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Objective: We have previously reported that low doses of [Met⁵]-enkephalin (YGGFM, met-enkephalin) and two of its derivatives (YGG and YG) enhanced and accelerated delayed-type hypersensitivity responses while much higher doses of these compounds suppressed these reactions. Since the underlying mechanisms by which this and other immunomodulatory effects occur have not been established, this report explores the in vitro modulation of Th1 and Th2 cytokine expression by these peptides. Methods: Murine splenocytes were stimulated with suboptimal concentrations of concanavalin A (ConA) in serum-free medium in the absence or presence of met-enkephalin, YGG, YG, [des-Tyr¹]-met-enkephalin (GGFM), [D-Ala²], [D-Met⁵]-enkephalin or tyrosine (Y). Cell-conditioned supernatants were assayed for interferon-γ (IFN-γ), interleukin (IL)-2 and IL-4. Relative IFN-γ and IL-2 mRNA levels were assessed by reverse transcription-polymerase chain reaction. The enhancing and suppressive effects of met-enkephalin and YG on IFN-γ production were also tested in the presence of naloxone (Nx). Results: Met-enkephalin, YGG and YG modulated the in vitro production of IFN-γ in a biphasic manner: stimulation at low doses and inhibition at high doses. At higher concentrations, met-enkephalin and YG also suppressed the production of IL-2 (type 1) and IL-4, a type 2 cytokine. Nx reversed the enhancing effect of met-enkephalin on IFN-γ production without affecting its suppressive action or any of the immunomodulating effects of YG. The degradation-resistant analog [D-Ala²], [D-Met⁵]-enkephalin enhanced IFN-γ production but did not suppress it. Conclusions: YG, the minimal molecular requirement for enhancement and suppression of immune responses by these metabolites, appears to mediate exclusively an across-the-board suppression via low-affinity, nonclassical, nonopioid receptors.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the novel respiratory disease COVID-19, has reached pandemic status and presents a wide range of manifestations of diverse magnitude, including fever, cough, shortness of breath, and damage to vital organs, such as the heart, lung, kidney, and brain. Normally, older individuals and those with underlying health issues are more at risk. However, about 40% of COVID-19 positive individuals are asymptomatic. This review aims to identify suggested mechanisms of diverse manifestations of COVID-19. Studies suggest that T cell-mediated immunity and specific and/or nonspecific immunity from other vaccines could protect against SARS-CoV-2. The potential role of cross-reacting antibodies to coronaviruses that cause the common cold, mumps virus, polio virus, and pneumococcal bacteria are also suggested to help protect against COVID-19. Decreased production of Type I interferons (IFN-α and IFN-β) could also be linked to COVID-19 manifestations. Several studies suggest that ACE2 cell membrane receptors are involved in SARS-CoV-2 infection. However, the relationship between an abundance of ACE2 receptors and the infectivity of the virus is unknown. Unlocking these manifestation mysteries could be crucial as this could help researchers better understand the virulence, pathology, and immune responses associated with SARS-CoV-2, leading to the development of effective therapies and treatment plans.

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