Publications

The COVID-19 pandemic has persisted for more than a year, and post-COVID-19 sequelae of neurological complications, including direct and indirect effects on the central nervous system (CNS), have been recognized. There is a plethora of evidence for neurological, cognitive, and emotional deficits in COVID-19 patients. Acute neurological symptoms like neuroinflammation, cognitive impairment, loss of smell, and brain stroke are common direct effects among SARS-CoV-2 infected individuals. Work-associated stress, lockdowns, social distancing, and quarantine in response to contain SARS-CoV-2 have also affected the mental health of large populations, regardless of age. Public health emergencies have affected individuals and communities, resulting in emotional reactions and unhealthy behaviors. Although vaccines have been widely distributed and administered among large populations, vaccine hesitancy still exists and may be due to apprehension about vaccine efficacy, preliminary trials, and associated side effects. This review highlights the impact of COVID-19 on the CNS by outlining direct and indirect effects and factors contributing to the decline in people's mental health throughout the COVID-19 pandemic both during and after vaccine administration. Furthermore, we also discuss reasons for vaccine hesitancy and why some groups of people are deprived of vaccines. Finally, we touched upon the social determinants of mental health and their impact on disadvantaged populations during times of crisis which may help policymakers set up some action plans to mitigate the COVID-19 mental health turmoil during this ongoing pandemic.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 19 (COVID-19) pandemic. Despite unprecedented research and developmental efforts, SARS-CoV-2-specific antivirals are still unavailable for the treatment of COVID-19. In most instances, SARS-CoV-2 infection initiates with the binding of Spike glycoprotein to the host cell ACE2 receptor. Utilizing the crystal structure of the ACE2/Spike receptor-binding domain (S-RBD) complex (PDB file 6M0J) in a computer-aided drug design approach, we identified and validated five potential inhibitors of S-RBD and ACE-2 interaction. Two of the five compounds, MU-UNMC-1 and MU-UNMC-2, blocked the entry of pseudovirus particles expressing SARS-CoV-2 Spike glycoprotein. In live SARS-CoV-2 infection assays, both compounds showed antiviral activity with IC50 values in the micromolar range (MU-UNMC-1: IC50 = 0.67 μM and MU-UNMC-2: IC50 = 1.72 μM) in human bronchial epithelial cells. Furthermore, MU-UNMC-1 and MU-UNMC-2 effectively blocked the replication of rapidly transmitting variants of concern: South African variant B.1.351 (IC50 = 9.27 and 3.00 μM) and Scotland variant B.1.222 (IC50 = 2.64 and 1.39 μM), respectively. Following these assays, we conducted "induced-fit (flexible) docking" to understand the binding mode of MU-UNMC-1/MU-UNMC-2 at the S-RBD/ACE2 interface. Our data showed that mutation N501Y (present in B.1.351 variant) alters the binding mode of MU-UNMC-2 such that it is partially exposed to the solvent and has reduced polar contacts. Finally, MU-UNMC-2 displayed high synergy with remdesivir, the only approved drug for treating hospitalized COVID-19 patients. IMPORTANCE The ongoing coronavirus infectious disease 2019 (COVID-19) pandemic is caused by a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). More than 207 million people have been infected globally, and 4.3 million have died due to this viral outbreak. While a few vaccines have been deployed, a SARS-CoV-2-specific antiviral for the treatment of COVID-19 is yet to be approved. As the interaction of SARS-CoV-2 Spike protein with ACE2 is critical for cellular entry, using a combination of a computer-aided drug design (CADD) approach and cell-based in vitro assays, we report the identification of five potential SARS-CoV-2 entry inhibitors. Out of the five, two compounds (MU-UNMC-1 and MU-UNMC-2) have antiviral activity against ancestral SARS-CoV-2 and emerging variants from South Africa and Scotland. Furthermore, MU-UNMC-2 acts synergistically with remdesivir (RDV), suggesting that RDV and MU-UNMC-2 can be developed as a combination therapy to treat COVID-19 patients.

The emergence and rapid spread of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 180 million confirmed cases resulting in over 4 million deaths worldwide with no clear end in sight for the coronavirus disease 19 (COVID-19) pandemic. Most SARS-CoV-2 exposed individuals experience mild to moderate symptoms, including fever, cough, fatigue, and loss of smell and taste. However, many individuals develop pneumonia, acute respiratory distress syndrome, septic shock, and multiorgan dysfunction. In addition to these primarily respiratory symptoms, SARS-CoV-2 can also infiltrate the central nervous system, which may damage the blood-brain barrier and the neuron's synapses. Resultant inflammation and neurodegeneration in the brain stem can further prevent efferent signaling to cranial nerves, leading to the loss of anti-inflammatory signaling and normal respiratory and gastrointestinal functions. Additionally, SARS-CoV-2 can infect enterocytes resulting in gut damage followed by microbial dysbiosis and translocation of bacteria and their byproducts across the damaged epithelial barrier. As a result, this exacerbates pro-inflammatory responses both locally and systemically, resulting in impaired clinical outcomes. Recent evidence has highlighted the complex interactions that mutually modulate respiratory, neurological, and gastrointestinal function. In this review, we discuss the ways SARS-CoV-2 potentially disrupts the gut-brain-lung axis. We further highlight targeting specific responses to SARS-CoV-2 for the development of novel, urgently needed therapeutic interventions. Finally, we propose a prospective related to the individuals from Low- and Middle-Income countries. Here, the underlying propensity for heightened gut damage/microbial translocation is likely to result in worse clinical outcomes during this COVID-19 pandemic.

Emerging and re-emerging viral diseases can create devastating effects on human lives and may also lead to economic crises. The ongoing COVID-19 pandemic due to the novel coronavirus (nCoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which originated in Wuhan, China, has caused a global public health emergency. To date, the molecular mechanism of transmission of SARS-CoV-2, its clinical manifestations and pathogenesis is not completely understood. The global scientific community has intensified its efforts in understanding the biology of SARS-CoV-2 for development of vaccines and therapeutic interventions to prevent the rapid spread of the virus and to control mortality and morbidity associated with COVID-19. To understand the pathophysiology of SARS-CoV-2, appropriate animal models that mimic the biology of human SARS-CoV-2 infection are urgently needed. In this review, we outline animal models that have been used to study previous human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV). Importantly, we discuss models that are appropriate for SARS-CoV-2 as well as the advantages and disadvantages of various available methods.

The concurrence of infection with human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), presents an intriguing problem with many uncertainties underlying their pathogenesis. Despite over 96.2 million cases of COVID-19 worldwide as of January 22, 2021, reports of patients coinfected with HIV and SARS-CoV-2 are scarce. It remains unknown whether HIV patients are at a greater risk of infection from SARS-CoV-2, despite their immunocompromised status. We present a systematic review of the literature reporting cases of HIV and SARS-CoV-2 coinfection, and examine trends of clinical outcomes among coinfected patients. We systematically compiled 63 reports of HIV-1 and SARS-CoV-2 coinfection, published as of January 22, 2021. These studies were retrieved through targeted search terms applied to PubMed/Medline and manual search. Despite scattered evidence, reports indicate a favorable prognosis for HIV patients with strict adherence to combined antiretroviral therapy (cART). However, the presence of comorbidities was associated with a poorer prognosis in HIV/SARS-CoV-2 patients, despite cART and viral suppression. Studies were limited by geographic coverage, small sample size, lack of patient details, and short follow-up durations. Although some anti-HIV drugs have shown promising in vitro activity against SARS-CoV-2, there is no conclusive evidence of the clinical efficacy of any anti-HIV drug in the treatment of COVID-19. Further research is needed to explain the under-representation of severe COVID-19 cases among the HIV patient population and to explore the possible protective mechanisms of cART in this vulnerable population.

Blood and semen are important body-fluids that carry exosomes for bioinformation transmission. Therefore, characterization of their proteomes is necessary for understanding body-fluid-specific physiologic and pathophysiologic functions. Using systematic multifactorial proteomic profiling, we characterized the proteomes of exosomes and exosome-free fractions from autologous blood and semen from three HIV-uninfected and three HIV-infected participants (total of 24 samples). We identified exosome-based protein signatures specific to blood and semen along with HIV-induced tissue-dependent proteomic perturbations. We validated our findings with samples from 16 additional donors and showed that unlike blood exosomes (BE), semen exosomes (SE) are enriched in clusterin. SE but not BE promote Protein·Nucleic acid binding and increase cell adhesion irrespective of HIV infection. This is the first comparative study of the proteome of autologous BE and SE. The proteins identified may be developed as biomarkers applicable to different fields of medicine, including reproduction and infectious diseases.

Development of novel antiviral molecules from the beginning costs an average of $350 million to $2 billion per drug, and the journey from the laboratory to the clinic takes about 10-15 years. Utilization of drug repurposing approaches has generated substantial interest in order to overcome these drawbacks. A drastic reduction in the failure rate, which otherwise is  92%, is achieved with the drug repurposing approach. The recent exploration of the drug repurposing approach to combat the COVID-19 pandemic has further validated the fact that it is more beneficial to reinvestigate the in-practice drugs for a new application instead of designing novel drugs. The first successful example of drug repurposing is zidovudine (AZT), which was developed as an anti-cancer agent in the 1960s and was later approved by the US FDA as an anti-HIV therapeutic drug in the late 1980s after fast track clinical trials. Since that time, the drug repurposing approach has been successfully utilized to develop effective therapeutic strategies against a plethora of diseases. Hence, an extensive application of the drug repurposing approach will not only help to fight the current pandemics more efficiently but also predict and prepare for newly emerging viral infections. In this review, we discuss in detail the drug repurposing approach and its advancements related to viral infections such as Human Immunodeficiency Virus (HIV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

HIV/SIV-associated oral mucosal disease/dysfunction (HAOMD) (gingivitis/periodontitis/salivary adenitis) represents a major comorbidity affecting HIV patients on anti-retroviral therapy. Using a systems biology approach, we investigated molecular changes (mRNA/microRNA) underlying HAOMD and its modulation by phytocannabinoids (delta-9-tetrahydrocannabinol (∆9-THC)) in uninfected (n = 5) and SIV-infected rhesus macaques untreated (VEH-untreated/SIV; n = 7) or treated with vehicle (VEH/SIV; n = 3) or ∆9-THC (THC/SIV; n = 3). Relative to controls, fewer mRNAs were upregulated in THC/SIV compared to VEH-untreated/SIV macaques. Gene enrichment analysis showed differential enrichment of biological functions involved in anti-viral defense, Type-I interferon, Toll-like receptor, RIG-1 and IL1R signaling in VEH-untreated/SIV macaques. We focused on the anti-ER-stress anterior gradient-2 (AGR2), epithelial barrier protecting and anti-dysbiotic WAP Four-Disulfide Core Domain-2 (WFDC2) and glucocorticoid-induced anti-inflammatory TSC22D3 (TSC22-domain family member-3) that were significantly downregulated in oropharyngeal mucosa (OPM) of VEH-untreated/SIV macaques. All three proteins localized to minor salivary gland acini and secretory ducts and showed enhanced and reduced expression in OPM of THC/SIV and VEH/SIV macaques, respectively. Additionally, inflammation associated miR-21, miR-142-3p and miR-29b showed significantly higher expression in OPM of VEH-untreated/SIV macaques. TSC22D3 was validated as a target of miR-29b. These preliminary translational findings suggest that phytocannabinoids may safely and effectively reduce oral inflammatory responses in HIV/SIV and other (autoimmune) diseases.