Many encapsulated bacteria use capsules to cause invasive diseases. However, it remains largely unknown how the capsules enhance bacterial virulence under in vivo infection conditions. Here we show that the capsules primarily target the liver to enhance bacterial survival at the onset of blood-borne infections. In a mouse sepsis model, the capsules enabled human pathogens Streptococcus pneumoniae and Escherichia coli to circumvent the recognition of liver-resident macrophage Kupffer cells (KCs) in a capsular serotype-dependent manner. In contrast to effective capture of acapsular bacteria by KCs, the encapsulated bacteria are partially (low-virulence types) or completely (high-virulence types) “untouchable” for KCs. We finally identified the asialoglycoprotein receptor (ASGR) as the first known capsule receptor on KCs to recognize the low-virulence serotype-7F and -14 pneumococcal capsules. Our data identify the molecular interplay between the capsules and KCs as a master controller of the fate and virulence of encapsulated bacteria, and suggest that the interplay is targetable for therapeutic control of septic infections.

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Summary Natural transformation mediates horizontal gene transfer, and thereby promotes exchange of antibiotic resistance and virulence traits among bacteria. Streptococcus pneumoniae, the first known transformable bacterium, rapidly activates and then terminates the transformation state, but it is unclear how the bacterium accomplishes this rapid turn‐around at the protein level. This work determined the transcriptomic and proteomic dynamics during the window of pneumococcal transformation. RNA sequencing revealed a nearly uniform temporal pattern of rapid transcriptional activation and subsequent shutdown for the genes encoding transformation proteins. In contrast, mass spectrometry analysis showed that the majority of transformation proteins were substantially preserved beyond the window of transformation. However, ComEA and ComEC, major components of the DNA uptake apparatus for transformation, were completely degraded at the end of transformation. Further mutagenesis screening revealed that the membrane‐associated serine protease HtrA mediates selective degradation of ComEA and ComEC, strongly suggesting that breakdown of the DNA uptake apparatus by HtrA is an important mechanism for termination of pneumococcal transformation. Finally, our mutagenesis analysis showed that HtrA inhibits natural transformation of Streptococcus mitis and Streptococcus gordonii. Together, this work has revealed that HtrA regulates the level and duration of natural transformation in multiple streptococcal species.

The present study was designed to investigate the impact of midcervical spinal cord injury on respiratory outputs and compare respiratory recovery following high- vs. midcervical spinal injury. A unilateral hemisection (Hx) in the spinal cord at C2 or C4 was performed in adult rats. Respiratory behaviors of unanesthetized animals were measured at normoxic baseline and hypercapnia by whole body plethysmography at 1 day and 1, 2, 4, and 8 wk after spinal injury. C2Hx and C4Hx induced a similar rapid shallow breathing pattern at 1 day postinjury. The respiratory frequency of C4Hx animals gradually returned to normal, but the tidal volume from 1 to 8 wk postinjury remained lower than that of the control animals. Linear regression analyses indicated that the tidal volume recovery was greater in the C4Hx animals than in the C2Hx animals at the baseline, but not at hypercapnia. The bilateral phrenic nerve activity was recorded in anesthetized animals under different respiratory drives at 8-9 wk postinjury. The phrenic burst amplitude ipsilateral to the lesion reduced following both high- and midcervical Hx; however, the ability to increase activity was lower in the C4Hx animals than in the C2Hx animals. When the data were normalized by the maximal inspiratory effort during asphyxia, the phrenic burst amplitude enhanced in the C4Hx animals, but reduced in the C2Hx animals compared with the control animals. These results suggest that respiratory deficits are evident following midcervical Hx, and that respiratory recovery and neuroplasticity of phrenic outputs are different following high- vs. midcervical spinal injury.

BackgroundRandom skin flaps are routinely placed during plastic and reconstructive surgery, but the distal areas often develop ischemia and necrosis. Baicalein, a major flavonoid extracted from the traditional Chinese herbal medicine huangqin, Scutellaria baicalensis Georgi, may improve flap viability.Materials and methodsRats were randomly divided into baicalein and control groups and they underwent placement of modified McFarlane flaps after intraperitoneal administration of baicalein or vehicle. Flap survival and water content were measured 7 days later, as were angiogenesis, apoptosis, and oxidative stress in ischemic flaps.ResultsBaicalein promoted flap survival, reduced edema, increased mean vessel density, and enhanced vascular endothelial growth factor production at both the translational and transcriptional levels. Baicalein reduced caspase 3 cleavage, increased superoxidase dismutase and glutathione levels, and decreased the malondialdehyde level.ConclusionBaicalein promoted flap viability by stimulating angiogenesis and inhibiting apoptosis and oxidation.