Monday, June 1, 2020

Promising News Regarding Cellular Immunity and COVID-19

As medical professionals, epidemiologists, immunologists, and molecular biologists work in the midst of the COVID-19 pandemic, many aspects of the biology of this virus are being studied and as a result, a new understanding is emerging.

As a result of these efforts some promising aspects of the immunological response have been revealed. Primary among the results of these accumulated data is the fact that individuals infected with this virus harbor T-cells – an important subset of circulating lymphocytes that play a critical role in the human immunological response – that actively target the virus and may assist in recovery. In addition, it seems that some individuals who have never been infected with COVID-19, have these cellular defenses – suggesting that this potential immunological defense arose; because they were previously infected with other coronaviruses that cause the common cold. 


Helper T Cells

These findings provide suggestive evidence that the potent T cell responses that were shown to exist may play an important role in long-term protective immunity. In addition, a more complete understanding of how the human body responds to this particular virus will undoubtedly enhance the search for an effective prophylactic vaccine.

There are more than 100 COVID-19 vaccines in various stages of development focusing on a wide rage of modalities. Within the arsenal of the so-called “adaptive” arm of the human immune system are circulating B and T lymphocytes. The B cells are responsible for the production of antibodies against particular targets. The mechanism that the immune system employs in this regard is that the B cell produced in response to exposure to the virus is to attach itself to the viral particle and prevent it from entering healthy tissue cells. This role can be exploited in the development of a vaccine. In addition, to this part of the natural arsenal against infection, there are circulating T cells that can activate and enhance B cell response. In addition to these players, there are killer T cells that actually target and destroy tissue cells that have been infected. Given the interrelationship of these defense mechanisms, there is a correlation between the severity of the disease and the strength of the T cell responses.

Shane Crotty and Alessandro Sette – immunologists from the La Jolla Institute of Immunology – determined what proteins from the surface of COVID-19 particles were most likely to stimulate immune response and subsequently exposed cells grown in culture (in-vitro) from 10 patients who had recovered from mild cases of COVID-19 to these virally-derived protein pieces. In all the samples studied, the patients carried helper T cells that were specific for the COVID-19 spike protein – the predominant protein of the viral surface that is involved in targeting tissue cells. In addition, 70% of the patients studied showed the presence of virus-specific killer T cells. Whether these patients also acquired long term immunity is not completely clear. These data, however, are very encouraging.

Although not unambiguous, these results are of great interest and suggest that an effective vaccine against COVID-19 infection needs to stimulate the production of helper T cells.

Saturday, May 2, 2020

The Mode of Action of the Anti-viral Drug Remdesivir

Currently, the United States along with many parts of the world is being severely impacted by the COVID-19 pandemic. As discussed in more detail in previous reports, COVID-19 is an RNA virus that was previously resident in another mammalian species and underwent a genetic modification that allowed it to cross species to humans – a not uncommon event among viral pathogens. The current genetic evidence is strongly suggestive that the mammalian species from where the virus originated was the bat. 

Recent clinical trials have demonstrated that the anti-viral drug remdesivir has some efficacy in the treatment of the illness brought about by COVID-19 infection. Remdesivir is a nucleoside analog (structure shown below)


Structure of Remdesivir



Inside the target host cell – lung tissue as an example – this substance functions as an inhibitor of the process that is involved in viral replication. The drug’s specific target tin RdRp (see diagram below) – the protein complex that the coronavirus uses to replicate its RNA genome.

Structure of RdRp

According to a report presented by E.S. Amirian, “After the host metabolizes remdesivir into active nucleoside triphosphate (NTP), the metabolite competes with adenosine triphosphate (ATP; the natural nucleotide normally used in this process) for incorporation into the nascent RNA strand – effectively substituting the drug metabolite for ATP. The incorporation of this substitute into the new strand results in premature termination of RNA synthesis, halting the growth of the RNA strand after a few more nucleotides are added. Although coronaviruses (CoVs) have a proofreading process that is able to detect and remove other nucleoside analogs, rendering them resistant to many of these drugs, remdesivir seems to outpace this viral proofreading activity, thus maintaining antiviral activity. Unsurprisingly, Agostini et al. reported that a mutant murine hepatitis virus (MHV) devoid of proofreading ability was more sensitive to remdesivir.”

Since viruses are prone to mutations, it is also possible that that mutations could spontaneously occur that would effectively improve proofreading and result in remdesivir resistance. In addition, it also quite possible that the effectiveness of this anti-viral drug could be due to additional factors that are currently unknown.

At the present time, in-vitro and clinical trials have yielded strong suggestive evidence that remdesivir may provide a clinical route to a therapy that could be applied to COVID-19 patients. Ongoing studies are also investigating the possibility of finding additional drugs that could provide a synergistic effect to further improve positive outcomes.

This line of investigation together with a fast-track search for an effective vaccine may ultimately safe countless lives worldwide. These scientific investigations highlight the intrinsic and inestimable value that the ongoing scientific studies contribute to humanity and its future.

Saturday, April 11, 2020

NIH Clinical Trial of Investigational Vaccine for COVID-19 Begins

"The following article has been take from the National Institutes of Health (NIH) website: http://www.nih.gov describing a study enrolling Seattle-based healthy adult volunteers. 

The image below shows a spike protein of SARS-CoV-2—also known as 2019-nCoV (COVID-19). The spike protein enables the virus to enter and infect human cells. On the virus model, the virus surface is covered with spike proteins that enable the virus to enter and infect human cells. For more information, visit NIH




"A Phase 1 clinical trial evaluating an investigational vaccine designed to protect against coronavirus disease 2019 (COVID-19) has begun at Kaiser Permanente Washington Health Research Institute (KPWHRI) in Seattle. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is funding the trial. KPWHRI is part of NIAID’s Infectious Diseases Clinical Research Consortium. The open-label trial will enroll 45 healthy adult volunteers ages 18 to 55 years over approximately 6 weeks. The first participant received the investigational vaccine today.

"The study is evaluating different doses of the experimental vaccine for safety and its ability to induce an immune response in participants. This is the first of multiple steps in the clinical trial process for evaluating the potential benefit of the vaccine.

"The vaccine is called mRNA-1273 and was developed by NIAID scientists and their collaborators at the biotechnology company Moderna, Inc., based in Cambridge, Massachusetts. The Coalition for Epidemic Preparedness Innovations (CEPI) supported the manufacturing of the vaccine candidate for the Phase 1 clinical trial.

'Finding a safe and effective vaccine to prevent infection with SARS-CoV-2 is an urgent public health priority,' said NIAID Director Anthony S. Fauci, M.D. 'This Phase 1 study, launched in record speed, is an important first step toward achieving that goal.'

"Infection with SARS-CoV-2, the virus that causes COVID-19, can cause a mild to severe respiratory illness and include symptoms of fever, cough and shortness of breath. COVID-19 cases were first identified in December 2019 in Wuhan, Hubei Province, China. As of March 15, 2020, the World Health Organization (WHO) has reported 153,517 cases of COVID-19 and 5,735 deaths worldwide. More than 2,800 confirmed COVID-19 cases and 58 deaths have been reported in the United States as of March 15, according to the Centers for Disease Control and Prevention (CDC).

"Currently, no approved vaccines exist to prevent infection with SARS-CoV-2.

"The investigational vaccine was developed using a genetic platform called mRNA (messenger RNA). The investigational vaccine directs the body’s cells to express a virus protein that it is hoped will elicit a robust immune response. The mRNA-1273 vaccine has shown promise in animal models, and this is the first trial to examine it in humans.

"Scientists at NIAID’s Vaccine Research Center (VRC) and Moderna were able to quickly develop mRNA-1273 because of prior studies of related coronaviruses that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Coronaviruses are spherical and have spikes protruding from their surface, giving the particles a crown-like appearance. The spike binds to human cells, allowing the virus to gain entry. VRC and Moderna scientists already were working on an investigational MERS vaccine targeting the spike, which provided a head start for developing a vaccine candidate to protect against COVID-19. Once the genetic information of SARS-CoV-2 became available, the scientists quickly selected a sequence to express the stabilized spike protein of the virus in the existing mRNA platform.

"The Phase 1 trial is led by Lisa A. Jackson, M.D., senior investigator at KPWHRI. Study participants will receive two doses of the vaccine via intramuscular injection in the upper arm approximately 28 days apart. Each participant will be assigned to receive a 25 microgram (mcg), 100 mcg or 250 mcg dose at both vaccinations, with 15 people in each dose cohort. The first four participants will receive one injection with the low dose, and the next four participants will receive the 100 mcg dose. Investigators will review safety data before vaccinating the remaining participants in the 25 and 100 mcg dose groups and before participants receive their second vaccinations. Another safety review will be done before participants are enrolled in the 250 mcg cohort.

"Participants will be asked to return to the clinic for follow-up visits between vaccinations and for additional visits across the span of a year after the second shot. Clinicians will monitor participants for common vaccination symptoms, such as soreness at the injection site or fever as well as any other medical issues. A protocol team will meet regularly to review safety data, and a safety monitoring committee will also periodically review trial data and advise NIAID. Participants also will be asked to provide blood samples at specified time points, which investigators will test in the laboratory to detect and measure the immune response to the experimental vaccine.

“This work is critical to national efforts to respond to the threat of this emerging virus,” Dr. Jackson said. “We are prepared to conduct this important trial because of our experience as an NIH clinical trials center since 2007.”

"Adults in the Seattle area who are interested in joining this study should visit https://corona.kpwashingtonresearch.org. For more information about the study, visit ClinicalTrials.gov and search identifier NCT04283461.

"NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

"About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

"Adults in the Seattle area who are interested in joining this study should visit https://corona.kpwashingtonresearch.org/. People who live outside of this region will not be eligible to participate in this trial."

The mode of action of mRNA vaccines is to introduce a messenger RNA (mRNA) into the individual recipient that codes for the production of a unique protein that is part of the structure of the pathogen being targeted. In this case the pathogen is COVID-19 and the protein is referred to as spike (see image above). Once spike is made by the individual vaccinated, that should alert the immune system to recognize an essential protein on COVID 19 and prepares the body if and when it is actually exposed to the virus. This methodology would obviate the need to introduce a weakened (attenuated) form of COVID-19 as part of a vaccine.  This kind of approach holds a lot of promise.

Friday, March 13, 2020

An Appreciation of the Commons

We are now in the midst of what might be regarded as a raging pandemic in relation to the spreading impact of the corona virus on human populations throughout the world. To me, this new reality is a not so subtle reminder of the precarious nature of civilization and the inescapable reality that our species in general and our place in the so-called “developed” world in particular does not grant us any immunity to the nature of our individual and collective frailty as living beings on our planetary home. We are all subject to the physical and biological forces that constitute our everyday existence for better or worse.

From a biological perspective, viruses portray unusual properties in that outside of living cells they are quite incapable of independent existence. They are specifically engineered to “infect” living cells and have the capacity to commandeer the cellular machinery that ordinarily sustains the life of the cell and appropriate cellular processes to a singular role – the production of more viral particles. They are so successful at this that the infected cell usually succumbs, and the viral progenies go on to invade neighboring cells that in the case of the corona virus are the cells that constitute lung tissue. As entities, viruses have been among the living for billions of years. As a matter of fact, portions of human DNA contain the remnants of an array of viral DNA from many sources. In this regard, viruses have apparently played an important role in the evolution of life, including human life, on the planet. For this reason, viruses will always be with us.

Thanks to the multitude of scientific discoveries and the cumulative efforts embodied in scientific research, we are extremely knowledgeable regarding the biology of many viruses including the corona virus and its mode of infection. One possible outcome of the acceptance of this basic reality, may hopefully be a renewed appreciation of the Commons – those aspects of civilization that are fundamental to the sustainability and viability of communal life. Examples of the these would be public health, clean air, drinkable water, adequate shelter and nutrition, etc.

It has become a patent reality that in the United States the wholesale neglect of the Commons has made us particularly vulnerable to this pandemic and its ineluctable impact on societal institutions. It also has placed particular emphasis on the essential importance of smart government leadership that places appropriate reliance on the important role that science and professional expertise can play in dealing with a national crisis such as this one.

It is my hope that the lessons from this throughout the world will find direct application in preparing for future calamities including climate change to help ensure the future viability of the species.

Tuesday, February 4, 2020

The Biology of the Coronavirus



The global spread of viral pneumonia associated with the so-called “Wuhan coronavirus” appears to be reaching pandemic proportions. Given this distressing reality, it is important to more fully understand the biology of this virus.

Viruses represent a class of infectious agents that pose interesting challenges as witnessed by the HIV/AIDS virus that is the causative agent of the devastating acquired immunodeficiency syndrome (AIDS) that targets a particularly important cell type in the human adaptive immune system – the so-called, “T-helper cells (CD4).” Viruses possess the unusual property of being inert when outside a living cell. However, once they gain access to a living cell, the infective agent – either ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) - commandeers the host cellular machinery to make copies of itself. This process can lead either to the ultimate death of the target cell or can result in a transformation of the host DNA that in some instances can lead to cancer – T-cell leukemia (HTLV-1 virus) and Cervical cancer (Human Papilloma virus – HPV) being some important examples.

Coronaviruses are a family of enveloped, single-stranded, positive-strand RNA viruses that are classified within the Nidovirales order. The name coronavirus was coined on account of the corona-like appearance of this virus as viewed under the electron microscope (See accompanying image). The existence of this type of virus was first reported in 1949 and the molecular mechanisms of both replication and disease formation was well-studied in the 1970s. The coronavirus family comprises pathogens that infect many animal species. Coronaviruses have been shown to be the causative agents for acute and chronic respiratory, enteric and central nervous system (CNS) diseases. This family of viruses have been associated with infectious disease in mouse (murine), a pig (porcine) transmissible gastroenteritis (TGEV), cow (bovine) and a bird (avian) bronchitis (BCoV). The first example of a potentially life-threatening human emerging coronavirus was the acute respiratory syndrome coronavirus (SARS-CoV).

Until 2003 the human coronavirus was only known to produce cold-like symptoms. This changed with the onset of severe acute respiratory syndrome (SARS) and now the Wuhan coronavirus that is apparently spread readily from human to human. These kinds of changes in infectivity are not unusual in the evolution of a virus; since, the infective material is prone to mutation. It is for this reason that it has proven exceedingly difficult to come up with an effective vaccine against HIV/AIDS.

Structurally, a virus particle consists of a protein outer coat that interacts and fuses with the cell membrane of the host cell. This is generally followed by the transfer of the infective agent – in this case the RNA of the coronavirus. Once this RNA enters the host cell, it directs the replication of its viral RNA and interferes with host cell processes. These tasks are accomplished through the transcription of viral RNA into proteins that exploit the cell’s protein synthesis “machinery.” It seems that coronavirus contains 7 genes – each gene having the blueprints for the production of a unique protein. One of the products of these genes is the so-called “spike” protein that plays a role in attaching to the host cell and has been shown to play a major part in the virus’ pathogenicity. The end result of this process is the formation of multiple copies of the virus followed by the death of the host cell and subsequent release of the new viruses into the extra-cellular environment.

The global nature of this threat can be circumvented by a number of different approaches - the first being isolating infected individuals and thereby thwarting the spread of the disease to others. It is likely that the virus is spread through aerosols as a result of coughing from infected individuals. This standard epidemiological approach is made particularly difficult given the reality of the constant movement of people to all areas of the globe.

However, it is also imperative that research efforts be directed towards developing a vaccine in order to assist the human immune system in its attempt to destroy the coronavirus once it has gained entry into the host. In regard to SARS, several studies were directed towards the development of active immunization strategies. These included Inactivated virions, recombinant antigen, DNA vaccines, and adenoviral vectors as well as other avenues of research. Undoubtedly, these kinds of studies will continue with added urgency.

Monday, January 20, 2020

Resistance to the anti-malarial drug Artemisinin in Malaria Parasites


Image showing human red blood cells infected with Plasmodium falciparum

Resistance of the anti-malarial drug Artemisinin in Malaria ParasitesMalaria continues to be a scourge in many parts of the world. The problem is particularly acute in Africa. Malaria is a pervasive illness characterized by high fevers, shaking chills, flu-like symptoms, and anemia. It is caused by a parasite referred to as Plasmodium falciparum. Plasmodium is carried by the Anopheles mosquito prevalent in the tropics.

The drug, Artemisinin (ART) has proven to be an effective drug against the malarial parasite – plasmodium falciparum. However, the parasite has apparently developed an immunity to this efficacious drug. It is, therefore, imperative that the mechanism of this resistance be more fully understood if an effective remedy is to be found. The collaborative efforts from research investigators at the Bernhard Nocht Institute of Tropical Medicine in Hamburg, Germany and the Department of Molecular Biology at Radbound University in the Netherlands have helped elucidate this mechanism.

The life-threatening aspect of infection by the Plasmodium falciparum parasite is the capacity of this parasite to continuously multiply within human red blood cells. Residing within human red blood cells, these parasites actively breakdown hemoglobin thereby obviating its capacity to deliver oxygen to the body’s tissues. Artemisinin has been long regarded as a first-line drug. However, ART resistance has manifested itself as a decreased susceptibility of young ring-stage parasites to a short pulse of this drug.

ART resistance has been shown to be associated with point mutations in the parasite’s so-called, Kelch propeller protein (Kelch13). However, the precise mechanism of this resistance to ART was essentially unknown. Although cellular stress, reduced protein translation and altered DNA replication had been implicated, the role of Kelch13 within the parasitic cell remained enigmatic. Here, the authors report an entire pathway in ART resistance and the Kelch13-dependent mechanism that effectively describes the reduced susceptibility to ART in resistant parasites.

The investigators in this extensive study, “show that Kelch13 defines an endocytosis pathway required for the uptake of host cell hemoglobin and its subsequent breakdown and that this pathway is critical for ART resistance. Their data indicate that Kelch13 and its compartment proteins mediate resistance upstream of both, drug activation and action. They have proposed a model where Kelch13 and its compartment proteins control endocytosis levels, thereby influencing the amount of hemoglobin available for degradation and hence the concentration of active drug.”

As a result of these findings that help elucidate the mechanism of ART resistance in malarial parasites, the authors conclude that, “We envisage that the mechanism of ART resistance indicated by this work will aid in finding ways to antagonize it. It may also inform the choice of ART partner drugs, particularly as hemoglobin digestive processes are the target of existing drugs.”

Tuesday, October 29, 2019

Microbiota and Immunity in Healthy Human Organisms

As a result of the millions of years of the evolution of the human species, the human body has established a commensal association with microbiota (microorganisms). This mutually beneficial relationship is essential for the maintenance of the health of the human host. However, it appears that when the natural barriers are disrupted, disease can result. The normal balance (homeostasis) between microbiota and host is apparently maintained by a robust immune system. The nature of this natural process, however, is poorly understood.

The current evidence is that specialized immunocompetent cells are implicated in this process. These are referred to as mucosal-associated invariant T (MAIT) cells and that these MAIT cells recognize and react to metabolites that are that are a byproduct of microbial metabolism. These metabolites are believed to play a role in microbial defense.

Drs Constantinides Legoux and their colleagues have reported that commensal bacteria exert control of the development of MAIT cells in the thymus (the organ involved in the development and proliferation of T cells) and their subsequent expansion within mucosal tissue. Additionally, the development of MAIT cells depends upon exposure in early life to well-defined microbial communities. Furthermore, it appears that a distinct subset of MAIT cells is actively involved in wound healing.

What makes MAIT cells distinct is the fact that in their activity they do not recognize the major histocompatibility complex (MHC) molecules like classic T cells. Instead, they are stimulated by nonpeptide (non-protein) antigens such as vitamin B2 precursor derivatives that are produced by many bacteria bound to an MHC-like protein referred to MR1.C-like H

Several recent studies point to an even broader range of activity for MAIT cells including: the control of bacterial, fungal and viral infections, a role in autoimmune disease and possible involvement in the immune processes involved in attacking the proliferation of tumor cells.

The results of extensive study of MAIT cells coming from the laboratories of Constantinides and Legoux have established that MAIT cells require a community of microbiota to enable their development in the thymus and insure their expansion into specific tissues. It seems that, in fact, newborns are rapidly colonized by a diverse complement of species and strains demonstrating the key role that these microorganisms play in establishing the healthy status of the rapidly developing new human. Furthermore, in humans, it appears that the frequency and localization of MAIT cells throughout the organism changes over a lifetime and is apparently diminished in the elderly population.

In summary, the diagram below illustrates the intimate relationship that exists between the development and function of MAIT cells and the resident commensal microbiota on barrier tissues such as the skin. These finding also emphasize the key role that these organisms play in the health of individuals beginning at birth and proceeding throughout an individual lifetime.