Pneumococcal Neuraminidases A and B Both Have Essential Roles during Infection of the Respiratory Tract and Sepsis

Abstract

We examined the role of the neuraminidases NanA and NanB in colonization and infection in the upper and lower respiratory tract by Streptococcus pneumoniae, as well as the role of these neuraminidases in the onset and development of septicemia following both intranasal and intravenous infection. We demonstrated for the first time using outbred MF1 mouse models of infection that both NanA and NanB were essential for the successful colonization and infection of the upper and lower respiratory tract, respectively, as well as pneumococcal survival in nonmucosal sites, such as the blood. Our studies have shown that in vivo a neuraminidase A mutant is cleared from the nasopharynx, trachea, and lungs within 12 h postinfection, while a neuraminidase B mutant persists but does not increase in either the nasopharynx, trachea, or lungs. We also demonstrated both neuraminidase mutants were unable to cause sepsis following intranasal infections. When administered intravenously, however, both mutants survived initially but were unable to persist in the blood beyond 48 h postinfection and were progressively cleared. The work presented here demonstrates the importance of pneumococcal neuraminidase A and for the first time neuraminidase B in the development of upper and lower respiratory tract infection and sepsis.

Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor

“…For example, NanA remodels mucosal cell surface glycoproteins to promote bacterial colonization of the upper respiratory tract (11,12) and contributes to pulmonary inflammation along with the development of SPN pneumonia (13,14). However, the host has adapted to counteract the pathological effects of this SPN virulence factor by the clearance from blood circulation of host factors bearing AMR ligands that have been unmasked by NanA desialylation.…”

Assessing the function of pneumococcal neuraminidases NanA, NanB and NanC inin vitroandin vivolung infection models using monoclonal antibodies

“…Previous studies reported a substantially reduced bacterial burden in the lungs of mice infected intranasally with nan A and/or nan B gene deletion mutant strains and improved host survival [39,40,68]. NanA was shown to contribute to nasopharyngeal colonisation [41,43,68–70].…”

“…Both enzymes were demonstrated to be involved in colonization and infection of the upper and lower murine respiratory tract [39,40], although no defect in murine colonization was reported by others using a pneumococcal strain deficient in nanA, bgaA and strH [28]. Additional roles of NanA during persistance in the chinchilla middle ear infection model were shown [41–43].…”

“…NanA is required for adherence and invasion of brain endothelial cells, indicating its involvement in the development of meningitis [44]. The role of NanA during sepsis is more controversial, with reports ranging from greatly attenuated virulence of S. pneumoniae nanA gene deletion strains to no effect [40,45]. …”

Ashwell that ends well

“…S. pneumoniae, for example, uses neuraminidase to break down the glycoprotein barrier to cellular entry. 3 However, by chopping off sialic acid, the bacterial enzyme actually helps the Ashwell receptor to recognize compromised proteins and thus, paradoxically, helps it clear these defective proteins from circulation.…”