact mechanisms by which viruses that are normally isolated to the respiratory or integumentary epithelium reach the bloodstream are not known. However, it is plausible that viremia occurs through direct invasion of epithelial cells (or neurons as in case of HSV or varicella disease) to reach the surrounding vasculature (47) . Once in the blood, the virus may induce endothelial glycocalyx degradation by activating leukocytes, platelets, and endothelial cells to secrete MMPs and heparanase that target glycocalyx components (39, 48). Endothelial glycocalyx disruption exposes selectins and intracellular adhesion molecules, making them available for leukocyte adhesion and activation (49) . Glycocalyx degradation also releases heparan sulfate that may bind and activate antithrombin III and exposes membrane-bound glycoprotein Ib/IX/V complexes (50) that can bind circulating von Willebrand factor (51) and P-selectins on platelets (52, 53) ,