His Excellency Prof. Manuel Alejandro Freire-Garabal, Director of International Relations of the Private Council of His Highness Mahmoud Salah Al Din Assaf, contributed in Harvard University about the development of medicines against the infection with micro-algae treatment.
Microalgae against Infection: From Shrimp Culture to Human Healthcare
At a time when we approach the shortage of available resources, oceans have become an attractive place for the search of new compounds that solve problems generated by the terrestrial activities. It is speculated that more than the 90% of marine resources remain to be discovered. The surveys carried out to date have great hopes for single-celled beings that populate the sea. These organisms, primarily microalgae, have a high capacity to proliferate at high speed, then to be cultivated rapidly, inexpensively, with relatively simple growth needs, and in large scale.
In recent years, microalgal culture technology has become is a business-oriented activity. It can become an important source of biomass to produce biofuels, food for human or animal nutrition, and a variety of chemicals that can be used as raw materials for different applications like drugs and cosmetics. In this regard, an important number of investigations have concluded that microalgae contain bioactive compounds of high value in healthcare – proteins, essential amino acids, fatty acids, polysaccharides, minerals, vitamins, photosynthetic enzymes, pigments – with antioxidant, anti-inflammatory, anti-tumor and anti-infective properties.
The resistance of germs to disposable antimicrobials has become a major problem worldwide, making it necessary to discover new drugs from different origins, including those present in living beings of the sea, to cure infections. Do not forget that nature provided us with the first effective weapons, like penicillin, against pathogenic bacteria.
Microalgae have demonstrated antimicrobial properties. Many of these findings come from the aquaculture industry, since microalgae are becoming a common ingredient in feed formulation for captive-bred marine species. Obtaining biomass from these organisms usually takes place in open ponds, which are susceptible to contamination by germs, which considerably reduce the quantity and quality of the end product. Therefore, the selection of the most resistant microalgae species and their genetic improvement are key factors in the success of companies. There are interactions between the different aquatic microbial communities that allow an ecological balance. The bacteria produce metabolites to protect and influence the life and growth cycle of their eukaryotic hosts, while the host also provides the bacteria with an environment enriched with nutrients. These chemical mediators are present in systems of multiple aquatic partners, in which algae, invertebrates and their associated bacteria coexist.
Certain bacteria behave like algaecides, but also some microalgae develop resistance mechanisms against them. These interactions have a special relevance in the management of small or medium-sized bodies of water, such as those treated in aquaculture, but also in the ecological balance of seas and oceans, highly exposed to the climate change impact.
The proper selection of marine microalgae to feed other marine species such as fish or crustaceans is very important, since you can limit the appearance of microbial infections. This is a good alternative to the use of conventional antibiotics, preventing their passage into the food chain and reducing the occurrence of microbial resistance.
Multiple experiments have been done to achieve microalgae that would allow the fish to defend against infections. Although we are still at the beginning of all this technology, progress is being made very quickly in the selection and optimization in the processes of cultivation, extraction and purification of products derived from microalgae for the development of sustainable aquaculture.
Bacterial blooms in ponds have been an important restriction in shrimp farming. The sources of carotenoids in shrimp diets have proven effective in improving survival, growth, reproductive capacity, resistance to stress and also in reducing disease of certain species.Litopenaeus vannamei has an innate immune system that lacks memory, what makes necessary to provide this specie with stimulant agents to alert the immune system against the invasion of pathogenic organisms. For example, under stress conditions, Dunaliella sp.can accumulate significant amounts of carotenoids, which are its only precursors of retinoids, increasing crustacean tolerance to stress and promoting its immune response against viruses and pathogenic bacteria. Other species like Chlamydomonas reinhardtii have the capacity to facilitate RNA interference mechanisms, an effective way of combating shrimp viruses when used as feed supplement.
Commercial diets for farm fish can contain soybean meal that may induce intestinal inflammation. When combined with some microalgae, these adverse effects, an even intestinal infection, can be reduced. Dietary supplementation with microalgae like Chlorellawas also implemented in pig farming to manage mild digestive piglet disorders.
These and other results have led to questioning the possibility that microalgae are an important source of immune enhancing compounds, but also as direct antibacterial, antiviral, source of drugs or supplements useful to help in human infections.
Research has demonstrated the antibacterial activity of different microalgae against both gram-positive and gram-negative human pathogens. This is the case of Pseudomonas aeruginosa, a gram-negative and opportunistic germ that is causing major problems in global health, being an important cause of infections in immunocompromised patients. Microalgae Oscillatoria subuliformis and S. platensis methanolic extracts have properties against germ virulence factors such as its ability to generate biofilms and for having a quorum sensing. Also, carotenoids, sulfated polysaccharides and polyunsaturated fatty acids from certain microalgae can block the adhesion of pathogens to the gastric surface. It is important to notice that carotenoids are effective against Helicobacter pylori infection, that has been targeted as a primary cause of ulcer and gastrointestinal cancer. Chlorella sp. supplemented diets have protective effects on intestinal mucosa barrier in rats suffering obstructive jaundice, reducing intestinal translocation of bacteria and endotoxin
Otitis externa can become another indication. Some studies have demonstrated that some salt and freshwater microalgae – like Dunaliella salina and Pseudokirchneriella subcapitata extracts, respectively – are capable to inhibit the growth of pathogen bacteria like S. aureus (including some of them resistant to methicillin) P. aeruginosa, Escherichia coli and Klebsiella, obtained from patients. Anti-infective properties of microalgae may also be of interest in the treatment of skin infections, as is the case with antibacterial compounds found in macroalgae that can fight acne and chronic wounds.
A number of studies have also reported interesting properties of some microalgae derivates against different types of virus responsible of disease in humans.
Herpes virus type 1 (HSV-1) infection causes highly prevalent genital and orolabial disease worldwide. Treatments are commonly based on antivirals that share the same mechanism of action what has led to the emergence of resistant viral strains, especially in immunocompromised patients. Water extract of Spirulina platensis Porphyridium sp. inhibit the in vitro replication and increases survival times of hamsters infected with HSV-1. Studies demonstrated that the sulfated polysaccharide calcium spirulan (Ca-SP), found in the microalgae, inhibits the in vitro replication HSV-1, as well as other enveloped viruses like human cytomegalovirus, measles virus, mumps virus, influenza A virus, and human immunodeficiency type 1 (HIV-1) virus. Ca-SP also blocks viral attachment and penetration into host cells. Using a clinical model of herpes exacerbation, a cream containing Ca-SP and microalgae extract also had higher prophylactic effects compared to a cream containing acyclovir.
The red microalgae Porphyridium sp. also exhibits antiviral activity against HSV-1 and -2 both in cell cultures and in animal models. A polysaccharide found in its cell wall inhibited or slowed down cytopathic effects of HSV in cells and prevented the appearance and development of symptoms both in HSV-1 infected rats and rabbits. This compound also may affect earlier steps in virus replication cycle, like virus absorption into host cells, as well as on a late step after provirus integration.
Protective effects of microalgae against influenza infection have been reported by different authors. Mice infected intranasally with influenza A/PR/8/34 (H1N1) virus who were previously fed with a diet containing the microalgae Euglena gracilis Z and its carbohydrate storage paramylon showed higher survival rates as well as lower plasmatic levels and virus titers compared to the control. Extracts obtained from Chlorellaceae family inhibit both oseltamivir-sensitive and resistance seasonal influenza A and B virus replication in cultured cells. The marine microalgae Gyrodinium impudium sulfated polysaccharide p-KG03 has demonstrated potent and specific influenza A viral entry inhibitor properties as well as beneficial effects against encephalomyocarditis virus infection.
Aqueous extracts from P. cruentum, C. autotrophica and Ellipsoidon sp., have been found to produce a significant inhibition of the in vitro replication of hemorrhagic septicemia virus and African swine fever virus in a dose-dependent manner.
Microalgae are also becoming biotechnological instruments of great importance, replacing animal cells in the production of high-value proteins that can be used as antimicrobials. Some results also come from aquaculture. For example, Nannochloropsis oculata can be genetically modified it to express bovine lactoferricin that increases survival rates of farm fish exposed to Vibrio parahaemolyticus
Microalgae are attractive hosts to produce and deliver vaccines or antibodies useful in human healthcare, with some candidates under preclinical evaluation. Diatoms are a particularly productive type of unicellular algae that have silicified cell walls that allow the development of silicon-responsive transcription elements to induce protein expression. For example, the diatom Thalassiosira pseudonana can be used to produce a vaccine against bovine respiratory disease.
The algae-made ZIKV vaccine represents another promising project. Using technology to express an antigenic protein named ZK comprising the B subunit of the heat labile Escherichia coli enterotoxin along with 3 epitopes from the ZIKV envelope glycoprotein, a group of scientists obtained an efficient expression of the ZK antigen in Schizochytrium sp. that was orally administered to mice eliciting significant humoral responses against the pathogen.
Other authors retrieved sequences for both chains of an IgG antibody against the nucleoprotein of Marburg virus – a close relative of Ebola virus – from a murine hybridoma cell line and engineered the microalgae Phaeodactylum tricornutum to produce monoclonal IgG antibodies. A recombinant IgG antibody directed against Hepatitis B surface antigen has also been obtained from cultures of this modified microalgae using a cellular binding assay and surface plasmon resonance.
These are some of the examples that make us think about the great potential of the oceans, and specifically of the unicellular beings that populate them, such as microalgae, to face the great threat that infections pose to human and animal health – that can even put the Millennium Development Goals at risk – and to maintain ecological balance in the coming decades. This seems to be just the beginning of a nice history; do not forget that the microalgae resource is estimated in more than 40,000 species, of which only a few of them, little more than a dozen, are in clinical use.