- Coding and Noncoding Transcripts in Inflammatory Responses
The recurring environmental exposures or so-called “experiments of nature” have helped evolve a trained immune response in several immune cells resulting from genetic and epigenetic remodeling. Specifically, the mechanism(s) by which the repetitive exposures affect innate mucosal immunity is unclear. Recent sequencing advances have revealed that the human genome produces a large number of coding and noncoding transcripts (RNAs) that play critical role in cellular functions, development, and diseases. However, only a fraction of these large sets of noncoding genes have established biological functions. Dr. Chand’s lab proposes that the airway epithelial cells (AECs) is in an altered state of homeostasis resulting in a trained mucous response. Recurring exposures to microbial ligands have been shown to propagate a memory-based host-beneficial immune response in monocytes, macrophages, and NK cells; however, contribution of the AECs in this trained response is not known. Specifically, we have identified a few novel noncoding RNAs that could possibly be involved in potentiating a hyperreactive mucous response. Studies are ongoing to validate the functional and the molecular characteristics of novel putative immunomodulatory lncRNAs and unravel the mechanisms of a trained mucous response that could provide novel strategies to prevent or intervene the debilitating lung pathologies.
- Mitochondrial Dynamics, Tobacco Products (E-Cigs), and Nanomedicine
Tobacco smoke (TS) exposure is strongly associated with the etiology of chronic obstructive pulmonary disease or COPD. Today, COPD is one of the leading causes of death worldwide, and the incidence of COPD in South Florida are rising at an alarming rate. COPD is characterized by an ‘accelerated’ decline or aging of lung function and is symptomatically manifested by chronic bronchitis (CB), upper airway obstruction, and lower airway destruction (or emphysema) due to dysregulated airway inflammatory responses. Lung epithelial cells are the sentinel cells of upper airway that are among first host cells to encounter the inhaled TS and help orchestrate the appropriate airway inflammatory responses. In addition to inflammatory factors, these cells secrete mucus to help mitigate the TS insult by mucociliary clearance mechanism and maintain normal mucus homeostasis. However, chronic TS exposure disrupts these responses causing uncontrolled inflammation and mucus production. Lung cell mitochondria modulate cellular biosynthetic and metabolic pathways as well as calcium and oxidative homeostasis, and therefore, are key regulators of cell survival. Mitochondria undergo dynamic remodeling by continually fusing and dividing to control their quality, distribution, size, and motility. Several proteins regulate the mitochondrial morphology and functions and Dr. Chand’s lab observed that TS exposure disrupts the expression and function of mitochondrial associated proteins to augment the mucous responses and mucus cell survival. Studies posit that TS exposure causes aberrant changes in lung epithelial cells and their mitochondria to help sustain mucous hyperexpression and contribute toward the development of CB. These and other ongoing studies will thus help in employing nanomedicine-based approaches to develop novel intervention strategies against chronic bronchitis and other lung diseases. In addition, the use of electronic cigarettes (E-cigs) has reached epidemic levels among young people in the US with very high prevalence of flavored E-cig products among adolescent and young adults. While some of the E-cig use-mediated long-term hazards are established, emerging evidence indicates that the acute effects of E-cigs on young developing lungs is of a particular concern. Currently, an estimated 10 million US adults and over 3 million high school adolescents are active E-cig users (including e-juices, puff bars, and pod-based systems) as per the recent CDC report. Flavoring compounds or additives like menthol has hugely contributed to the popularity of E-cig use and menthol/mint flavor is widely popular among young adults. There is a substantial knowledge gap regarding the impact of menthol flavor E-cig products on respiratory system, addictive behavior, and toxicology. Considering the ongoing outbreak of e-cigarette/vaping use-associated lung injury (EVALI) at the top of the ongoing COVID-19 pandemic may result in severe health outcomes among the E-cig users. Thus, the ongoing studies at Dr. Chand’s lab will help in employing nanomedicine-based approaches to develop novel intervention strategies in reducing or mitigating the effects of smoke- or E-Cig-induced lung pathologies.
- Interaction of HIV, Tobacco Smoke, and Opioids at the Lung-Brain Axis
Contemporary antiretroviral therapy has transformed HIV infection into a medically manageable chronic condition. However, the longer lifespan of people living with HIV (PLWH) has made them more susceptible to other infections and comorbid diseases. Tobacco smoking is highly prevalent among PLWH and smokers living with HIV (SLWH) exhibit an early onset of COPD with an accelerated decline in lung functions. Our data suggested that HIV is a strong independent risk factor in causing epithelial barrier dysfunction and chronic lung pathologies, and CS-exposure synergistically exacerbated the lung epithelial remodeling. Nonetheless, not much is known about the host lung factors contributing to this condition in SLWH. Our studies suggest that novel immunomodulatory long noncoding RNAs (lncRNAs) could be an essential modulator of airway epithelial response and COPD pathogenesis in the context of HIV infection. The objectives of the ongoing studies at Dr. Chand’s lab are to help improve the current understanding on the effects of environmental exposures like CS and HIV in lung epithelial cells and may provide new insights for restoring and improving the pulmonary and overall health of SLWH. The opioid abuse is on the rise and the pathophysiological interaction of opioids and HIV are highly complex severely affecting the immune system by modulating the functions of variety of immune cells. Opioid receptors are widely expressed on immune cells and opioids can modulate immune function, which mostly results in immune suppression. Our group is actively engaged in exploring molecular mechanisms underlying neuro-immunopathogenesis of HIV infection and substances abuse. Mechanistically, the long-term opioid use results in brain tissue remodeling and epigenetic alterations with changes in DNA methylation and noncoding RNA expression, which can persist years following abstinence. Along with the bench-to-bedside translational research, the reverse-translational approaches with appropriate preclinical models are essential to improve the current understanding of a disease pathogenesis and improve therapeutic efficacies. Evidence suggests that HIV compartmentalizes within the CNS early following the infection to establish latent reservoirs harboring intact proviral HIV within CNS cells, perivascular macrophages and we reported recently in respiratory epithelium. Accordingly, specific preclinical studies are needed to analyze the comorbid effects of opioids and SARS-CoV-2 to permit mechanistic understanding of how the neuropathological effects of opioids and viral infection affect respiratory system and contribute to the accentuating effects of opioids among PLWH in this COVID-19 pandemic era.
- Understanding the Impact of COVID-19 on Innate Mucosal Immunity
The effects and prevalence of current COVID-19 (coronavirus disease of 2019) pandemic among people living with HIV (PLWH) is not completely defined yet. Therefore, more focused studies are urgently needed to understand the risk and the pathophysiology of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection among PLWH. Specifically, the asymptomatic COVID-19 condition pose a major limitation. PLWH are highly susceptible to early onset of chronic lung diseases compared to the non-HIV population. In addition, there is a very high prevalence of opioid abuse among PLWH that further compromises the immune response among these subjects. As lung airway epithelial cells express high levels of viral entry receptors and cofactors, they are the primary target of SARS-CoV-2 host infection. Even for HIV infection, we have observed that lung airway epithelial cells are susceptible to HIV infection and even after well-controlled viremia; HIV-infected lungs contain large numbers of HIV provirus particles in epithelial cells. Lung epithelial cells are critical airway barrier cells that orchestrate immune responses to airborne viral infections such as HIV and SARS-CoV-2 and are crucial for successful resolution of infection. Epidemiological studies suggest HIV infection as an independent risk factor for chronic lung diseases; and other emerging/opportunistic viral infections synergize to promote these comorbidities. However, most of these associations are putative and lack scientific evidence, therefore, rigorous studies are needed to investigate the role of SARS-CoV-2 in lung cell responses and in overall immune defense against COVID-19 and help improve the efficacy of ongoing vaccination efforts.
- Pathophysiology of HIV, COPD, and Alzheimer’s Disease
Dr. Chand’s lab investigates the fundamental role of immunomodulatory lncRNAs in regulating the neuroinflammation and neurodegeneration observed in Alzheimer’s disease (AD). Pathological features leading to the development of AD include the progressive and irreversible inflammation, synaptic dysfunction, and neurodegeneration that symptomatically manifests as memory loss and cognitive impairment or AD-related dementias (ADRD). Despite the high prevalence, the etiology of AD/ADRD is not completely understood, therefore, a better understanding of the molecular mechanisms responsible for AD-associated neuroinflammation and neurodegeneration could contribute to the discovery of novel intervention targets that could prevent or delay the AD-associated pathologies. Specifically, these AD-related pathologies are also highly prevalent among the HIV-infected population. As mentioned in the parent application, the combination antiretroviral therapy (cART) has been very effective in suppressing the viremia and has improved the lifespan of people living with HIV (PLWH). With longer life expectancy, PLWH is highly susceptible to neurocognitive disorders such as HIV-associated neurocognitive disorder (HAND) and aging-related comorbidities such as AD. The long-term cART, chronic immune activation, and accelerated aging are implicated in the observed neurodegeneration and neurocognitive impairment; however, not much is known about the molecular mechanisms responsible for the higher incidences of AD among PLWH. Despite high prevalence, the etiology of AD among PLWH is not completely understood, therefore, a better understanding of the molecular mechanisms responsible for HIV- and AD-associated neurocognitive impairment could contribute to the discovery of novel intervention targets that could prevent or delay these neurodegenerative pathologies.