The role of CD44 in the acute and resolution phase of the host response during pneumococcal pneumonia

Abstract

Streptococcus pneumoniae is the most prevalent pathogen causing community-acquired pneumonia. CD44 is a transmembrane adhesion molecule, expressed by a wide variety of cell types, that has several functions in innate and adaptive immune responses. In this study, we tested the hypothesis that CD44 is involved in the host response during pneumococcal pneumonia. On intranasal infection with a lethal dose of S. pneumoniae CD44-knockout (KO) mice showed a prolonged survival when compared with wild-type mice, which was accompanied by a diminished pulmonary bacterial growth and reduced dissemination to distant body sites. Whereas, proinflammatory cytokine responses and lung pathology were not affected, CD44 deficiency resulted in increased early neutrophil influx into the lung. In separate experiments, we confirmed a detrimental role of CD44 in host defense against pneumococci during sublethal pneumonia, as demonstrated by an improved capacity of CD44 KO mice to clear a low infectious dose. In addition, CD44 appeared important for the resolution of lung inflammation during sublethal pneumonia, as shown by histopathology of lung tissue slides. In conclusion, we show here that CD44 facilitates bacterial outgrowth and dissemination during pneumococcal pneumonia, which in lethal infection results in a prolonged survival of CD44 KO mice. Moreover, during sublethal pneumonia CD44 contributes to the resolution of the inflammatory response.

L-Plastin Is Essential for Alveolar Macrophage Production and Control of Pulmonary Pneumococcal Infection

“…The increased pneumococcal burden in the BAL fluid of LPL Ϫ/Ϫ mice as early as 3 h after infection distinguishes our model from previous models of pneumococcal susceptibility (45)(46)(47)(48). In a recent report, neutrophilic defects in antipneumococcal killing increased the pulmonary pneumococcal burden 12 and 24 h after challenge, but differences were not observed at 6 h, a point in infection when alveolar macrophages would be expected to dominate the initial immune response (46).…”

Tissue integrity signals communicated by high-molecular weight hyaluronan and the resolution of inflammation

“…Upon reconstitution with CD44 + leukocytes, the inflammation is resolved [6, 40, 43]. Similar defects were subsequently demonstrated in other injury models including bacterial pneumonia [29, 39]. Myocardial infarcts in CD44 −/− mice are associated with reduced collagen deposition and fewer fibroblasts [32, 45], suggesting that the loss of CD44 impairs the effectiveness and efficiency of wound repair.…”

“…LMW-HA promotes the activation and maturation of dendritic cells (DC) [1, 25], drives the release of pro-inflammatory cytokines such as IL-1β, TNF-α, IL-6, and IL-12 by multiple cell types [6, 26–28], drives chemokine expression and cell trafficking [29–31], and promotes proliferation [32–34] (Fig. 1).…”

Role of hyaluronan and hyaluronan-binding proteins in lung pathobiology

“…Some examples of signaling pathways and molecules activated by HA binding of CD44 include Rac activation, leading to lamellipodia formation (103); ERM and merlin proteins (93); Src (124); and Rho kinase (ROCK) (123,124). The importance of CD44 in the lung has been demonstrated through the use of the CD44 knockout mouse in multiple models of lung disease, including inflammation, vascular leak syndromes, and noninfectious lung diseases, which are discussed below (45,56,111,139,145,147).…”