Abstract
Streptococcus pneumoniae is the main cause of bacterial pneumonia, a condition that currently produces significant global morbidity and mortality. The initial immune response to this bacterium occurs when the innate system recognizes common motifs expressed by many pathogens, events driven by pattern recognition receptors like the Toll-like family receptors (TLRs). In this study, lung myeloid-cell populations responsible for the innate immune response (IIR) against S. pneumoniae, and their dependence on the TLR4-signaling axis, were analyzed in TLR4–/– and Myeloid-Differentiation factor-88 deficient (MyD88–/–) mice. Neutrophils and monocyte-derived cells were recruited in infected mice 3-days post-infection. Compared to wild-type mice, there was an increased bacterial load in both these deficient mouse strains and an altered IIR, although TLR4–/– mice were more susceptible to bacterial infection. These mice also developed fewer alveolar macrophages, weaker neutrophil infiltration, less Ly6Chigh monocyte differentiation and a disrupted classical and non-classical monocyte profile. The pro-inflammatory cytokine profile (CXCL1, TNF-α, IL-6, and IL-1β) was also severely affected by the lack of TLR4 and no induction of Th1 was observed in these mice. The respiratory burst (ROS production) after infection was profoundly dampened in TLR4–/– and MyD88–/– mice. These data demonstrate the complex dynamics of myeloid populations and a key role of the TLR4-signaling axis in the IIR to S. pneumoniae, which involves both the MyD88 and TRIF (Toll/IL-1R domain-containing adaptor-inducing IFN-β) dependent pathways.
Highlights
IntroductionStreptococcus pneumoniae (pneumococcus) is a Gram-positive bacterium that colonizes and invades the respiratory tract
Streptococcus pneumoniae is a Gram-positive bacterium that colonizes and invades the respiratory tract
We performed initial experiments to establish the optimal dose for S. pneumoniae serotype 3 strain 1195 infection and the time required to mount an innate immune response (IIR), parameters that allowed us to study the myeloid cell subpopulations involved, as well as the role of TLR4 and MyD88 expression
Summary
Streptococcus pneumoniae (pneumococcus) is a Gram-positive bacterium that colonizes and invades the respiratory tract. It is the main etiological agent of community acquired pneumonia, accounting for about 90% of all pneumonia deaths, especially in young children and the elderly [1, 2]. As a consequence, it is a major cause of morbidity and mortality worldwide [2], the present pandemic induced by SARS-Cov is currently changing the top list of the most dangerous. As the immune lung response underlying S. pneumoniae infection is still not fully understood, a better understanding of this response will be essential to design new effective therapeutic interventions
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