Diverse Manifestations of COVID-19: Some Suggested Mechanisms.

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-ß) 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.

In vitro modulation of cytokine expression by enkephalin-derived peptides.

OBJECTIVE: We have previously reported that low doses of [Met(5)]-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-Tyr(1)]-met-enkephalin (GGFM), [D-Ala(2)], [D-Met(5)]-enkephalin or tyrosine (Y). Cell-conditioned supernatants were assayed for interferon-gamma (IFN-gamma), interleukin (IL)-2 and IL-4. Relative IFN-gamma 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-gamma production were also tested in the presence of naloxone (Nx). RESULTS: Met-enkephalin, YGG and YG modulated the in vitro production of IFN-gamma 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-gamma production without affecting its suppressive action or any of the immunomodulating effects of YG. The degradation-resistant analog [D-Ala(2)], [D-Met(5)]-enkephalin enhanced IFN-gamma 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.

Modulation of delayed-type hypersensitivity responses in hairless guinea pigs by peptides derived from enkephalin.

Although opioid peptides such as methionine (met)-enkephalin have been previously shown to enhance or suppress immune responses, few studies in animal models have addressed the immunomodulatory activity of their metabolic derivatives. Hairless (IAF/HA-HO) guinea pigs immunized with Freund's complete adjuvant containing Mycobacterium tuberculosis and repeatedly skin tested with purified protein derivative of tuberculin (PPD) display high levels of stable delayed-type hypersensitivity (DTH) to PPD. Met-enkephalin (YGGFM) and two of its metabolites (YGG, YG) enhanced and accelerated PPD-elicited DTH inflammatory reactions when injected together with elicitor in these animals. At 24 h, 5 x 10(-3) pmol met-enkephalin significantly enhanced DTH responses by 30% over PPD alone, while 5 x 10(-5) pmol of YGG and 5 x 10(-9) pmol of YG significantly enhanced these responses by 62 and 32%, respectively. At much higher doses (5 x 10(3) pmol), met-enkephalin and its metabolites significantly suppressed DTH reactions by 25-32%. Tyrosine and glycine had no effect on PPD-elicited DTH. All DTH reactions (control, enhanced, suppressed) displayed typical perivascular mononuclear cell infiltrates. We conclude that the immunoactivity of met-enkephalin resides in its first two amino acids and suggest that cleavage of enkephalin molecules to YG occurs in serum and/or on the cell surface.