Differential impact of acute and chronic opioids on ocular innate immunity and infections - Project Summary Opioid Use Disorder (OUD) poses serious consequences including overdose or death from excessive and prolonged use of prescribed or illicit opioids. The opioid epidemic has also resulted in a striking, nationwide increase in infectious diseases including HIV, hepatitis, and invasive bacterial and fungal infections, which worsen long-term health outcomes. The consensus is that opioids are immunosuppressive and thereby increase the vulnerability to infections. However, the effect of acute or repeated opioid exposure on immunity remains elusive. In the eye, substance use is an important risk factor for developing endogenous endophthalmitis, a blinding infectious disease primarily caused by fungal (Candida sp.) and bacterial (S. aureus) pathogens. Several clinical and epidemiological studies have reported an increasing number of opioid use-associated endophthalmitis cases. Our preliminary data showed that cultured human retinal pigment epithelium (RPE) cells, human monocytes, and mouse retina express the mu-opioid receptor (MOR) which is activated in response to morphine exposure. Acute morphine exposure increased, whereas repeated morphine exposure decreased, inflammatory response in cultured cells. Similarly, repeated morphine administration in B6 mice reduced cytokine levels in the plasma but elevated them in the retinal tissue. Additionally, systemic Candida auris infection in morphine-dependent mice increased fungal burden in the eye, brain, and kidneys. Based on these findings, we hypothesize that repeated opioid exposure (e.g., morphine and fentanyl) impairs both systemic and ocular innate immunity resulting in increased incidence and severity of infectious endophthalmitis. The overall goal of this proposal is to evaluate the effect of opioids on innate immunity and its impact on the pathogenesis of endophthalmitis. Here, we will elucidate mechanisms underlying impaired innate responses of retinal and myeloid cells under opioid exposure (Aim 1) and determine whether OUD increases the susceptibility and severity of endophthalmitis in mouse models (Aim 2). The knowledge gained from this study could have a significant impact on ocular infections among substance abusers and could contribute to the advancement of therapeutic interventions in the field, offering new hope for preserving vision and improving outcomes in patients affected by these conditions.
