Gilson Costa Macedo

On the computational modeling of the innate immune system

In recent years, there has been an increasing interest in the mathematical and computational modeling of the human immune system (HIS). Computational models of HIS dynamics may contribute to a better understanding of the relationship between complex phenomena and immune response; in addition, computational models will support the development of new drugs and therapies for different diseases. However, modeling the HIS is an extremely difficult task that demands a huge amount of work to be performed by multidisciplinary teams. In this study, our objective is to model the spatio-temporal dynamics of representative cells and molecules of the HIS during an immune response after the injection of lipopolysaccharide (LPS) into a section of tissue. LPS constitutes the cellular wall of Gram-negative bacteria, and it is a highly immunogenic molecule, which means that it has a remarkable capacity to elicit strong immune responses. We present a descriptive, mechanistic and deterministic model that is based on partial differential equations (PDE). Therefore, this model enables the understanding of how the different complex phenomena interact with structures and elements during an immune response. In addition, the models parameters reflect physiological features of the system, which makes the model appropriate for general use.

A three-dimensional computational model of the innate immune system

The Human Immune System is a complex system responsible for protecting the organism against diseases. Although understanding how it works is essential to develop better treatments against diseases, its complexity makes this task extremely hard. In this work a three-dimensional mathematical and computational model of part of this system, the innate immune system, is presented. The high computational costs associated to simulations lead the development of a parallel version of the code, which has achieved a speedup of about 72 times over its sequential counterpart.

Implementation of a computational model of the innate immune system

In the last few years there has been an increasing interest in mathematical and computational modelling of the human immune system (HIS). Computational models of the HIS dynamics may contribute to a better understanding of the complex phenomena associate to the immune system, and support the development of new drugs and therapies for different diseases. However, the modelling of the HIS is an extremely hard task that demands huge amount of work to be performed by multi-disciplinary teams. In this scenario, the objective of this work is to model the dynamics of some cells and molecules of the HIS during an immune response to lipopolysaccharide (LPS) in a section of the tissue. The LPS constitutes the cellular wall of Gram-negative bacteria, and it is a highly immunogenic molecule, which means that it has a remarkable capacity to elicit strong immune responses.

Computational Modeling of Microabscess Formation

Bacterial infections can be of two types: acute or chronic. The chronic bacterial infections are characterized by being a large bacterial infection and/or an infection where the bacteria grows rapidly. In these cases, the immune response is not capable of completely eliminating the infection which may lead to the formation of a pattern known as microabscess (or abscess). The microabscess is characterized by an area comprising fluids, bacteria, immune cells (mainly neutrophils), and many types of dead cells. This distinct pattern of formation can only be numerically reproduced and studied by models that capture the spatiotemporal dynamics of the human immune system (HIS). In this context, our work aims to develop and implement an initial computational model to study the process of microabscess formation during a bacterial infection.

What do we know about the role of regulatory B cells (Breg) during the course of infection of two major parasitic diseases, malaria and leishmaniasis?

Abstract Parasitic diseases, such as malaria and leishmaniasis, are relevant public health problems worldwide. For both diseases, the alarming number of clinical cases and deaths reported annually has justified the incentives directed to better understanding of host’s factors associated with susceptibility to infection or protection. In this context, over recent years, some studies have given special attention to B lymphocytes with a regulator phenotype, known as Breg cells. Essentially important in the maintenance of immunological tolerance, especially in autoimmune disease models such as rheumatoid arthritis and experimentally induced autoimmune encephalomyelitis, the function of these lymphocytes has so far been poorly explored during the course of diseases caused by parasites. As the activation of Breg cells has been proposed as a possible therapeutic or vaccine strategy against several diseases, here we reviewed studies focused on understanding the relation of parasite and Breg cells in malaria and leishmaniasis, and the possible implications of these strategies in the course of both infections.

Modelling the Innate Immune System

The Human Immune System (HIS) is a complex network composed of specialized cells, tissues, and organs that is responsible for protecting the organism against diseases caused by distinct pathogenic agents, such as viruses, bacteria and other parasites. The first line of defence against pathogenic agents consists of physical barriers of skin and the mucous membranes. If the pathogenic agents breach this first protection barrier, the innate immune system will be ready for recognize and combat them. The innate immune system is therefore responsible for powerful non-specific defences that prevent or limit infections by most pathogenic microorganisms.

In vitro antifungal activity of organic compounds derived from amino alcohols against onychomycosis

Onychomycosis is a fungal infection of the nail caused by high densities of filamentous fungi and yeasts. Treatment for this illness is long-term, and recurrences are frequently detected. This study evaluated in vitro antifungal activities of 12 organic compounds derived from amino alcohols against standard fungal strains, such as Trichophyton rubrum CCT 5507 URM 1666, Trichophyton mentagrophytes ATCC 11481, and Candida albicans ATCC 10231. The antifungal compounds were synthesized from p-hydroxybenzaldehyde (4a–4f) and p-hydroxybenzoic acid (9a–9f). Minimum inhibitory concentrations and minimum fungicidal concentrations were determined according to Clinical and Laboratory Standards Institute protocols M38-A2, M27-A3, and M27-S4. The amine series 4b–4e, mainly 4c and 4e compounds, were effective against filamentous fungi and yeast (MIC from 7.8 to 312 μg/mL). On the other hand, the amide series (9a–9f) did not present inhibitory effect against fungi, except amide 9c, which demonstrated activity only against C. albicans. This allowed us to infer that the presence of amine group and intermediate carbon number (8C–11C) in its aliphatic side chain seems to be important for antifungal activity. Although these compounds present cytotoxic activity on macrophages J774, our results suggest that these aromatic compounds might constitute potential as leader molecules in the development of more effective and less toxic analogs that could have considerable implications for future therapies of onychomycosis.

Parthenolide Modulates Immune Response in Cells from C57BL/6 Mice Induced with Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis is a chronic inflammatory and autoimmune disease of the central nervous system that affects more than 2.5 million people worldwide. Experimental autoimmune encephalomyelitis is a murine autoimmune disease used to study multiple sclerosis. Parthenolide, a natural sesquiterpene lactone found in Tanacetum parthenium L., is known for its strong anti-inflammatory activity. Herein, we have investigated the in vitro immunomodulatory effects of parthenolide on cytokine production and nitric oxide in cultured cells from myelin oligodendrocyte glycoprotein 35-55 amino acid peptide mice. Experimental autoimmune encephalomyelitis was induced in C57BL/6 mice with myelin oligodendrocyte glycoprotein 35-55 amino acid peptide, and parthenolide was isolated from T. parthenium. Splenocytes and peritoneal cells were obtained from experimental autoimmune encephalomyelitis-induced mice and incubated with parthenolide (1, 5, and 20 µM). After in vitro treatment with parthenolide, supernatants were collected, and nitric oxide and cytokines were measured. The results suggested that parthenolide may regulate the activity of Th17 and Th1 cells, mainly by decreasing IL-17, TNF-α, and interferon gamma production. This modulation may be related to the lower levels of IL-12p40 and IL-6 after treatment with parthenolide. It was shown, for the first time, that parthenolide presents in vitro immunomodulatory effects on inflammatory mediators produced by cells from experimental autoimmune encephalomyelitis-induced mice.

Modeling Human Immune System Using a System Dynamics Approach

The Human Immune System (HIS) consists of a complex network of cells, tissues and organs that protects the body against invaders. Understanding how the HIS works is therefore essential to obtain new insights into its nature and to deal effectively with diseases. Computational modeling can be used for this purpose: it allows researchers to perform virtual experiments in silico, that can speed up the discovery of new drugs against diseases and reduce their cost. To create a computational model of the HIS, the behavior of its components and their relationships must be modeled using a formal language, such as those used in Mathematics. This paper presents the JynaCore, an API that uses System Dynamics instead of pure mathematical equations to model complex systems. In particular, this API is used to model and simulate the dynamics of the immune response to lipopolysaccharide (LPS) in a microscopic section of tissue.

Novel organic salts based on quinoline derivatives: The in vitro activity trigger apoptosis inhibiting autophagy in Leishmania spp.

Leishmaniases are infectious diseases, caused by protozoa of the Leishmania genus. These drugs present high toxicity, long-term administration, many adverse effects and are expensive, besides the identification of resistant parasites. In this work, the antileishmanial activity of quinoline derivative salts (QDS) was evaluated, as well as the toxicity on mammalian cells and the mechanism of action of the most promising compound. Among the compound tested, only the compound QDS3 showed activity against promastigotes and amastigotes of Leishmania spp., being more active against the intracellular amastigotes of L. amazonensis-GFP (IC50 of 5.48 μM). This value is very close to the one observed for miltefosine (IC50 of 4.05 μM), used as control drug. Furthermore, the compound QDS3 exhibited a selective effect, being 40.35 times more toxic to the amastigote form than to the host cell. Additionally, promastigotes of L. amazonensis treated with this compound exhibited characteristics of cells in the process of apoptosis such as mitochondrial membrane depolarization, mitochondrial swelling, increase of ROS production, phosphatidylserine externalization, reduced and rounded shape, and cell cycle alteration. The integrity of the plasma membrane remained unaltered, excluding necrosis in treated promastigotes. The compound QDS3 inhibited the formation of autophagic vacuoles, which may have contributed to parasite death by preventing autophagic mechanisms in the removal of damaged organelles, intensifying the damage caused by the treatment, highlighting the antileishmanial effect of this compound. In addition, treatment with QDS3 induced increased ROS levels in L. amazonensis-infected macrophages, but not in uninfected host cell. These data reinforce that the induction of oxidative stress is one of the main toxic effects caused by the treatment with the compound QDS3 in L. amazonensis, causing irreversible damage and triggering a selective death of intracellular parasites. Data shown here confirm the biological activity of quinoline derivatives and encourage future in vivo studies with this compound in the murine model.