Bruton's Tyrosine Kinase Inhibitors Impair FcγRIIA-Driven Platelet Responses to Bacteria in Chronic Lymphocytic Leukemia.

Bacterial infections are a major cause of morbidity and mortality in chronic lymphocytic leukemia (CLL), and infection risk increases in patients treated with the Bruton's tyrosine kinase (Btk) inhibitor, ibrutinib. Btk and related kinases (like Tec) are expressed in non-leukemic hematopoietic cells and can be targeted by ibrutinib. In platelets, ibrutinib therapy is associated with bleeding complications mostly due to off-target effects. But the ability of platelets to respond to bacteria in CLL, and the potential impact of ibrutinib on platelet innate immune functions remain unknown. FcγRIIA is a tyrosine kinase-dependent receptor critical for platelet activation in response to IgG-coated pathogens. Crosslinking of this receptor with monoclonal antibodies causes downstream activation of Btk and Tec in platelets, however, this has not been investigated in response to bacteria. We asked whether ibrutinib impacts on FcγRIIA-mediated activation of platelets derived from CLL patients and healthy donors after exposure to Staphylococcus aureus Newman and Escherichia coli RS218. Platelet aggregation, α-granule secretion and integrin αIIbß3-dependent scavenging of bacteria were detected in CLL platelets but impaired in platelets from ibrutinib-treated patients and in healthy donor-derived platelets exposed to ibrutinib in vitro. While levels of surface FcγRIIA remained unaffected, CLL platelets had reduced expression of integrin αIIbß3 and GPVI compared to controls regardless of therapy. In respect of intracellular signaling, bacteria induced Btk and Tec phosphorylation in both CLL and control platelets that was inhibited by ibrutinib. To address if Btk is essential for platelet activation in response to bacteria, platelets derived from X-linked agammaglobulinemia patients (lacking functional Btk) were exposed to S. aureus Newman and E. coli RS218, and FcγRIIA-dependent aggregation was observed. Our data suggest that ibrutinib impairment of FcγRIIA-mediated platelet activation by bacteria results from a combination of Btk and Tec inhibition, although off-target effects on additional kinases cannot be discarded. This is potentially relevant to control infection-risk in CLL patients and, thus, future studies should carefully evaluate the effects of CLL therapies, including Btk inhibitors with higher specificity for Btk, on platelet-mediated immune functions.

Groups of bats improve sonar efficiency through mutual suppression of pulse emissions.

How bats adapt their sonar behavior to accommodate the noisiness of a crowded day roost is a mystery. Some bats change their pulse acoustics to enhance the distinction between theirs and another bat's echoes, but additional mechanisms are needed to explain the bat sonar system's exceptional resilience to jamming by conspecifics. Variable pulse repetition rate strategies offer one potential solution to this dynamic problem, but precisely how changes in pulse rate could improve sonar performance in social settings is unclear. Here we show that bats decrease their emission rates as population density increases, following a pattern that reflects a cumulative mutual suppression of each other's pulse emissions. Playback of artificially-generated echolocation pulses similarly slowed emission rates, demonstrating that suppression was mediated by hearing the pulses of other bats. Slower emission rates did not support an antiphonal emission strategy but did reduce the relative proportion of emitted pulses that overlapped with another bat's emissions, reducing the relative rate of mutual interference. The prevalence of acoustic interferences occurring amongst bats was empirically determined to be a linear function of population density and mean emission rates. Consequently as group size increased, small reductions in emission rates spread across the group partially mitigated the increase in interference rate. Drawing on lessons learned from communications networking theory we show how modest decreases in pulse emission rates can significantly increase the net information throughput of the shared acoustic space, thereby improving sonar efficiency for all individuals in a group. We propose that an automated acoustic suppression of pulse emissions triggered by bats hearing each other's emissions dynamically optimizes sonar efficiency for the entire group.

A mechanism for antiphonal echolocation by Free-tailed bats.

Bats are highly social and spend much of their lives echolocating in the presence of other bats. To reduce the effects of acoustic interferences from other bats' echolocation calls, we hypothesized that bats might shift the timing of their pulse emissions to minimize temporal overlap with another bat's echolocation pulses. To test this hypothesis we investigated whether free-tailed bats (Tadarida brasiliensis) echolocating in the lab would shift the timing of their own pulse emissions in response to regularly repeating artificial acoustic stimuli. A robust phase-locked temporal pattern in pulse emissions was displayed by every bat tested which included an initial suppressive phase lasting more than 60 ms after stimulus onset, during which the probability of emitting pulses was reduced by more than fifty percent, followed by a compensatory rebound phase, the timing and amplitude of which were dependent on the temporal pattern of the stimulus. The responses were non-adapting and were largely insensitive to broad changes in the acoustic properties of the stimulus. Randomly occurring noise-bursts also suppressed calling for up to 60 ms, but the time-course of the compensatory rebound phase was more rapid than when the bats were responding to regularly repeating patterns of noise bursts. These findings provide the first quantitative description of how external stimuli may cause echolocating bats to alter the timing of subsequent pulse emissions.