Breaching the wall: How malaria parasites enter the human brain - Advanced Science News

Posted: 18 May 2021 04:04 AM PDT

Researchers uncover how malaria infiltrates the blood–brain barrier and contributes to disease severity.

3D z-projection of a blood-brain barrier spheroid. The red dots are P. falciparum-infected red blood cells.

Malaria is a disease that has threatened mankind for millennia. The latest WHO World Malaria Report published in November 2020 stated that 220 million clinical cases and 400,000 deaths occurred in the previous year, with the majority of cases occurring in the WHO African Region. While researchers are working tirelessly to provide therapies and develop vaccines to help treat this rampant disease — which disproportionally affects children — understanding the underlying mechanisms that trigger disease severity is important.

Malaria is caused by a single-celled parasite called Plasmodium, with different Plasmodium species capable of infecting humans, and each causing a different form of the disease. Severe cases of malaria occur when infection leads to complications in the body's major organs, and are usually related to infection by Plasmodium falciparum (P. falciparum), the causative agent of malaria tropica. P. falciparum has a complex lifecycle that involves infection via an insect host (female Anopheles mosquitoes) and eventually the invasion of red blood cells for asexual reproduction. This triggers the majority of disease symptoms, such as the distinct fevers malaria patients often experience.

Cerebral malaria, one manifestation of severe malaria, is caused when infected red blood cells obstruct blood circulation within brain blood vessels. This leads to swelling and inflammation in the brain and serious consequences for the patient. Deciphering the exact origin and development of cerebral malaria is crucial to minimizing disease severity and ultimately saving lives.

This is what a team of international researchers led by Professors Anja Jensen and Yvonne Adams from the University of Copenhagen set out to do. In a study published in the Journal of Experimental Medicine, they deciphered an important aspect of cerebral malaria. That is, they observed that P. falciparum-infected red blood cells are taken up by endothelial cells in the blood–brain barrier — a well-defined structure of tightly connected cells which protect the brain against invasion. Interestingly, parasite-carrying red blood cells were found not only within the endothelial cells.

Human red blood cells are highly specialized and are generally responsible for oxygen transport around the body. Old red blood cells are removed from blood circulation after approximately 120 days, an important task carried out by the spleen, which not only ensures a proper oxygen supply but also aids in mitigating infection as infected cells will be eliminated before the disease can ramp up.

This is a detrimental process to malaria parasites, and one that they need to circumvent at all costs to ensure its survival. As a result, the parasites facilitate the presentation of their own proteins on the surface of the red blood cells that they had infected. This action serves to essentially trick the body and its army of immune cells, saving the infected cells from removal from the blood by the spleen.

One of these parasitic surface proteins is called PfEMP1 (P. falciparum erythrocyte membrane protein 1), and interestingly, the malaria parasite is capable of producing not just one version of it, but different versions that form what biologists call a "protein family". Every single member of this PfEMP1 protein family is encoded within the genome of the malaria parasite, but it will only display one version of the PfEMP1 protein on the surface of the infected red blood cell at a time.

To make things even more interesting, individual parasites are able to switch the PfEMP1 version they present on the surface of the infected red blood cell in order to avoid detection by the immune system if the previously used protein is recognized. This allows the parasite to continue with their red blood cell infection and progeny production.

In addition to helping the infected red blood cells avoid elimination, PfEMP1 proteins allow them to bind to different receptor proteins found on the endothelial cells of different organs, such as the brain. Where the binding to the endothelial cells occurs is determined by the PfEMP1 version presented on the red blood cell surface.

*Electron micrograph of an endothelial cell which has taken up a P. falciparum-infected red blood cell. © 2021 Adams, Y. et al. Originally published in J Exp Med https://doi.org/10.1084/jem.20201266*

These PfEMP1-based interactions and their association with cerebral malaria has fascinated Jensen and Adams for years.

In 2015, they first spotted P. falciparum-infected red blood cells within human brain endothelial cells, a rather unexpected observation because malaria parasites have, until now, only been shown to infect red blood cells and liver cells called hepatocytes. However, the novel observation was supported by pathologists who had previously witnessed the same phenomenon.

Interestingly, endothelial cells have the natural ability to remove damaged red blood cells and clear blood clots from the body, and so Jensen and Adams hypothesized that the malaria parasites might actually be triggering this mechanism with specific members of the PfEMP1 protein family. Subsequent experiments showed that only infected red blood cells that presented a particular PfEMP1 version could bind receptors (ICAM-1 and EPCR) found on the surface of these endothelial cells. It had previously been shown that this event was connected to cerebral malaria episodes.

To assess whether the same phenomenon was occurring at the blood–brain barrier, the team employed a spheroid model, which is a versatile platform used for studying different biological conditions. Cells that grow in culture in the laboratory usually form only one single cell layer. However, the advantage of the spheroid model is that it allows cells, such as endothelial cells, to grow into a 3D cluster, which is a very elegant way to mimic the blood–brain barrier outside of the human body.

The spheroid model verified previous observations and provided a possible pathway explanation for the route to brain infection. Namely, it showed that malaria-infected red blood cells, which present ICAM-1 and EPCR-binding PfEMP1 proteins on their surface, are taken up and internalized by the endothelial cells. Interestingly, the endothelial cells eventually begin to swell and become more permeable, possibly opening the doorway to the brain even further. Whether this can be directly linked to the swelling of the brain observed in patients with severe malaria requires further investigation, say the authors.

In the near future, Jensen and Adams aim to look closer at the interaction between infected red blood cells and endothelial cells to gain more detailed understanding of cerebral malaria in order to provide a platform for the development of better therapies and vaccines, which are sorely needed.

For now, understanding how the malaria uses its own versatile toolbox of proteins to facilitate its uptake by endothelial cells and gain access to the brain is an important first step in that direction.

Reference: Yvonne Adams, et al., Plasmodium falciparum erythrocyte membrane protein 1 variants induce cell swelling and disrupt the blood–brain barrier in cerebral malaria, Journal of Experimental Medicine (2021). DOI: 10.1084/jem.20201266

Ivermectin: why a potential COVID treatment isn’t recommended for use - The Conversation UK

Posted: 19 Apr 2021 12:00 AM PDT

As the search continues for treatments for COVID-19, the results from a number of studies have led to changes in the advice on which drugs to give people who are suffering from the disease.

The European Medicines Agency and the United States National Institutes of Health have recently stated that one previously promising treatment – the antiparasitic drug, ivermectin – is not recommended for use in routine management of COVID-19 patients.

Despite these decisions, support for ivermectin has been circulating on social media and in WhatsApp groups, with rumours abounding that the drug is being blocked on purpose. Some have dubbed it the "new hydroxycholoroquine", after a treatment that received a significant amount of online support but was found in trials to be ineffective against COVID-19.

So what is ivermectin, and why have national agencies ruled against it?

What is ivermectin?

Ivermectin was first developed in the 1970s from a bacterium in a soil sample collected from woods alongside a Japanese golf course (no other source has ever been found).

In the intervening years, the effectiveness of ivermectin and its derivatives in treating parasitic worm infections transformed human and veterinary medicine, leading to a Nobel Prize for its discoverers, William C Campbell and Satoshi Ömura.

In humans, ivermectin is currently prescribed in tablet form to treat certain roundworm infections that cause illnesses such as river blindness. It may also be applied as a cream to control the common inflammatory skin condition papulopustular rosacea.

A packet of ivrmectin capsules. — The drug has its supporters, but not enough evidence for use against COVID. HJBC/Shutterstock

But ivermectin is most commonly used for veterinary parasitic diseases, especially gastrointestinal worm infestations. Consequently, it is readily available and relatively inexpensive.

As ivermectin is more extensively used in veterinary than human medicine, however, the US Food and Drug Administration found it necessary to issue a warning in April 2020 against use of veterinary preparations in human patients with COVID-19.

Why might it be used to treat COVID?

How did a drug mainly used to treat intestinal parasites in cows come to be of interest to doctors treating humans with COVID-19?

In early 2020, a paper was made public (before it was reviewed by other scientists) which showed ivermectin suppresses the replication of the SARS-CoV-2 virus, which causes COVID-19, under laboratory conditions. This was one of many studies over the past 50 years to show that the antiparisitic drug could also have antiviral uses.

There appear to be two key ways in which the drug could prevent coronavirus replication. First, it could prevent the virus from suppressing our cells' natural antiviral responses. Second, it's possible the drug prevents the "spike" protein on the surface of the virus from binding to the receptors that allow it to enter our cells. Along with the anti-inflammatory actions apparent from ivermectin's efficacy in rosacea, these may point towards useful effects in a viral disease that causes significant inflammation.

These initial findings were used as the basis of numerous recommendations for ivermectin's use to treat COVID-19, particularly in Latin America, which were later retracted.

Why is it controversial?

Since then, there have been numerous studies into ivermectin as a potential treatment for COVID-19.

In late 2020, a research group in India was able to summarise the results of four small studies of ivermectin as an add-on treatment in COVID-19 patients. This review showed a statistically significant improvement in survival among patients who received ivermectin in addition to other treatments.

But the authors stated clearly that the quality of the evidence was low and that the findings should be treated with caution. As is frequently the case for reviews of multiple small studies, the paper suggested that further trials were needed to determine whether ivermectin was indeed clinically effective.

A shaggy cow in a field — Ivermectin: we know it's good for cows, but is it good for COVID? Farlap/Alamy Stock Photo

A controversy subsequently blew up over an article by the Front Line COVID-19 Critical Care Alliance, a group of doctors and researchers that lobbies for the use of ivermectin.

This article, summarising multiple small studies of the effects of ivermectin on COVID-19 patients, was provisionally accepted for publication in the journal Frontiers in Pharmacology in January 2021 but then rejected and removed from the journal's website in March. The journal's editor stated that the standard of evidence in the paper was insufficient and that the authors were inappropriately promoting their own ivermectin-based treatment.

One larger randomised clinical trial was published in March 2021. This showed no effect of ivermectin on duration of symptoms of adults with mild COVID-19. The authors stated that the findings did not support the use of ivermectin in these patients, but again highlighted that larger trials were needed to determine whether the drug had other benefits.

Why isn't it recommended?

While some other studies did appear to show benefits of ivermectin, many did not. These were summarised by the National Institutes of Health, showing severe limitations arising from small sample sizes and problems with study design.

Both the National Institutes of Health and the European Medicines Agency judged, on the basis of these studies, that there is currently insufficient evidence to support the use of ivermectin in treatment of COVID-19.

More studies are underway. A large, multicentre trial began in February to determine the effectiveness of ivermectin as well as metformin (an anti-diabetes medication) and fluvoxamine (an antidepressant) in preventing COVID-19 disease progression.

It would therefore be premature to conclude absolutely that ivermectin has no place in COVID-19 treatment. On the basis of current evidence, however, its use cannot be recommended.

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