Research Article: Single Cell Bottlenecks in the Pathogenesis of Streptococcus pneumoniae

Date Published: October 12, 2016

Publisher: Public Library of Science

Author(s): Masamitsu Kono, M. Ammar Zafar, Marisol Zuniga, Aoife M. Roche, Shigeto Hamaguchi, Jeffrey N. Weiser, Michael R. Wessels.


Herein, we studied a virulent isolate of the leading bacterial pathogen Streptococcus pneumoniae in an infant mouse model of colonization, disease and transmission, both with and without influenza A (IAV) co-infection. To identify vulnerable points in the multiple steps involved in pneumococcal pathogenesis, this model was utilized for a comprehensive analysis of population bottlenecks. Our findings reveal that in the setting of IAV co-infection the organism must pass through single cell bottlenecks during bloodstream invasion from the nasopharynx within the host and in transmission between hosts. Passage through these bottlenecks was not associated with genetic adaptation by the pathogen. The bottleneck in transmission occurred between bacterial exit from one host and establishment in another explaining why the number of shed organisms in secretions is critical to overcoming it. These observations demonstrate how viral infection, and TLR-dependent innate immune responses it stimulates and that are required to control it, drive bacterial contagion.

Partial Text

The pathogenesis of microbial diseases generally involves multiple stages (entry, establishment, invasion, exit) that often begin with the colonization of host surfaces. For organisms without an environmental reservoir, their continued success requires proliferation within their obligate host and transmission to new susceptible hosts. The induction of disease, which usually results from a combination of impaired host defense and microbial virulence attributes, may benefit the organism if it increases proliferation and/or transmission. An example of an organism with a predominantly commensal lifestyle that also is a leading cause of disease is Streptococcus pneumoniae (the pneumococcus) [1]. Pneumococci serially and sequentially colonize the mucosal surface of the human nasopharynx asymptomatically beginning in early childhood (the carrier state). Transmission occurs from carriers to non-carriers and is most frequent in settings of close contact, such as among siblings or in daycare centers, and results from direct or indirect exposure to respiratory secretions [2][3]. Disease occurs when the organism transits to normally sterile sites within the respiratory tract to the middle ear cavity or lungs. The organism may also gain access to the bloodstream from the nasopharynx or sites of localized disease to cause systemic infection. Because of high rates of carriage and these complications, the pneumococcus is a leading cause of otitis media, pneumonia, and sepsis [1][4]. An additional consideration is that recent upper respiratory viral infection, particularly with influenza, increases rates of carriage and is a major risk factor for all pneumococcal diseases [5][6][7].

This report describes an animal model that allows for the study of many of the consequences of bacterial colonization including localized and systemic disease and host-to-host transmission. We utilized this model to examine the effects of a clinically important viral co-infection. We found that IAV increases the burden of colonizing pneumococci consistent with prior observations in infant mice [18]. A similar effect had been shown in adult mice and was attributed to the increased availability of the nutrient sialic acid in secretions stimulated by IAV [16]. The greatly increased bacterial shedding and transmission in the setting of IAV described in the current report was out of proportion to the relatively modest difference in colonization density and could be attributable to the effect of the virus on secretions enhancing bacterial egress from the host. The higher rate of otitis media in the setting of IAV is consistent with prior reports and could be due to either an increased number of colonizing organisms or eustachian tube dysfunction [19][20].




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