Mechanism of Pneumococcal Hemolytic Uremic Syndrome: the Role of Neuraminidases and Their Potential Application in Diagnosis and Treatment

Streptococcus pneumoniae (pneumococcus) is the most common cause of community-acquired pneumonia, meningitis, and bacteremia in children and adults and the most common cause of acute otitis media (AOM) in children. One of the most severe complications of invasive pneumococcal infection is hemolytic uremic syndrome (HUS) that mainly occurs in children and is associated with hemolytic anemia, thrombocytopenia, and acute renal failure. HUS tends to occur in healthy young children and is one of the most common causes of acute renal failure in pediatric patients. S. pneumoniae encodes many virulence factors, but only secreted neuraminidase A (NanA) which is similar to viral neuraminidase was attributed to HUS. Neuraminidase cleaves N-acetylneuraminic acid (sialic acid) residues on red blood cells (RBC), platelets and endothelial cells leading to the exposure of the Thomsen-Friedenrich antigen (T antigen) and allowing normally circulating anti-T antigen antibodies to react with the exposed T antigen on cells. The interpretation of the role of neuraminidase in pneumococcal diseases is complicated by the fact that the pneumococcus produces two or three distinct neuraminidases, NanA, NanB, and NanC. All three neuraminidases have typical signal peptides for export; however, NanA, unlike NanB and NanC, contains a C-terminal cell surface anchorage domain. NanA and NanB can cleave sialic acid from cell surface glycans and mucin, thereby promoting the colonization of the upper respiratory tract by exposing host cell surface receptors for pneumococcal adherence. The mortality of patients with HUS was high in early studies; furthermore, of the 14 cases recently reported from USA, 1 (7%) died and 4 (29%) developed chronic kidney disease. Although pnerumococcal infection is common in Taiwan, there has been a lack of information about S. pneumoniae-associated HUS. The risk factors and associated mechanism remains unknown. We propose this project to 1) identify risk factors for necrotizing pneumonia and hemolytic uremic syndrome caused by S. pneumoniae in children; 2) unveil mechanism of pneumococcal hemolytic uremic syndrome: and the role of neuraminidases; 3) check to see if we can use pneumococcal neuraminidase level in serum as a marker for necrotizing pneumonia or hemolytic uremic syndrome; and 4) screen for pneumococcal neuraminidase inhibitors, that could be used in the future as therapeutic agents for invasive pneumococcal infection. The study would shed new insights into the pathogen-host interaction in pneumococcal HUS. The microbiological and clinical factors identified will be useful for physicians to diagnose and treat patients with HUS and invasive pneumococcal diseases.

Project ID:PC10101-2104
External Project ID:NSC100-2314-B182A-079-MY3