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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.

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.

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., (Copyright 2004 S. Karger AG, Basel)

Guinea pigs are a classic animal model for studying delayed-type hypersensitivity (DTH) reactions. However, skin irritation due to hair removal can interfere with the evaluation of the modulation of these responses by various mediators. A DTH model using hairless (IAF/HA-HO) guinea pigs, sensitized with complete Freund's adjuvant and repeatedly skin tested with tuberculin, purified protein derivative, (PPD) has therefore been developed. At 10 weeks after sensitization, intradermal PPD elicited minimal erythema at 6 h, which increased over the next 18 h to a maximum at 24 h, and declined by 48 h. The response could be quantified by bioassay using graded doses of PPD. Reactions at 24 h were characterized by predominantly mononuclear cell deep and superficial dermal infiltrates. Dermal DTH in hairless guinea pigs is thus, grossly and histologically similar to that seen in Hartley guinea pigs.

Leucocyte dialysates contain a number of substances which exert important effects on human cell-mediated immunity. In this report, we describe several properties of a designated subfraction, IMREGR-1, which is obtained by a second dialysis against a membrane having a 3500 m.w. cutoff. These include the ability to augment and accelerate reactions of delayed hypersensitivity against antigens to which the test subject has been previously sensitized, and the ability to enhance the expression in vitro on CD4 lymphocytes of the p55 subunit of the receptor for Interleukin-2. We also report our observation that in a patient with advanced HIV disease whose lymphocytes had lost there ability to properly express the IL-2 receptor, treatment with IMREGR-1 over a period of months restored the expression of the IL-2 receptor on the patient's CD4+ lymphocytes towards normal.

IMREG-1, a low-molecular-weight immunomodulator derived from normal human leukocyte dialysates, has been shown to enhance cutaneous delayed-type hypersensitivity (DTH) responses to recall antigens. Both IMREG-1 and the biologically active peptides (Tyr-Gly[YG] and Tyr-Gly-Gly[YGG]) identified therein are able to accelerate and enhance DTH in a concentration-dependent manner. In this study, we describe a novel methodology for analyzing and quantitating this response and demonstrate its use with data comparing drug to placebo. Subjects demonstrating prior sensitivity to a recall antigen (tetanus toxoid) received intradermal injections of tetanus toxoid alone (control) and either dilutions of IMREG-1 plus antigen, or placebo plus antigen, on the volar surface of the forearm. The response, as measured by area of erythema, was calculated and plotted as a function of time. The area under the resulting curve (AUC) was then determined by use of the trapezoidal rule, whereby the area of a trapezoid formed between each sequential pair of time points was calculated. The AUC computed for each site receiving a dilution of IMREG-1 or placebo (test) was compared with the AUC computed at the site that received antigen alone (control) by means of a test to control (T/C) ratio. The respective T/C ratios for designated dilutions of IMREG-1 or placebo provided a basis of comparison between responses to IMREG-1 and to placebo, while also controlling for individual sensitivity in response to antigen. We demonstrate in this study that the enhanced response to IMREG-1 plus antigen is statistically different from that seen with placebo plus antigen. This response, as a function to time, predominantly appears in the 12- to 24-hr period after injection, illustrating the ability of the immunomodulator to accelerate, enhance, and sustain a DTH response. We further conclude that the effect of IMREG-1 in this context is one of immunopotentiation of cell-mediated immunity.

This article presents the new hypothesis that HIV retrotransposon insertional mutagenesis induces genomic effects that bring about immune dysfunction through disruption, deletion or rearrangement of the genome of the host. This activity may be augmented by the action of most, if not all, the cofactors of HIV-induced disease.

We have developed a system in which human peripheral blood mononuclear cells (PBMC) stimulated with concanavalin A (Con A) can be examined for regulatory cell activity upon coculture with responder cells undergoing mitogenic proliferation. Low concentrations of Con A resulted in the induction of helper function, while higher concentrations of Con A induced suppressor activity in the PBMC population. However, for each individual donor a particular concentration of Con A can be found at which point no regulatory cell activity is observed. This "balance point" provides a set of conditions under which the ability of an immunomodulator to up-regulate or down-regulate the system can be studied. The ability of leu-enkephalin to positively or negatively regulate an immune response was examined under these circumstances. The addition of leu-enkephalin to cultures stimulated by Con A at this balance point enhanced both suppressor cell (Ts) and helper cell (Th) activity in a concentration-dependent manner. The induction of Ts activity displayed a bimodal response at concentrations between 10(-12) to 10(-13) M and 10(-9) to 10(-10) M, while the induction of Th activity was consistently observed at 10(-11) M. Similar effects were seen with either of the peptides Tyr-Gly and Tyr-Gly-Gly, corresponding to the first two and three amino acids of the N-terminal ends of the enkephalins. Th activity was consistently enhanced at 10(-13) M Tyr-Gly-Gly and 10(-14) M Tyr-Gly. This suggests that leu-enkephalin may either positively or negatively regulate immune responses and that the intact leu-enkephalin molecule is not required for these effects.

The immunosuppression that occurs in mice experimentally infected with African trypanosomiasis has been examined further. In the present study we have examined lymph node cells from Trypanosoma rhodesiense-infected C57Bl/6J mice for the ability to produce mitogen induced antigen-nonspecific suppressor T cells (Ts). Inguinal, mesenteric, and brachial lymph node cells were harvested from uninfected control mice and from mice at different periods of infection. These cells were cultured with or without concanavalin A (Con A) for 48 hr to induce Ts activity. After stimulation, the control and infected lymph node cells were passed over Sephadex G-10 columns to remove suppressor macrophages that arise during the infection from Con A-induced Ts. The column passed cells were then added to normal mouse responder spleen cells in a primary in vitro antibody response culture system with sheep erythrocytes (SRBC) as antigen. The resultant plaque-forming cell responses to SRBC indicated that Ts function was not induced in infected lymph node cell populations. However, early in the infection, a stimulatory signal was provided by both the untreated and Con A-treated infected lymph node cells, which was lost in the terminal stage. Determinations of T cell subpopulations revealed that the infected Lyt 2.2-bearing subpopulation was not significantly altered from normal controls. We conclude that T. rhodesense infected mice fail to mount normal lymph node cell antigen nonspecific Ts responses and that this loss of activity may be due to an intrinsic dysfunction in the suppressor T cell population.

Three functionally distinct leukocyte subpopulations were isolated from the peripheral blood of channel catfish. Surface immunoglobulin-positive (sIg+) and sIg- lymphocytes were isolated by an indirect "planning" procedure employing monoclonal antibodies specific for channel catfish Ig. A third population composed of macrophages was isolated by adherence to baby hamster kidney cell microexudate-coated surfaces. Functional features of these three cell types were established by assessing their role(s) in primary in vitro anti-hapten PFC responses to known murine thymus-dependent (TD) and thymus-independent (TI) antigens. The results indicated that anti-hapten PFC responses to a TI antigen required the presence of sIg+ lymphocytes and macrophages. In contrast, all three cell types were required for responses to TD antigens. Furthermore, the results of studies involving the depletion of antigen-reactive lymphocytes demonstrated that both hapten-specific sIg+ cells and carrier-specific sIg- cells were required for anti-hapten responses to TD antigens. These studies provide direct evidence that catfish have separable B cells (sIg+ lymphocytes), T helper cells (sIg- lymphocytes), and accessory cells (macrophages) quite similar to those seen in higher animals.

The extent of immunosuppression occurring in mice infected with the pathogenic African trypanosomes was studied. Spleen cells from Trypanosoma rhodesiense-infected C57BL/6J mice were tested for antigen-nonspecific suppressor-T-cell (Ts) activity after concanavalin A (Con A) treatment in vitro. After exposure to Con A, control and infected mouse spleen cells were added to responder spleen cell cultures stimulated with sheep erythrocytes (SRBC). Assays for the resultant plaque-forming cell responses to SRBC revealed that antigen-nonspecific Ts activity was lost during the first week of infection. Changes in infected mouse T-cell subpopulations, including a terminal loss of Lyt 2.2+ cells, accompanied but did not precede the demonstrable loss of Ts function. Splenic suppressor macrophages which arise during infections with T. rhodesiense also did not seem to be associated with the loss of antigen-nonspecific Ts activity. It is concluded that the generalized immunosuppression associated with experimental African trypanosomiasis extends to the mitogen-induced Ts population.

The binding of [1,2-3H]cholesterol to Neisseria gonorrhoeae CS-7, Pseudomonas aeruginosa, and Salmonella typhimurium (smooth and rough strains) was investigated. The kinetics of cholesterol binding to N. gonorrhoeae CS-7 demonstrated that binding occurred slowly with maximum binding by 10 h. Under optimum conditions, a large percentage (65%) of the added cholesterol was associated with the cells. Chemical fractionation revealed that ca. 98% of the labeled cholesterol was associated with the cell membrane(s). The bound cholesterol was not esterified and was associated primarily with the cytoplasmic membrane. Intact gonococci bound 4 to 30 times more cholesterol than the deep rough mutant S. typhimurium TA1535, the wild-type S. typhimurium DB-21, and P. aeruginosa. In contrast, isolated cell membranes from all organisms rapidly bound cholesterol to the same extent. Therefore, the outer membrane can function as a permeability barrier to cholesterol. Cholesterol binding to both whole cells and isolated cell membranes was influenced by the incubation temperature. The rate of cholesterol binding by whole cells of N. gonorrhoeae decreased markedly at lower temperatures, with almost complete cessation of binding at 0 degrees C. A similar temperature effect on the binding of cholesterol to isolated membranes was not observed. Thus, the effect of temperature on the binding of cholesterol to whole cells was an effect not on the actual binding process but rather on the ability of the cholesterol molecule to penetrate the lipid domain of the gonococcal outer membrane.

Cell separation and enrichment techniques were employed to isolate three distinct leukocyte subpopulations present in channel catfish (Ictalurus punctatus) peripheral blood. Surface immunoglobulin-positive (sIg+) and sIg- lymphocytes were separated by an indirect "panning" technique employing monoclonal antibodies reactive with channel catfish Ig. A third cell population composed of macrophages was isolated by adherence to baby hamster kidney cell microexudate-coated surfaces. Functional features of these three subpopulations were assessed by in vitro mitogenic responses to lipopolysaccharide (LPS) and concanavalin A (Con A). The results that were obtained indicated that the sIg+ cells responded only to LPS stimulation regardless of the presence or absence of macrophages. The sIg- subpopulation, however, responded to neither LPS nor Con A unless macrophages were present, in which case responses were obtained to both mitogens. The accessory cell nature of the macrophages was shown by experiments utilizing fixed numbers of one cell type mixed with varying numbers of another cell type. Furthermore, the accessory cell function was abrogated by passage through Sephadex G-10 and preincubation with L-leucine methyl ester. These studies provide further evidence that teleosts not only contain B and T cells akin to those in mammalian systems, but contain accessory cells (macrophages) as well.