Modulation of Human Macrophages by Plasma from COVID-19 Patients Following BCG Vaccination: BATTLE Trial.

Purpose: To analyze the interfering effect of plasma from COVID-19 convalescent adults vaccinated or not with intradermal Bacillus Calmette-Guérin (BCG) on human macrophages. Methods: The BATTLE clinical trial (NCT04369794) was initiated in the 2020 SARS-CoV-2 pandemic to study the safety and efficacy of BCG revaccination of COVID-19 convalescent adults. We measured the expression induction of eleven COVID-19-related genes in human macrophages cultured in plasma taken from 22 BCG vaccinated and 17 placebo patients at baseline and 45 days post-intervention. Subgroup analysis was based on gender, age, job type (healthcare worker [HCW] vs non-HCW), and the presence of anosmia/dysgeusia. Results: Compared to plasma from placebo counterparts, the plasma of BCG vaccinated patients increased the expression induction of interferon (IFN)ß-1b (p = 0.042) in human macrophages. This increase was more pronounced in females and in healthcare workers (HCW) (p = 0.007 and 0.001, respectively). Interferon-induced transmembrane protein 3 (IFITM3) expression induction was increased by plasma from BCG vaccinated females, young age group, and HCWs (p = 0.004, 0.011, and 0.040, respectively). Interleukin (IL)-10 induction increased by the plasma of young BCG recipients (p = 0.008). Induction of IL-6 expression increased by non-HCW BCG recipients plasma but decreased by HCW BCG recipients plasma (p = 0.005). Baseline plasma of patients who presented with anosmia/dysgeusia at the time of admission induced lower angiotensin-converting enzyme 2 (ACE2) compared to those without the symptom (0.76 vs 0.97, p = 0.004). ACE2 expression induction significantly increased by plasma of BCG recipients if they had anosmia/dysgeusia on admission (p = 0.028). Conclusion: The expressions of IFNß-1b, IFITM3, IL-6, and IL-10 in human macrophages incubated with the plasma of COVID-19 convalescent patients were modulated by BCG. These modulations depended on subject-specific characteristics, including gender, age, clinical presentation (anosmia/dysgeusia), job type, and previous exposure to mycobacteria.

Forms and Methods for Interferon's Encapsulation.

Interferons (IFNs) are cytokines involved in the immune response that act on innate and adaptive immunity. These proteins are natural cell-signaling glycoproteins expressed in response to viral infections, tumors, and biological inducers and constitute the first line of defense of vertebrates against infectious agents. They have been marketed for more than 30 years with considerable impact on the global therapeutic protein market thanks to their diversity in terms of biological activities. They have been used as single agents or with combination treatment regimens, demonstrating promising clinical results, resulting in 22 different formulations approved by regulatory agencies. The 163 clinical trials with currently active IFNs reinforce their importance as therapeutics for human health. However, their application has presented difficulties due to the molecules' size, sensitivity to degradation, and rapid elimination from the bloodstream. For some years now, work has been underway to obtain new drug delivery systems to provide adequate therapeutic concentrations for these cytokines, decrease their toxicity and prolong their half-life in the circulation. Although different research groups have presented various formulations that encapsulate IFNs, to date, there is no formulation approved for use in humans. The current review exhibits an updated summary of all encapsulation forms presented in the scientific literature for IFN-α, IFN-ß, and IFN-γ, from the year 1996 to the year 2021, considering parameters such as: encapsulating matrix, route of administration, target, advantages, and disadvantages of each formulation.

Adjuvants: friends in vaccine formulations against infectious diseases.

Infectious diseases represent a major cause of deaths worldwide. No vaccine or effective treatment exists nowadays, especially against intracellular pathogens. The increase in multiple drug and superbug antibiotic resistance strains, excessive medication, or misuse of drugs has prompted the search for other safe and effective alternatives. Consistent with this, adjuvants (Latin word "adjuvare": "help or aid") co-administered (Exo) in vaccines have emerged as a promising alternative to initiate and boost an innate, downstream signal that led to adaptative immune response. Nowadays, a promising model of strong immunogens and adjuvants at mucosal sites are the microbial bacterial toxins. Other adjuvants that are also used and might successfully replace aluminum salts in combination with nanotechnology are CpG-ODN, poly IC, type I IFNs, mRNA platforms. Therefore, in the present review, we focused to revisit the old to the new adjuvants compounds, the properties that make them friends in vaccine formulations against infectious diseases.

MALAT1 is involved in type I IFNs-mediated systemic lupus erythematosus by up-regulating OAS2, OAS3, and OASL

Systemic lupus erythematosus (SLE) is an autoimmune disease associated with an aberrant activation of immune cells partly due to the dysfunction of cytokines such as type I interferons (IFNs). Long non-coding RNA MALAT1 has been found to play a pathogenic role in SLE; however, the underlying mechanisms are still poorly understood. Bioinformatics analysis showed the up-regulation of type I IFN downstream effectors OAS2, OAS3, and OASL (OAS-like) in CD4+ T cells, CD19+ B cells, and CD33+ myeloid cells in patients with active SLE compared to healthy participants. In this study, peripheral blood mononuclear cells (PBMCs), CD19+ B, and CD4+ T cells were isolated from active SLE patients and healthy participants. PCR was performed to quantify MALAT1, OAS2, OAS3, and OASL expression in immune cells. MALAT1, OAS2, OAS3, and OASL were knocked down in CD4+ T cells to investigate the regulatory effect of MALAT1 on the effectors and their involvement in type I IFNs-mediated inflammation. Results showed higher OAS2, OAS3, and OASL expression in active SLE patients. MALAT1 expression was positively correlated to OAS2, OAS3, and OASL expression in CD19+ B or CD4+ T cells. MALAT1 knockdown decreased OAS2, OAS3, and OASL expression. Treatment with IFN-α-2a increased the expression of TNF-α, IL-1β, and IFN-α in CD4+ T cells. However, knockdown of MALAT1, OAS2, OAS3, and OASL alone inhibited the effect of IFN-α-2a on TNF-α and IL-1β. This study suggested the involvement of MALAT1 in type I IFNs-mediated SLE by up-regulating OAS2, OAS3, and OASL.

The Syk-Coupled C-Type Lectin Receptors Dectin-2 and Dectin-3 Are Involved in Paracoccidioides brasiliensis Recognition by Human Plasmacytoid Dendritic Cells.

Plasmacytoid dendritic cells (pDCs), which have been extensively studied in the context of the immune response to viruses, have recently been implicated in host defense mechanisms against fungal infections. Nevertheless, the involvement of human pDCs during paracoccidioidomycosis (PCM), a fungal infection endemic to Latin America, has been scarcely studied. However, pDCs were found in the cutaneous lesions of PCM patients, and in pulmonary model of murine PCM these cells were shown to control disease severity. These findings led us to investigate the role of human pDCs in the innate phase of PCM. Moreover, considering our previous data on the engagement of diverse Toll-like receptors and C-type lectin receptors receptors in Paracoccidioides brasiliensis recognition, we decided to characterize the innate immune receptors involved in the interaction between human pDCs and yeast cells. Purified pDCs were obtained from peripheral blood mononuclear cells from healthy donors and they were stimulated with P. brasiliensis with or without blocking antibodies to innate immune receptors. Here we demonstrated that P. brasiliensis stimulation activates human pDCs that inhibit fungal growth and secrete pro-inflammatory cytokines and type I IFNs. Surprisingly, P. brasiliensis-stimulated pDCs produce mature IL-1ß and activate caspase 1, possibly via inflammasome activation, which is a phenomenon not yet described during pDC engagement by microorganisms. Importantly, we also demonstrate that dectin-2 and dectin-3 are expressed on pDCs and appear to be involved (via Syk signaling) in the pDC-P. brasiliensis interaction. Moreover, P. brasiliensis-stimulated pDCs exhibited an efficient antigen presentation and were able to effectively activate CD4+ and CD8+ T cells. In conclusion, our study demonstrated for the first time that human pDCs are involved in P. brasiliensis recognition and may play an important role in the innate and adaptive immunity against this fungal pathogen.