Marine glycosaminoglycan-like carbohydrates as potential drug candidates for infectious disease

Glycosaminoglycans (GAGs), present in the extracellular matrix, are exploited by numerous, distinct microbes for cellular attachment, adhesion, invasion and evasion of the host immune system. Glycosaminoglycans, including the widely used, clinical anticoagulant heparin and semi-synthetic analogues thereof, have been reported to inhibit and disrupt interactions between microbial proteins and carbohydrates present on the surface of host cells. However, the anticoagulant properties of unmodified, pharmaceutical heparin preparations preclude their capabilities as therapeutics for infectious disease states. Here, unique Glycosaminoglycan-like saccharides from various, distinct marine species are reported for their potential use as therapeutics against infectious diseases; many of which possess highly attenuated anticoagulant activities, while retaining significant antimicrobial properties.

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QTL Mapping of Intestinal Neutrophil Variation in Threespine Stickleback Reveals Possible Gene Targets Connecting Intestinal Inflammation and Systemic Health

G3 Genes|Genome|Genetics ◽

10.1534/g3.119.400685 ◽

2019 ◽

Vol 10 (2) ◽

pp. 613-622

Author(s):

Emily A. Beck ◽

Mark C. Currey ◽

Clayton M. Small ◽

William A. Cresko

Keyword(s):

Immune System ◽

Inflammatory Response ◽

Intestinal Inflammation ◽

Threespine Stickleback ◽

Microbial Interactions ◽

Host Cells ◽

Host Immune System ◽

Complex Genetics ◽

Disease States ◽

Host Genetic

Selection, via host immunity, is often required to foster beneficial microbial symbionts and suppress deleterious pathogens. In animals, the host immune system is at the center of this relationship. Failed host immune system-microbial interactions can result in a persistent inflammatory response in which the immune system indiscriminately attacks resident microbes, and at times the host cells themselves, leading to diseases such as Ulcerative Colitis, Crohn’s Disease, and Psoriasis. Host genetic variation has been linked to both microbiome diversity and to severity of such inflammatory disease states in humans. However, the microbiome and inflammatory states manifest as quantitative traits, which encompass many genes interacting with one another and the environment. The mechanistic relationships among all of these interacting components are still not clear. Developing natural genetic models of host-microbe interactions is therefore fundamental to understanding the complex genetics of these and other diseases. Threespine stickleback (Gasterosteus aculeatus) fish are a tractable model for attacking this problem because of abundant population-level genetic and phenotypic variation in the gut inflammatory response. Previous work in our laboratory identified genetically divergent stickleback populations exhibiting differences in intestinal neutrophil activity. We took advantage of this diversity to genetically map variation in an emblematic element of gut inflammation - intestinal neutrophil recruitment - using an F2-intercross mapping framework. We identified two regions of the genome associated with increased intestinal inflammation containing several promising candidate genes. Within these regions we found candidates in the Coagulation/Complement System, NFkB and MAPK pathways along with several genes associated with intestinal diseases and neurological diseases commonly accompanying intestinal inflammation as a secondary symptom. These findings highlight the utility of using naturally genetically diverse ‘evolutionary mutant models’ such as threespine stickleback to better understand interactions among host genetic diversity and microbiome variation in health and disease states.

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QTL mapping of intestinal neutrophil variation and inflammation between threespine stickleback populations reveals links to neurodegenerative disease

10.1101/757351 ◽

2019 ◽

Author(s):

Emily A. Beck ◽

Mark C. Currey ◽

Clayton M. Small ◽

William A. Cresko

Keyword(s):

Immune System ◽

Inflammatory Response ◽

Intestinal Inflammation ◽

Threespine Stickleback ◽

Microbial Interactions ◽

Host Cells ◽

Host Immune System ◽

Complex Genetics ◽

Disease States ◽

Host Genetic

AbstractHost selection is often required to foster beneficial microbial symbionts and suppress deleterious pathogens. In animals, the host immune system is at the center of this relationship. Failed host immune system-microbial interactions can result in a persistent inflammatory response in which the immune system indiscriminately attacks resident microbes, and at times the host cells themselves, leading to diseases such as Ulcerative Colitis, Crohn’s Disease, and Psoriasis. Host genetic variation has been linked to both microbiome diversity and to severity of such inflammatory disease states in humans. However, the microbiome and inflammatory states manifest as quantitative traits, which encompass many genes interacting with one another and the environment. The mechanistic relationships among all of these interacting components are still not clear. Developing natural genetic models of host-microbe interactions is therefore fundamental to understanding the complex genetics of these and other diseases. Threespine stickleback (Gasterosteus aculeatus) fish are a tractable model for attacking this problem because of abundant population-level genetic and phenotypic variation in the gut inflammatory response. Previous work in our laboratory identified genetically divergent stickleback populations exhibiting differences in intestinal neutrophil activity. We took advantage of this diversity to genetically map variation in an emblematic element of gut inflammation – intestinal neutrophil recruitment – using an F2-intercross mapping framework. We identified three regions of the genome associated with increased intestinal inflammation containing several promising candidate genes. Within these regions we found candidates in the Coagulation/Complement System, NFkB and MAPK pathways along with several genes associated with neurodegenerative diseases commonly accompanying intestinal inflammation as a secondary symptom. These findings highlight the utility of using naturally genetically diverse ‘evolutionary mutant models’ such as threespine stickleback to better understand interactions among host genetic diversity and microbiome variation in health and disease states.

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Recent Advances in the Development of Antimicrobial Peptides (AMPs): Attempts for Sustainable Medicine?

Current Medicinal Chemistry ◽

10.2174/0929867325666180117142142 ◽

2018 ◽

Vol 25 (21) ◽

pp. 2503-2519 ◽

Cited By ~ 4

Author(s):

Anne Kokel ◽

Marianna Torok

Keyword(s):

Side Effects ◽

Antimicrobial Peptides ◽

Potential Drug ◽

Green Technologies ◽

Specific Antibodies ◽

Structural Modifications ◽

Drug Candidates ◽

Induce Resistance ◽

Conventional Antibiotics

Background: Since the first isolation of antimicrobial peptides (AMPs) they have attracted extensive interest in medicinal chemistry. However, only a few AMP-based drugs are currently available on the market. Despite their effectiveness, biodegradability, and versatile mode of action that is less likely to induce resistance compared to conventional antibiotics, AMPs suffer from major issues that need to be addressed to broaden their use. Notably, AMPs can lack selectivity leading to side effects and cytotoxicity, and also exhibit in vivo instability. Several strategies are being actively considered to overcome the limitations that restrain the success of AMPs. Methods: In the current work, recent strategies reported for improving AMPs in the context of drug design and delivery were surveyed, and also their possible impact on patients and the environment was assessed. Results: As a major advantage AMPs possess an easily tunable skeleton offering opportunities to improve their properties. Strategic structural modifications and the beneficial properties of cyclic or branched AMPs in term of stability have been reported. The conjugation of AMPs with nanoparticles has also been explored to increase their in vivo stability. Other techniques such as the coupling of AMPs with specific antibodies aim to increase the selectivity of the potential drug towards the target. These strategies were evaluated for their effect on the environment highlighting green technologies. Conclusion: Although further research is needed taking into account both environmental and human health consequences of novel AMPs, several of these compounds are promising drug candidates for use in sustainable medicine.

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Phytochemicals as potential drug candidates for targeting SARS CoV 2 proteins, an in silico study

VirusDisease ◽

10.1007/s13337-021-00654-x ◽

2021 ◽

Author(s):

Anish Nag ◽

Ritesh Banerjee ◽

Rajshree Roy Chowdhury ◽

Chandana Krishnapura Venkatesh

Keyword(s):

In Silico ◽

Potential Drug ◽

Drug Candidates ◽

In Silico Study

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Apoptosis-like cell death upon kinetoplastid induction by compounds isolated from the brown algae Dictyota spiralis

Parasites & Vectors ◽

10.1186/s13071-021-04693-7 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Olfa Chiboub ◽

Ines Sifaoui ◽

Manef Abderrabba ◽

Mondher Mejri ◽

José J. Fernández ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Cell Death ◽

Mitochondrial Membrane ◽

Brown Seaweed ◽

Cell Permeability ◽

Oxygen Species ◽

Potential Drug ◽

Concentration Cell ◽

Drug Candidates

Abstract Background The in vitro activity of the brown seaweed Dictyota spiralis against both Leishmania amazonensis and Trypanosoma cruzi was evaluated in a previous study. Processing by bio-guided fractionation resulted in the isolation of three active compounds, classified as diterpenes. In the present study, we performed several assays to detect clinical features associated to cell death in L. amazonensis and T. cruzi with the aim to elucidate the mechanism of action of these compounds on parasitic cells. Methods The aims of the experiments were to detect and evaluate specific events involved in apoptosis-like cell death in the kinetoplastid, including DNA condensation, accumulation of reactive oxygen species and changes in ATP concentration, cell permeability and mitochondrial membrane potential, respectively, in treated cells. Results The results demonstrated that the three isolated diterpenes could inhibit the tested parasites by inducing an apoptosis-like cell death. Conclusions These results encourage further investigation on the isolated compounds as potential drug candidates against both L. amazonensis and T. cruzi. Graphic abstract

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The novel Dbl homology/BAR domain protein, MsgA, of Talaromyces marneffei regulates yeast morphogenesis during growth inside host cells

Scientific Reports ◽

10.1038/s41598-020-79593-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Harshini Weerasinghe ◽

Hayley E. Bugeja ◽

Alex Andrianopoulos

Keyword(s):

Pathogenic Fungi ◽

Host Cells ◽

Microbial Pathogens ◽

Mammalian Host ◽

Host Immune System ◽

Nucleotide Exchange ◽

Phagocytic Cells ◽

Macrophage Infection ◽

Bar Domain ◽

Talaromyces Marneffei

AbstractMicrobial pathogens have evolved many strategies to evade recognition by the host immune system, including the use of phagocytic cells as a niche within which to proliferate. Dimorphic pathogenic fungi employ an induced morphogenetic transition, switching from multicellular hyphae to unicellular yeast that are more compatible with intracellular growth. A switch to mammalian host body temperature (37 °C) is a key trigger for the dimorphic switch. This study describes a novel gene, msgA, from the dimorphic fungal pathogen Talaromyces marneffei that controls cell morphology in response to host cues rather than temperature. The msgA gene is upregulated during murine macrophage infection, and deletion results in aberrant yeast morphology solely during growth inside macrophages. MsgA contains a Dbl homology domain, and a Bin, Amphiphysin, Rvs (BAR) domain instead of a Plekstrin homology domain typically associated with guanine nucleotide exchange factors (GEFs). The BAR domain is crucial in maintaining yeast morphology and cellular localisation during infection. The data suggests that MsgA does not act as a canonical GEF during macrophage infection and identifies a temperature independent pathway in T. marneffei that controls intracellular yeast morphogenesis.

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Evolutionary Genetics of Mycobacterium tuberculosis and HIV-1: “The Tortoise and the Hare”

Microorganisms ◽

10.3390/microorganisms9010147 ◽

2021 ◽

Vol 9 (1) ◽

pp. 147

Author(s):

Ana Santos-Pereira ◽

Carlos Magalhães ◽

Pedro M. M. Araújo ◽

Nuno S. Osório

Keyword(s):

Genetic Diversity ◽

Drug Resistance ◽

Mycobacterium Tuberculosis ◽

Evolutionary Dynamics ◽

Evolutionary Genetics ◽

Host Cells ◽

Whole Genome Sequencing Data ◽

Host Immune System ◽

Viral Mutant ◽

Hiv 1

The already enormous burden caused by Mycobacterium tuberculosis and Human Immunodeficiency Virus type 1 (HIV-1) alone is aggravated by co-infection. Despite obvious differences in the rate of evolution comparing these two human pathogens, genetic diversity plays an important role in the success of both. The extreme evolutionary dynamics of HIV-1 is in the basis of a robust capacity to evade immune responses, to generate drug-resistance and to diversify the population-level reservoir of M group viral subtypes. Compared to HIV-1 and other retroviruses, M. tuberculosis generates minute levels of genetic diversity within the host. However, emerging whole-genome sequencing data show that the M. tuberculosis complex contains at least nine human-adapted phylogenetic lineages. This level of genetic diversity results in differences in M. tuberculosis interactions with the host immune system, virulence and drug resistance propensity. In co-infected individuals, HIV-1 and M. tuberculosis are likely to co-colonize host cells. However, the evolutionary impact of the interaction between the host, the slowly evolving M. tuberculosis bacteria and the HIV-1 viral “mutant cloud” is poorly understood. These evolutionary dynamics, at the cellular niche of monocytes/macrophages, are also discussed and proposed as a relevant future research topic in the context of single-cell sequencing.

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A Comparative Genomic Study of Attenuated and Virulent Strains of Babesia bigemina

Pathogens ◽

10.3390/pathogens10030318 ◽

2021 ◽

Vol 10 (3) ◽

pp. 318

Author(s):

Bernardo Sachman-Ruiz ◽

Luis Lozano ◽

José J. Lira ◽

Grecia Martínez ◽

Carmen Rojas ◽

...

Keyword(s):

In Vitro Culture ◽

Virulence Genes ◽

Laboratory Strain ◽

Host Cells ◽

Comparative Genomic ◽

Local Alignment ◽

Host Immune System ◽

Babesia Bigemina ◽

Genomic Study

Cattle babesiosis is a socio-economically important tick-borne disease caused by Apicomplexa protozoa of the genus Babesia that are obligate intraerythrocytic parasites. The pathogenicity of Babesia parasites for cattle is determined by the interaction with the host immune system and the presence of the parasite’s virulence genes. A Babesia bigemina strain that has been maintained under a microaerophilic stationary phase in in vitro culture conditions for several years in the laboratory lost virulence for the bovine host and the capacity for being transmitted by the tick vector. In this study, we compared the virulome of the in vitro culture attenuated Babesia bigemina strain (S) and the virulent tick transmitted parental Mexican B. bigemina strain (M). Preliminary results obtained by using the Basic Local Alignment Search Tool (BLAST) showed that out of 27 virulence genes described and analyzed in the B. bigemina virulent tick transmitted strain, only five were fully identified in the attenuated laboratory strain. In all cases, the identity and coverture of the identified genes of the wildtype strain were higher than those of the laboratory strain. This finding is putatively associated with the continuous partial loss of virulence genes in the laboratory strain after several passages of the parasite population under optimal in vitro growth conditions. The loss of virulence factors might be reflected in the absence of symptoms of the disease in cattle inoculated with the attenuated strain despite the presence of infection in the bovine host cells.

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Leishmania donovani Secretory Mevalonate Kinase Regulates Host Immune Response and Facilitates Phagocytosis

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.641985 ◽

2021 ◽

Vol 11 ◽

Author(s):

Tanvir Bamra ◽

Taj Shafi ◽

Sushmita Das ◽

Manjay Kumar ◽

Manas Ranjan Dikhit ◽

...

Keyword(s):

Immune Response ◽

Immune System ◽

Leishmania Donovani ◽

Indian Subcontinent ◽

Parasite Burden ◽

Host Immune Response ◽

Host Cells ◽

Interleukin 4 ◽

Host Immune System ◽

Mevalonate Kinase

Summary StatementLeishmania secretes over 151 proteins during in vitro cultivation. Cellular functions of one such novel protein: mevalonate kinase is discussed here; signifying its importance in Leishmania infection.Visceral Leishmaniasis is a persistent infection, caused by Leishmania donovani in Indian subcontinent. This persistence is partly due to phagocytosis and evasion of host immune response. The underlying mechanism involves secretory proteins of Leishmania parasite; however, related studies are meagre. We have identified a novel secretory Leishmania donovani glycoprotein, Mevalonate kinase (MVK), and shown its importance in parasite internalization and immuno-modulation. In our studies, MVK was found to be secreted maximum after 1 h temperature stress at 37°C. Its secretion was increased by 6.5-fold in phagolysosome-like condition (pH ~5.5, 37°C) than at pH ~7.4 and 25°C. Treatment with MVK modulated host immune system by inducing interleukin-10 and interleukin-4 secretion, suppressing host’s ability to kill the parasite. Peripheral blood mononuclear cell (PBMC)-derived macrophages infected with mevalonate kinase-overexpressing parasites showed an increase in intracellular parasite burden in comparison to infection with vector control parasites. Mechanism behind the increase in phagocytosis and immunosuppression was found to be phosphorylation of mitogen-activated protein (MAP) kinase pathway protein, Extracellular signal-regulated kinases-1/2, and actin scaffold protein, cortactin. Thus, we conclude that Leishmania donovani Mevalonate kinase aids in parasite engulfment and subvert the immune system by interfering with signal transduction pathways in host cells, which causes suppression of the protective response and facilitates their persistence in the host. Our work elucidates the involvement of Leishmania in the process of phagocytosis which is thought to be dependent largely on macrophages and contributes towards better understanding of host pathogen interactions.

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Virtual screening as therapeutic strategy of COVID-19 targeting angiotensin-converting enzyme 2

Frontiers in Molecular Immunology ◽

10.25082/fmi.2021.01.002 ◽

2021 ◽

Vol 2 (1) ◽

pp. 16-27

Author(s):

Zahra Sharifinia ◽

◽

Samira Asadi ◽

Mahyar Irani ◽

Abdollah Allahverdi ◽

...

Keyword(s):

Virtual Screening ◽

Angiotensin Converting Enzyme ◽

Host Cells ◽

Spike Protein ◽

Potential Drug ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Approved Drugs ◽

Fda Approved Drugs

Objective: The receptor-binding domain (RBD) of the S1 domain of the SARS-CoV- 2 Spike protein performs a key role in the interaction with Angiotensin-converting enzyme 2 (ACE2), leading to both subsequent S2 domain-mediated membrane fusion and incorporation of viral RNA in host cells. Methods: In this study, we investigated the inhibitor’s targeted compounds through existing human ACE2 drugs to use as a future viral invasion. 54 FDA approved drugs were selected to assess their binding affinity to the ACE2 receptor. The structurebased methods via computational ones have been used for virtual screening of the best drugs from the drug database. Key Findings: The ligands “Cinacalcet” and “Levomefolic acid” highaffinity scores can be a potential drug preventing Spike protein of SARS-CoV-2 and human ACE2 interaction. Levomefolic acid from vitamin B family was proved to be a potential drug as a spike protein inhibitor in previous clinical and computational studies. Besides that, in this study, the capability of Levomefolic acid to avoid ACE2 and Spike protein of SARS-CoV-2 interaction is indicated. Therefore, it is worth to consider this drug for more in vitro investigations as ACE2 and Spike protein inhibition candidate. Conclusion: The two Cinacalcet and Levomefolic acid are the two ligands that have highest energy binding for human ACE2 blocking among 54 FDA approved drugs.

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