Efficacy of Mesenchymal Stem Cells Therapy in Parasitic Infections: Are Anti-parasitic Drugs Combined with MSCs More Effective?

PURPOSE: Mesenchymal stem cells (MSCs) are mesodermal-origin postnatal stem cells that are able to self-renew and differentiate into several cell lineages. MSCs possess anti-inflammatory and anti-apoptotic activity, immunomodulatory action, as well as regenerative properties. Since MSCs also have antimicrobial properties, it has been suggested that they should be utilized for treating infectious diseases. In this study, the last pre-clinical advances in the efficacy of MSCs' therapy against parasitic diseases were reviewed. METHODS: Data about the effects of MSCs' therapy on experimental and pre-clinical parasitic infections were collected by searching relevant articles and reviewing them. RESULTS: In the present study, empirical findings on the impacts of MSCs' therapy against parasitic diseases were recapitulated. Studies have reported that the administration of MSCs reduces the burden of the parasite and modulates the levels of inflammatory and anti-inflammatory cytokines in parasitic diseases, including schistosomiasis, malaria, cystic echinococcosis, toxocariasis, leishmaniasis, and trypanosomiasis. Also, the administration of MSCs combined with anti-parasitic drugs enhanced anti-parasitic effects and immunomodulatory actions. CONCLUSION: Based on this review, empirical studies have revealed the beneficial effects of MSCs against some parasitic infections. This new therapeutic strategy showed both anti-parasitic and immunomodulatory effects. Also, the combination of anti-parasitic drugs with MSCs' therapy promoted anti-parasitic and immunomodulatory activities against parasitic infections.

Immunomodulatory Potential of Non-Classical HLA-G in Infections including COVID-19 and Parasitic Diseases.

Human Leukocyte Antigen-G (HLA-G), a polymorphic non-classical HLA (HLA-Ib) with immune-regulatory properties in cancers and infectious diseases, presents both membrane-bound and soluble (sHLA-G) isoforms. Polymorphism has implications in host responses to pathogen infections and in pathogenesis. Differential expression patterns of HLA-G/sHLA-G or its polymorphism seem to be related to different pathological conditions, potentially acting as a disease progression biomarker. Pathogen antigens might be involved in the regulation of both membrane-bound and sHLA-G levels and impact immune responses during co-infections. The upregulation of HLA-G in viral and bacterial infections induce tolerance to infection. Recently, sHLA-G was found useful to identify the prognosis of Coronavirus disease 2019 (COVID-19) among patients and it was observed that the high levels of sHLA-G are associated with worse prognosis. The use of pathogens, such as Plasmodium falciparum, as immune modulators for other infections could be extended for the modulation of membrane-bound HLA-G in COVID-19-infected tissues. Overall, such information might open new avenues concerning the effect of some pathogens such as parasites in decreasing the expression level of HLA-G to restrict pathogenesis in some infections or to influence the immune responses after vaccination among others.

Viruses of protozoan parasites and viral therapy: Is the time now right?

Infections caused by protozoan parasites burden the world with huge costs in terms of human and animal health. Most parasitic diseases caused by protozoans are neglected, particularly those associated with poverty and tropical countries, but the paucity of drug treatments and vaccines combined with increasing problems of drug resistance are becoming major concerns for their control and eradication. In this climate, the discovery/repurposing of new drugs and increasing effort in vaccine development should be supplemented with an exploration of new alternative/synergic treatment strategies. Viruses, either native or engineered, have been employed successfully as highly effective and selective therapeutic approaches to treat cancer (oncolytic viruses) and antibiotic-resistant bacterial diseases (phage therapy). Increasing evidence is accumulating that many protozoan, but also helminth, parasites harbour a range of different classes of viruses that are mostly absent from humans. Although some of these viruses appear to have no effect on their parasite hosts, others either have a clear direct negative impact on the parasite or may, in fact, contribute to the virulence of parasites for humans. This review will focus mainly on the viruses identified in protozoan parasites that are of medical importance. Inspired and informed by the experience gained from the application of oncolytic virus- and phage-therapy, rationally-driven strategies to employ these viruses successfully against parasitic diseases will be presented and discussed in the light of the current knowledge of the virus biology and the complex interplay between the viruses, the parasite hosts and the human host. We also highlight knowledge gaps that should be addressed to advance the potential of virotherapy against parasitic diseases.

CCR5 and CCR5Δ32 in bacterial and parasitic infections: Thinking chemokine receptors outside the HIV box.

The CCR5 molecule was reported in 1996 as the main HIV-1 co-receptor. In that same year, the CCR5Δ32 genetic variant was described as a strong protective factor against HIV-1 infection. These findings led to extensive research regarding the CCR5, culminating in critical scientific advances, such as the development of CCR5 inhibitors for the treatment of HIV infection. Recently, the research landscape surrounding CCR5 has begun to change. Different research groups have realized that, since CCR5 has such important effects in the chemokine system, it could also affect other different physiological systems. Therefore, the effect of reduced CCR5 expression due to the presence of the CCR5Δ32 variant began to be further studied. Several studies have investigated the role of CCR5 and the impacts of CCR5Δ32 on autoimmune and inflammatory diseases, various types of cancer, and viral diseases. However, the role of CCR5 in diseases caused by bacteria and parasites is still poorly understood. Therefore, the aim of this article is to review the role of CCR5 and the effects of CCR5Δ32 on bacterial (brucellosis, osteomyelitis, pneumonia, tuberculosis and infection by Chlamydia trachomatis) and parasitic infections (toxoplasmosis, leishmaniasis, Chagas disease and schistosomiasis). Basic information about each of these infections was also addressed. The neglected role of CCR5 in fungal disease and emerging studies regarding the action of CCR5 on regulatory T cells are briefly covered in this review. Considering the "renaissance of CCR5 research," this article is useful for updating researchers who develop studies involving CCR5 and CCR5Δ32 in different infectious diseases.

Checkpoint Inhibition and Infectious Diseases: A Good Thing?

The mammalian immune system has evolved the capacity to detect and destroy tumor cells. Tumors utilize multiple strategies to evade host immune surveillance, including the induction of the checkpoint molecules cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) to suppress antitumor immunity. Pharmacologic blockade of these molecules with checkpoint inhibitors (CPIs) restores T cell function and prolongs survival in patients with various malignancies. Emerging evidence suggests that the same checkpoint pathways may play a crucial role during infections. Indeed, CPIs appear promising as immunotherapeutic agents in infectious diseases, although their efficacy varies depending on pathogen-, cell-, and organ-specific factors. More research will be necessary to clarify the effects and safety of CPIs on clinically relevant outcomes of human infection.

Parasitic infections of the spine: case series and review of the literature.

OBJECTIVEAlthough parasitic infections are endemic to parts of the developing world and are more common in areas with developing economies and poor sanitary conditions, rare cases may occur in developed regions of the world.METHODSArticles eligible for the authors' literature review were initially searched using PubMed with the phrases "parasitic infections" and "spine." After the authors developed a list of parasites associated with spinal cord infections from the initial search, they expanded it to include individual diagnoses, using search terms including "neurocysticercosis," "schistosomiasis," "echinococcosis," and "toxoplasmosis."RESULTSTwo recent cases of parasitic spinal infections from the authors' institution are included.CONCLUSIONSKey findings on imaging modalities, laboratory studies suggestive of parasitic infection, and most importantly a thorough patient history are required to correctly diagnose parasitic spinal infections.

Neurocysticercosis: mimics and chameleons.

Neurocysticercosis is the most common parasitic neurological disease worldwide, yet in Europe, it remains relatively uncommon, with many practitioners rarely seeing a case. However, immigration and international travel mean that it is becoming increasingly recognised and diagnosed in developed countries. Being a treatable condition, it is essential to be familiar with the diagnosis and to appreciate its mimics and breadth of its possible clinical presentations.

Multifaceted roles of basophils in health and disease.

Until recently, basophils had often been neglected in immunologic studies because of their minority status among immune cells or confused with tissue-resident mast cells because of some phenotypic similarities between them in spite of different anatomic localization. It is now appreciated that basophils and mast cells are distinct cell lineages and that basophils play important and nonredundant roles distinct from those played by mast cells. On the one hand, basophils contribute beneficially to protective immunity, particularly against parasitic infections. On the other hand, basophils are involved in the development of various disorders, including allergy and autoimmune disease. Basophils interact with other immune cells and nonhematopoietic cells through cell-to-cell contact or basophil-derived factors, such as cytokines and proteases, contributing to the regulation of immune and allergic responses. In this review article we highlight recent advances in our understanding of basophil pathophysiology in human subjects and animal models by consolidating research findings reported during the past 5 years. Further studies on basophils and their products will help identify suitable targets for novel therapeutics in allergy and effective vaccines against parasitic infection.

Aptamers as a promising approach for the control of parasitic diseases

ABSTRACT Aptamers are short single-stranded RNA or DNA oligonucleotides that are capable of binding various biological targets with high affinity and specificity. Their identification initially relies on a molecular process named SELEX (Systematic Evolution of Ligands by EXponential enrichment) that has been later modified in order to improve aptamer sensitivity, minimize duration and cost of the assay, as well as increase target types. Several biochemical modifications can help to enhance aptamer stability without affecting significantly target interaction. As a result, aptamers have generated a large interest as promising tools to compete with monoclonal antibodies for detection and inhibition of specific markers of human diseases. One aptamer-based drug is currently authorized and several others are being clinically evaluated. Despite advances in the knowledge of parasite biology and host-parasite interactions from "omics" data, protozoan parasites still affect millions of people around the world and there is an urgent need for drug target discovery and novel therapeutic concepts. In this context, aptamers represent promising tools for pathogen identification and control. Recent studies have reported the identification of "aptasensors" for parasite diagnosis, and "intramers" targeting intracellular proteins. Here we discuss various strategies that have been employed for intracellular expression of aptamers and expansion of their possible application, and propose that they may be suitable for the clinical use of aptamers in parasitic infections.

Antimicrobial photodynamic inactivation: a bright new technique to kill resistant microbes.

Photodynamic therapy (PDT) uses photosensitizers (non-toxic dyes) that are activated by absorption of visible light to form reactive oxygen species (including singlet oxygen) that can oxidize biomolecules and destroy cells. Antimicrobial photodynamic inactivation (aPDI) can treat localized infections. aPDI neither causes any resistance to develop in microbes, nor is affected by existing drug resistance status. We discuss some recent developments in aPDI. New photosensitizers including polycationic conjugates, stable synthetic bacteriochlorins and functionalized fullerenes are described. The microbial killing by aPDI can be synergistically potentiated (several logs) by harmless inorganic salts via photochemistry. Genetically engineered bioluminescent microbial cells allow PDT to treat infections in animal models. Photoantimicrobials have a promising future in the face of the unrelenting increase in antibiotic resistance.

Human pentastomiasis in Sub-Saharan Africa.

Pentastomiasis is a rare zoonotic infection but it is frequently observed in Africa and Asia. Most human infections are caused by members of the Armillifer armillatus species. They are responsible for visceral pentastomiasis in Western and Central Africa. Humans may be infected by eating infected undercooked snake meat or by direct contact with an infected reptile. An increasing number of infections are being reported in Congo, Nigeria, and Cameroon. Despite an occasionally high number of nymphs observed in human viscera, most infections are asymptomatic and often diagnosed by accident during surgery or autopsy. The clinical presentation of pentastomiasis is quite varied and depends on infected tissues. The liver, lungs, and pleura are most frequently involved. Abdominal emergencies have been reported. Diagnostic delays always occur and diagnosis focuses on the patient's lifestyle and living environment. It is mainly based on the morphological description of the parasite's calcified cuticle, the site of the lesion, and the parasite's region of origin. Most patients do not require any treatment. Personal measures such as avoidance of contact with snake droppings are recommended to prevent transmission. Imported pentastomiasis has been observed in African migrants.

[Advances in research of stem cell therapy for human parasitic diseases: a review].

The stem cell is a class of primitive cells with self-renewal, and multiple pluripotent potential capacities, which can differentiate into multiple specialized cells and generate human organs and tissues. Stem cell therapy is an interventional treatment that introduces new stem cells to damaged tissues, which facilitates the regeneration of trauma, disease and ageing-induced damaged human tissues to repair or replace the damaged tissues, thereby achieving the goal of disease treatment. It has been proved that the stem cell therapy is effective in the treatment of multiple human diseases, including cancer, diabetes, neurological disorders, autoimmune diseases, cardiovascular disorders and blood diseases. This review summarizes the advances in the research of stem cell therapy for human parasitic infections.

Gordon Wilson Lecture: Infectious Disease Causes of Cancer: Opportunities for Prevention and Treatment.

The role of infectious agents in cancer is generally underappreciated. However, approximately 20% of human cancers are caused by infectious agents and as such they rank second only to tobacco as a potentially preventable cause in humans. Specific viruses, parasites, and bacteria have been linked to specific human cancers. The infectious etiology for these specific cancers provides opportunities for prevention and treatment.

Análise da reinfecção pelo Schistosoma mansoni entre escolares com idade de 5 15 anos em área endêmica: Vale do Jequitinhonha, MG / The analyze of reinfection by Schistosoma mansoni in school children aged 5-15 years

A esquistossomose é uma das parasitoses mais prevalentes no mundo e é um grande problema de saúde pública, principalmente nos países em desenvolvimento. Atualmente a medida mais utilizada para o controle da doença é a quimioterapia. Entretanto, sabe-se que mesmo após o tratamento os indivíduos se reinfectam. Sabe-se também que há uma estreita relação entre os fatores demográficos, socioeconômicos e comportamentais na dinâmica da transmissão da esquistossomose. Diante disso, a realização deste estudo teve como objetivo analisar a reinfecção pelo Schistosoma mansoni entre escolares com idade de 5 a 15 anos. Os participantes foram 407 crianças e adolescentes infectados pelo S. mansoni e residentes no município de Ponto dos Volantes, nas comunidades de Palha, Astraluta, Caju (Jequitinhonha) e Córrego São João (Itaobim), sendo todas essas áreas consideradas endêmicas para a esquistossomose. No início do estudo, todos os voluntários foram tratados com Praziquantel e responderam aos questionários socioeconômico e de contato com a água. Foram coletadas, também, as coordenadas geográficas das suas residências. Um ano após o tratamento foram realizados exames parasitológicos de fezes de todos os escolares para avaliar a reinfecção tendo sido encontrada uma taxa de 21,6 %. O modelo multivariado mostrou que a carga parasitária pré-tratamento (p < 0,001) e a falta de fornecimento de água tratada (p = 0,010) mantiveram-se associadas à reinfecção. Aqueles que reinfectaram tiveram um maior contato com água potencialmente contaminada apesar da diferença não ter sido significativa. A análise espacial apontou que, em todas as áreas estudadas, a reinfecção ocorreu de forma heterogênea. Concluiu-se que a taxa de reinfecção pelo S. mansoni é preocupante e que possuir uma alta carga parasitária antes do tratamento e residir em local onde não há água tratada foram os principais fatores de risco para a reinfecção pelo S. mansoni.

Schistosomiasis is one of the most prevalent parasitic diseases in the world and is a major public health problem, particularly in developing countries. Currently the most commonly used measure for controlling the condition is chemotherapy. However, after the treatment, the individuals become infected again. It is well known that there is a close relationship between demographic, socioeconomic and behavioral factors in the dynamics of schistosomias is transmission. Therefore, this study aimed to analyze reinfection by Schistosoma mansoni in school children aged 5-15 years. Participants were 407 children and adolescents infected with S. mansoni and residents in the municipality of Ponto dos Volantes, and the communities of Palha, Astraluta, Caju and Córrego São João, all of which are endemic areas for schistosomiasis. At baseline, all subjects were treated with Praziquantel, responded to socioeconomic and water contact questionnaires. The geographical coordinates of all houses were collected. One year after the treatment another faecal exam was performed to evaluate reinfection rates. The results showed a reinfection rate of 21.6%. The multivariate model showed that parasite load before treatment (p < 0.001) and lack of treated water supply (p = 0.010) remained associated to reinfection. Spatial analys is showed that in all areas studied reinfection occurred heterogeneously. It is concluded that the reinfection rate is worrisome and having high intensity of infection before treatment and leaving in areas with no treated water were considered the main risk factors to re-infection with S. mansoni.

Rickettsiae, protozoa, and opisthokonta/metazoa.

Rhizobiales (formerly named Rickettsiales) cause in rare instances meningitis and meningovasculitis, respectively. In case of history of exposure, infection by Rhizobiales needs to be considered since both diagnosis and therapy may be extremely difficult and pathogen-specific. The same applies to protozoa; in this chapter, Babesia species, free-living amoebae and Entamoeba histolytica infection, including severe meningitis and brain abscess, infection by Trypanosoma species (South American and African trypanosomiasis) are discussed with respect to history, epidemiology, clinical signs, and symptoms as well as differential diagnosis and therapy. Parasitic flatworms and roundworms, potentially able to invade the central nervous system, trematodes (flukes), cestodes (in particular, Cysticercus cellulosae), but also nematodes (in particular, Strongyloides spp. in the immunocompromised) are of worldwide importance. In contrast, filarial worms, Toxocara spp., Trichinella spp., Gnathostoma and Angiostrongylus spp. are seen only in certain geographically confined areas. Even more regionally confined are infestations of the central nervous system by metazoa, in particular, tongue worms (=arthropods) or larvae of flies (=maggots). The aim of this chapter is (1) to alert the neurologist to these infections, and (2) to enable the attending emergency neurologist to take a knowledgeable history, with an emphasis on epidemiology, clinical signs, and symptoms as well as therapeutic management possibilities.