Importance of Bacterial Replication and Alveolar Macrophage-Independent Clearance Mechanisms during Early Lung Infection with Streptococcus pneumoniae

Abstract

f Although the importance of alveolar macrophages for host immunity during early Streptococcus pneumoniae lung infection is well established, the contribution and relative importance of other innate immunity mechanisms and of bacterial factors are less clear. We have used a murine model of S. pneumoniae early lung infection with wild-type, unencapsulated, and para-amino benzoic acid auxotroph mutant TIGR4 strains to assess the effects of inoculum size, bacterial replication, capsule, and alveolar macrophage-dependent and -independent clearance mechanisms on bacterial persistence within the lungs. Alveolar macrophage-dependent and -independent (calculated indirectly) clearance half-lives and bacterial replication doubling times were estimated using a mathematical model. In this model, after infection with a high-dose inoculum of encapsulated S. pneumoniae, alveolar macrophage-independent clearance mechanisms were dominant, with a clearance half-life of 24 min compared to 135 min for alveolar macrophage-dependent clearance. In addition, after a high-dose inoculum, successful lung infection required rapid bacterial replication, with an estimated S. pneumoniae doubling time of 16 min. The capsule had wide effects on early lung clearance mechanisms, with reduced half-lives of 14 min for alveolar macrophage-independent and 31 min for alveolar macrophage-dependent clearance of unencapsulated bacteria. In contrast, with a lower-dose inoculum, the bacterial doubling time increased to 56 min and the S. pneumoniae alveolar macrophage-dependent clearance half-life improved to 42 min and was largely unaffected by the capsule. These data demonstrate the large effects of bacterial factors (inoculum size, the capsule, and rapid replication) and alveolar macrophage-independent clearance mechanisms during early lung infection with S. pneumoniae. Microaspiration of potentially pathogenic bacteria colonizing the nasopharynx is the probable cause of most cases of bacterial pneumonia. Whether microaspiration results in pneumonia will depend on the numbers of bacteria reaching the lung, their virulence, and the host's ability to clear the invading bacteria. Defining the efficacy of different lung immune mechanisms and the bacterial characteristics for successful infection will be essential for understanding the epidemiology of pneumonia and for the design of effective preventative strategies. Initial lung immune defenses include the resident alveolar macrophages (AMs) (1-3), physical removal of microbes by mucociliary clearance, and mucosal antibacterial peptides (e.g., defensins) and proteins (e.g., lysozyme and lactoferrin) (4, 5). The importance of AMs for preventing lung infections due to Streptococcus pneumoniae, the commonest cause of bacterial pneumonia, is well established (2, 6-9). The published data indicate that AM recognition and AM phagocytosis of S. pneumoniae are essential for controlling bacterial numbers during the first few hours of lung infection. Impairment of AMmediated bacterial clearance during early infection, ...

A Critical, Nonlinear Threshold Dictates Bacterial Invasion and Initial Kinetics During Influenza

“…5B). The nonlinearity of the relationship between dose and AM depletion is important and non-intuitive, even with our previous knowledge that these two effects are related16202122 and that they both influence coinfection kinetics16171819. Knowing how the combination of two factors work together and quantifying the conditions that yield each of the outcomes in addition to the trajectory of bacterial titers is crucial to understanding coinfection kinetics.…”

“…In both naive and influenza-infected hosts, the trajectory of bacterial titers is dependent on the inoculating dose1617202122. Further, in the context of the coinfection, a distinct dichotomous pattern emerged with a low dose (10 2  CFU) compared to a higher dose (10 3  CFU) such that some individuals had high bacterial titers, an indication of severe pneumonia, while others had low bacterial titers and, presumably, a more mild infection17.…”

Alveolar macrophage development in mice requires L-plastin for cellular localization in alveoli

“…5,6 Alveolar macrophages represent a distinct lineage of tissue-resident macrophages that mature during neonatal development. [7][8][9] During fetal development, monocytes migrate through the bloodstream to seed the embryonic lungs and subsequently upregulate CD11c and SiglecF, which identify them as mature alveolar macrophages.…”

Influenza A Virus Infection Predisposes Hosts to Secondary Infection with Different Streptococcus pneumoniae Serotypes with Similar Outcome but Serotype-Specific Manifestation

“…The capsule confers antiphagocytic and antiopsonophagocytic properties that determine the invasive pneumococcal disease (IPD) potential of different serotypes (11). IPD is defined as the recovery of S. pneumoniae from a normally sterile site such as the blood or brain (7,12,13). To date, 97 distinct serotypes have been described based on the unique chemical and immunogenic properties of their capsule (10,14), and these serotypes can be divided into invasive as well as noninvasive/carrier serotypes (15, 16).…”