Elevated cochlear adenosine causes hearing loss via ADORA2B signaling

Over 538 million people in the world have been diagnosed with hearing loss (HL). Current treatments for the most common type of HL, sensorineural HL, are limited to hearing aids and cochlear implants with no FDA-drugs available. The hearing process demands an abundance of ATP and HL is often attributed to a disruption in this metabolic energy currency. Patients who lack adenosine deaminase (ADA), the enzyme that irreversibly metabolizes adenosine, have high levels of adenosine that yield severe health problems, including HL; however, the pathogenic mechanisms behind HL and adenosine remain elusive. Our lab has found a HL phenotype in Ada-deficient mice (Ada-/-) that parallels ADA-deficient humans. We characterized shifts in both DPOAE and ABR thresholds in Ada-/- mice with high adenosine levels. Moreover, we found that these mice have an overall lowered firing capacity of both peripheral and cochlear nucleus and slow latency transmission between structures. We also observed nerve fiber density loss and aberrant myelin compaction. More importantly, we found that treatment of FDA-approved drug, polyethylene glycol-ADA (PEG-ADA), lowered cochlear adenosine levels and improved functional and structural phenotypes of Ada-/- mice. In addition to continuous treatment of PEG-ADA in Ada-/- mice, we also rescued these phenotypes in mice with HL after adenosine accumulation for two weeks. Together, these results provide fundamental evidence that elevated cochlear adenosine causes hearing loss via perturbations of myelin structures. Interestingly, out of all four adenosine receptors, adenosine a2b (ADORA2B) was found to have the highest mRNA expression in untreated Ada-/- cochlea. We observed that genetically and pharmacologically ablating ADORA2B in the Ada-/- mice attenuated hearing deficiencies and rescued nerve fiber density and myelin compaction of cochlear nerve. With these findings, we reveal that elevated adenosine-mediated hearing loss is dependent on ADORA2B signaling that leads to overall hearing sensitivity decline. Extending from our Ada-/- mice, we used aged mice as an additional SNHL model. Aging organs have been associated with hypoxia and, consequently, increased adenosine levels. Indeed, we found that aged Adora2b-/- rescued hearing sensitivity. Moreover, we used a therapeutic approach for both models to further validate the role of ADORA2B by using a specific- ADORA2B antagonist, PSB1115. PSB1115-treated aging mice also have rescued hearing sensitivity. We also explored another disease model that our lab found to have elevated systemic adenosine with reported HL in the clinic: sickle-cell disease (SCD). We found that C57B6/J mice transplanted with SCD mice bone marrow (BM) have hearing loss; however, we found that Adora2b-/- mice with SCD BM have attenuated hearing loss. Overall, our study supports the clinical and existing research on the relationship between adenosine signaling and hearing loss. Understanding this purinergic signaling establishes a strong foundation for molecular-based therapy in a very common disability

Glial-specific deletion of Med12 results in rapid hearing loss via degradation of the stria vascularis

Mediator protein complex subunit 12 (Med12) is a core component of the basal transcriptional apparatus and plays a critical role in the development of many tissues. Mutations in Med12 are associated with X-linked intellectual disability syndromes and hearing loss; however, its role in nervous system function remains undefined. Here, we show that temporal conditional deletion of Med12 in astrocytes in the adult CNS results in region-specific alterations in astrocyte morphology. Surprisingly, behavioral studies revealed rapid hearing loss after adult deletion of Med12 that was confirmed by a complete abrogation of auditory brainstem responses. Cellular analysis of the cochlea revealed degeneration of the stria vascularis, in conjunction with disorganization of basal cells adjacent to the spiral ligament and downregulation of key cell adhesion proteins. Physiologic analysis revealed early changes in endocochlear potential, consistent with strial-specific defects. Together, our studies reveal that Med12 regulates auditory function in the adult by preserving the structural integrity of the stria vascularis

Risk of COVID-19 after natural infection or vaccinationResearch in context

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health

Risk of COVID-19 after natural infection or vaccinationResearch in context

Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health