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VIROLOGY COURSE 2021 This Columbia University virology course is offered each year in the spring semester. Textbook. The recommended textbook is Principles of Virology.Vol I: Molecular Biology, Vol. II: Pathogenesis and Control (S.J. Flint et al., Fifth Edition, ASM Press 2020). SARS-COV-2 FURIN CLEAVAGE SITE REVISITED SARS-CoV-2 furin cleavage site revisited. 14 May 2020 by Vincent Racaniello. The spike glycoprotein of SARS-CoV-2 contains a cleavage site for host cell proteases called furins. Deciphering the role of this cleavage site during infection is important for understanding the origin of the pandemic virus and its disease pattern in humans. UNDERSTANDING VIRUS ISOLATES, VARIANTS, AND STRAINS A small amount of fluid was inserted into their lungs, withdrawn, and placed on cells in culture. The virus in the fluid reproduced in the cells and voila, we had the first isolates of the virus. Virus isolate is a very basic term that implies nothing except that the virus was isolated from an infected host. An isolate comes from a single host. ANCIENT VIRUSES IN GLACIER ICE The year 2019 was the second-hottest year on record, closing out the warmest decade.As the temperature rises, ice melts, and out come novel viruses. And there are many viruses frozen in ice, ready to spill out.. We know that viruses are frozen in ice: multiple giant viruses have been isolated from the 30,000 year old Siberian permafrost. HOW MANY VIRUSES ON EARTH? How many different viruses are there on planet Earth? Twenty years ago Stephen Morse suggested that there were about one million viruses of vertebrates (he arrived at this calculation by assuming ~20 different viruses in each of the 50,000 vertebrates on the planet). The results of a new study suggest that at least 320,000 different viruses infectmammals.
CRISPR-ING HERPES SIMPLEX VIRUS CRISPR-ing herpes simplex virus. 6 February 2020 by Vincent Racaniello. by Gertrud U. Rey. Herpes simplex viruses establish lifelong persistent infection in sensory neurons of infected individuals, a phenomenon called latency. Latent viral genomes are “dormant” but can sporadically reactivate and begin replicating in a phase called lytic REPLICATION OF DNA VIRUS GENOMES Replication of DNA Virus Genomes Lecture 7 Virology W3310/4310 Spring2013
THE ZOONOTIC POOL
In other words, the zoonotic pool is very large – providing many opportunities for new human infections, and for the scientists that study them. This realization has lead to the rapidly growing field of pathogen discovery, of which Ian Lipkin and Joe RECEPTOR FOR NEW CORONAVIRUS-EMC IDENTIFIED The cell receptor for the recently identified coronavirus-EMC, which has so far infected 15 humans with 9 deaths, has been identified as dipeptidyl peptidase 4 (DPP4). Enveloped viruses such as CoVs typically attach to cell receptors via spike glycoproteins embedded inthe viral envelope.
VIROLOGY BLOGTHREADING THE NEIDLINFLUENZA 101TABLE OF CONTENTSME/CFSVIROLOGY COURSEVIROLOGY 101 virology blog. About viruses and viral disease. Novel human coronaviruses from pigs and dogs. 20 May 2021 by Vincent Racaniello 2 Comments. The seven human coronaviruses have all originated from spillover events from a variety of nonhuman animals, including bats, rodents, and camels. Recently isolated coronaviruses from humansappear to have
VIROLOGY COURSE 2021 This Columbia University virology course is offered each year in the spring semester. Textbook. The recommended textbook is Principles of Virology.Vol I: Molecular Biology, Vol. II: Pathogenesis and Control (S.J. Flint et al., Fifth Edition, ASM Press 2020). SARS-COV-2 FURIN CLEAVAGE SITE REVISITED SARS-CoV-2 furin cleavage site revisited. 14 May 2020 by Vincent Racaniello. The spike glycoprotein of SARS-CoV-2 contains a cleavage site for host cell proteases called furins. Deciphering the role of this cleavage site during infection is important for understanding the origin of the pandemic virus and its disease pattern in humans. UNDERSTANDING VIRUS ISOLATES, VARIANTS, AND STRAINS A small amount of fluid was inserted into their lungs, withdrawn, and placed on cells in culture. The virus in the fluid reproduced in the cells and voila, we had the first isolates of the virus. Virus isolate is a very basic term that implies nothing except that the virus was isolated from an infected host. An isolate comes from a single host. ANCIENT VIRUSES IN GLACIER ICE The year 2019 was the second-hottest year on record, closing out the warmest decade.As the temperature rises, ice melts, and out come novel viruses. And there are many viruses frozen in ice, ready to spill out.. We know that viruses are frozen in ice: multiple giant viruses have been isolated from the 30,000 year old Siberian permafrost. HOW MANY VIRUSES ON EARTH? How many different viruses are there on planet Earth? Twenty years ago Stephen Morse suggested that there were about one million viruses of vertebrates (he arrived at this calculation by assuming ~20 different viruses in each of the 50,000 vertebrates on the planet). The results of a new study suggest that at least 320,000 different viruses infectmammals.
CRISPR-ING HERPES SIMPLEX VIRUS CRISPR-ing herpes simplex virus. 6 February 2020 by Vincent Racaniello. by Gertrud U. Rey. Herpes simplex viruses establish lifelong persistent infection in sensory neurons of infected individuals, a phenomenon called latency. Latent viral genomes are “dormant” but can sporadically reactivate and begin replicating in a phase called lytic REPLICATION OF DNA VIRUS GENOMES Replication of DNA Virus Genomes Lecture 7 Virology W3310/4310 Spring2013
THE ZOONOTIC POOL
In other words, the zoonotic pool is very large – providing many opportunities for new human infections, and for the scientists that study them. This realization has lead to the rapidly growing field of pathogen discovery, of which Ian Lipkin and Joe RECEPTOR FOR NEW CORONAVIRUS-EMC IDENTIFIED The cell receptor for the recently identified coronavirus-EMC, which has so far infected 15 humans with 9 deaths, has been identified as dipeptidyl peptidase 4 (DPP4). Enveloped viruses such as CoVs typically attach to cell receptors via spike glycoproteins embedded inthe viral envelope.
VIROLOGY COURSE 2021 This Columbia University virology course is offered each year in the spring semester. Textbook. The recommended textbook is Principles of Virology.Vol I: Molecular Biology, Vol. II: Pathogenesis and Control (S.J. Flint et al., Fifth Edition, ASM Press 2020). SARS-COV-2 FURIN CLEAVAGE SITE REVISITED SARS-CoV-2 furin cleavage site revisited. 14 May 2020 by Vincent Racaniello. The spike glycoprotein of SARS-CoV-2 contains a cleavage site for host cell proteases called furins. Deciphering the role of this cleavage site during infection is important for understanding the origin of the pandemic virus and its disease pattern in humans. TRIAL BY ERROR: NORWAY REJECTS NEW CLINICAL TRIAL OF WOO By David Tuller, DrPH. In a welcome display of scientific acumen, Norwegian research ethics authorities have rejected a proposed study of the woo-woo called the Lightning Process as a treatment for ME/CFS. Since Norway generally appears to be a hotbed of biopsychosocial thinking, this excellent decision is a bit of a surprise.2020 – PAGE 15
SARS-CoV-2 not only infects humans but can also spread occasionally from humans to cats, dogs, and tigers. A recent addition to this menagerie is the farmed mink.. In mid-April 2020 mink on two farms in the Netherlands developed signs of respiratory disease whichARE VIRUSES ALIVE?
The question of whether viruses are living or not always provokes lively discussion. On TWiV 59 we decided to take an informal poll of our listeners on this issue. Let’s open up the poll to readers of virology blog. This survey had been online since November 2009 and had collected several thousand responses. TRIAL BY ERROR: ANOTHER EXCELLENT READ ON LONG COVID, ME Trial By Error: Another Excellent Read on Long Covid, ME/CFS and Medically Unexplained Symptoms. 20 March 2021 by David Tuller. By David Tuller, DrPH. In a post earlier this week, I noted some differences in the tenor of the debate over Long Covid in the US and UK. Yesterday, another excellent and in-depth piece on the issuesappeared on the
TRIAL BY ERROR: WHAT IS THE DYNAMIC NEURAL RETRAINING SYSTEM? On its website, DNRS is described as “a drug-free, step-by-step, intensive limbic rehabilitation program” that is based on “neuroplasticity therapy, which rewires the limbic system to build more functional neural pathways.”. People who apply the system can, per the website, “find relief from” the following disorders:Adrenal Fatigue.
INFECTION FATALITY RATE 11 April 2020 at 10:50 pm. The incidence of Covid-19 in S. Korea is so far around 0.0002 (10,500 per 50 M of population). The incidence of possible secondary re-infection in the population of the survivors of Covid-19 is minimum 0.01 (91 reinfected per 10,500 cases ofVIROLOGY BLOG
About viruses and viral disease. Frederick Hayden, Professor of Medicine and Pathology, University of Virginia School of Medicine, U.K., has focused on the use of antiviral agents to prevent and treat respiratory viral infections.His interests range from the use of in vitro assays to study viral susceptibility and antiviral mechanisms of action, to clinical trials utilizing experimentally METABOLIC MANIPULATIONS IN VIRUS-INFECTED CELLS Metabolic manipulations in virus-infected cells. 18 January 2018 by Vincent Racaniello. The large quantities of viral macromolecules and virus particles that are produced in an infected cell impose heavy demands on the host. Synthesis of the building blocks of a virus particle – nucleotides, amino acids, and sometimes fatty acids –requires
VIROLOGY BLOGTHREADING THE NEIDLINFLUENZA 101TABLE OF CONTENTSME/CFSVIROLOGY COURSEVIROLOGY 101 Based on such observations, the authors of a recent study explored the effect of infection with Heligmosomoides polygyrus bakeri (Hpb) – a naturally occurring intestinal roundworm of rodents – on West Nile virus (WNV) infection outcome in mice. WNV is a member of the Flavivirus genus, along with Dengue virus, Zika virus, yellow fever virus, tick-borne encephalitis virus, and Powassan virus. VIROLOGY COURSE 2021 This Columbia University virology course is offered each year in the spring semester. Textbook. The recommended textbook is Principles of Virology.Vol I: Molecular Biology, Vol. II: Pathogenesis and Control (S.J. Flint et al., Fifth Edition, ASM Press 2020). SARS-COV-2 FURIN CLEAVAGE SITE REVISITED The spike glycoprotein of SARS-CoV-2 contains a cleavage site for host cell proteases called furins. Deciphering the role of this cleavage site during infection is important for understanding the origin of the pandemic virus and its disease pattern in humans. ANCIENT VIRUSES IN GLACIER ICE The year 2019 was the second-hottest year on record, closing out the warmest decade.As the temperature rises, ice melts, and out come novel viruses. And there are many viruses frozen in ice, ready to spill out.. We know that viruses are frozen in ice: multiple giant viruses have been isolated from the 30,000 year old Siberian permafrost. HOW MANY VIRUSES ON EARTH? How many different viruses are there on planet Earth? Twenty years ago Stephen Morse suggested that there were about one million viruses of vertebrates (he arrived at this calculation by assuming ~20 different viruses in each of the 50,000 vertebrates on the planet). The results of a new study suggest that at least 320,000 different viruses infectmammals.
DAVID TULLER
By David Tuller, DrPH. What does it mean that the top investigators in a field of research have collectively and consistently misrepresented a seminal figure in their purported domain of expertise?THE ZOONOTIC POOL
I previously discussed the idea that new human virus infections will continue to emerge from animal hosts. Stephen Morse, my colleague here at Columbia, has called this collection of viruses the ‘zoonotic pool’.How many viruses are in this pool? Here are Dr. Morse’s calculations: assume that there are 50,000 vertebrates on earth, each of which harbors 20 different viruses. RECEPTOR FOR NEW CORONAVIRUS-EMC IDENTIFIED The cell receptor for the coronavirus-EMC, which has so far infected 15 humans with 9 deaths, has been identified as dipeptidyl peptidase 4(DPP4).
STRUCTURE OF ZIKA VIRUS Six months after Zika virus became a household word, we now know the three-dimensional structure of the virus particle. And it looks likevery much like
TRIAL BY ERROR: OPEN LETTER TO THE LANCET, VERSION 3.0 By David Tuller, DrPH. Two months ago, Professor Racaniello sent Lancet editor Richard Horton an open letter about the indisputable methodological and ethical failings of the PACE trial. This was a follow-up to Virology Blog’s 2016 open letter to Dr. Horton; the new one detailed what has happened since then.Last month, I re-sent and reposted this new open letter, with organizations also VIROLOGY BLOGTHREADING THE NEIDLINFLUENZA 101TABLE OF CONTENTSME/CFSVIROLOGY COURSEVIROLOGY 101 Based on such observations, the authors of a recent study explored the effect of infection with Heligmosomoides polygyrus bakeri (Hpb) – a naturally occurring intestinal roundworm of rodents – on West Nile virus (WNV) infection outcome in mice. WNV is a member of the Flavivirus genus, along with Dengue virus, Zika virus, yellow fever virus, tick-borne encephalitis virus, and Powassan virus. VIROLOGY COURSE 2021 This Columbia University virology course is offered each year in the spring semester. Textbook. The recommended textbook is Principles of Virology.Vol I: Molecular Biology, Vol. II: Pathogenesis and Control (S.J. Flint et al., Fifth Edition, ASM Press 2020). SARS-COV-2 FURIN CLEAVAGE SITE REVISITED The spike glycoprotein of SARS-CoV-2 contains a cleavage site for host cell proteases called furins. Deciphering the role of this cleavage site during infection is important for understanding the origin of the pandemic virus and its disease pattern in humans. ANCIENT VIRUSES IN GLACIER ICE The year 2019 was the second-hottest year on record, closing out the warmest decade.As the temperature rises, ice melts, and out come novel viruses. And there are many viruses frozen in ice, ready to spill out.. We know that viruses are frozen in ice: multiple giant viruses have been isolated from the 30,000 year old Siberian permafrost. HOW MANY VIRUSES ON EARTH? How many different viruses are there on planet Earth? Twenty years ago Stephen Morse suggested that there were about one million viruses of vertebrates (he arrived at this calculation by assuming ~20 different viruses in each of the 50,000 vertebrates on the planet). The results of a new study suggest that at least 320,000 different viruses infectmammals.
DAVID TULLER
By David Tuller, DrPH. What does it mean that the top investigators in a field of research have collectively and consistently misrepresented a seminal figure in their purported domain of expertise?THE ZOONOTIC POOL
I previously discussed the idea that new human virus infections will continue to emerge from animal hosts. Stephen Morse, my colleague here at Columbia, has called this collection of viruses the ‘zoonotic pool’.How many viruses are in this pool? Here are Dr. Morse’s calculations: assume that there are 50,000 vertebrates on earth, each of which harbors 20 different viruses. RECEPTOR FOR NEW CORONAVIRUS-EMC IDENTIFIED The cell receptor for the coronavirus-EMC, which has so far infected 15 humans with 9 deaths, has been identified as dipeptidyl peptidase 4(DPP4).
STRUCTURE OF ZIKA VIRUS Six months after Zika virus became a household word, we now know the three-dimensional structure of the virus particle. And it looks likevery much like
TRIAL BY ERROR: OPEN LETTER TO THE LANCET, VERSION 3.0 By David Tuller, DrPH. Two months ago, Professor Racaniello sent Lancet editor Richard Horton an open letter about the indisputable methodological and ethical failings of the PACE trial. This was a follow-up to Virology Blog’s 2016 open letter to Dr. Horton; the new one detailed what has happened since then.Last month, I re-sent and reposted this new open letter, with organizations also SARS-COV-2 FURIN CLEAVAGE SITE REVISITED The spike glycoprotein of SARS-CoV-2 contains a cleavage site for host cell proteases called furins. Deciphering the role of this cleavage site during infection is important for understanding the origin of the pandemic virus and its disease pattern in humans. TRIAL BY ERROR: NORWAY REJECTS NEW CLINICAL TRIAL OF WOO By David Tuller, DrPH. In a welcome display of scientific acumen, Norwegian research ethics authorities have rejected a proposed study of the woo-woo called the Lightning Process as a treatment for ME/CFS. Since Norway generally appears to be a hotbed of biopsychosocial thinking, this excellent decision is a bit of a surprise.2020 – PAGE 15
SARS-CoV-2 not only infects humans but can also spread occasionally from humans to cats, dogs, and tigers. A recent addition to this menagerie is the farmed mink.. In mid-April 2020 mink on two farms in the Netherlands developed signs of respiratory disease which TRIAL BY ERROR: WHAT IS THE DYNAMIC NEURAL RETRAINING SYSTEM? Erik Johnson, who is a survivor of the 1980’s Tahoe epidemic of the disease now called ME/CFS, and I have both been outspoken in ourcriticisms
CRISPR-ING HERPES SIMPLEX VIRUS i was tested Herpes 1&2 last 3years. I keep on managing the drugs i usually purchase from the health care agency to keep me healthy and strengthen, i tried all i can to make this disease leave me alone, but unfortunately, it keep on eating up my life, this is what i caused myself, for allowing my fiance make sex to me insecurely without protection, although i never knew he is Herpes positive. MULTIPLICITY OF INFECTION I want to claim a point we usually forget: Infectious doses, infectious particles, infectious units are a relative concept as “infectious” depends on the cell type used to run the assay, i.e Vero cells, HeLa cells, BHK21There is no an unique in vitro system to make a pfu assay for every virus, for instance you can use A9 or NB324K cells to titrate parvovirus MVMp and the same stock REPLICATION OF DNA VIRUS GENOMES Replication of DNA Virus Genomes Lecture 7 Virology W3310/4310 Spring2013
VIROLOGY BLOG
About viruses and viral disease. Frederick Hayden, Professor of Medicine and Pathology, University of Virginia School of Medicine, U.K., has focused on the use of antiviral agents to prevent and treat respiratory viral infections.His interests range from the use of in vitro assays to study viral susceptibility and antiviral mechanisms of action, to clinical trials utilizing experimentallyVIROLOGY BLOG
Integration of retroviral DNA into the cellular genome is essential for the production of new infectious particles. A strong argument that the novel human retrovirus XMRV is not a laboratory contaminant is the finding that viral DNA is integrated in chromosomal DNA of prostate tumors.Nucleotide sequence analyses of 14 integration sites in prostate tumor DNAs from 9 different patientsVINCENT RACANIELLO
Wired Magazine recently published an article with a headline distinctly opposite of mine, which claims that the traditional lecture is dead.. I disagree, and here is why. The thesis of the article, by Rhett Allain, is that modern technologies have made the traditionallecture obsolete.
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About viruses and viral disease WHEN VIRUSES COLLIDE WITH PARASITIC WORMS 3 June 2021 by Gertrud U. Rey 1Comment
by Gertrud U. Rey
The absence of infection with some parasitic worms (also known as helminths) often coincides with the development of asthma, allergy, and autoimmune disorders, suggesting that these worms may have co-evolved a commensal relationship with their human hosts. However, infection with these worms may also lead to an impaired immune response against pathogenic infections by other parasites, bacteria,and some viruses.
Based on such observations, the authors of a recent study explored the effect of infection with Heligmosomoides polygyrus bakeri (Hpb) – a naturally occurring intestinal roundworm of rodents – on West Nile virus (WNV) infection outcome in mice. WNV is a member of the Flavivirus genus, along with Dengue virus, Zika virus, yellow fever virus, tick-borne encephalitis virus, and Powassan virus. These viruses all infect their human hosts through the bite of an arthropod and ultimately target cells of the central nervous system. To assess the effect of intestinal Hpb infection on the pathogenesis of WNV, the authors used three groups of mice: the first group was only fed Hpb larvae to initiate an Hpb infection, the second group was only infected with WNV by inoculation in the foot pad, and the third group was infected with both Hpb and WNV. Infection with Hpb alone had no adverse effect on body weight or survival of the mice, and infection with WNV alone caused moderate weight loss and 86% survival. In contrast, infection with both Hpb and WNV led to greater weight loss and only 28% survival. To determine the reason for this enhanced pathogenicity, the mice were euthanized, and different organs were assessed for viral titers. Mice infected only with WNV, or with both WNV and Hpb, had similar levels of virus in the spleen, an organ that filters the blood and produces immune cells in response to the presence of infectious pathogens. However, mice infected with both Hpb and WNV had higher levels of virus in different parts of the colon and the mesenteric lymph nodes, which serve as a firewall to prevent systemic spread of microorganisms. The presence of such high viral titers in these regions suggested that co-infection with Hpb and WNV leads to the infection of cells in gut-proximal places. To determine which gut cells are targeted by WNV during a Hpb/WNV co-infection, the authors stained pieces of gut tissue from Hpb/WNV co-infected mice with a combination of fluorescent antibodies that bind WNV antigens or neuronal cell markers. Analysis of these tissues by fluorescence microscopy revealed that co-infected animals have higher levels of viral antigens in intestinal neurons compared to control animals infected only with Hpb or WNV, suggesting that infection with both Hpb and WNV increases the frequency of infection of gut neuronal cells. Microscopic analysis also revealed certain gut abnormalities in co-infected animals, including changes in the composition of intestinal villi, which are small, finger-like projections that extend into the lumen of the small intestine. Co-infected animals had shortened villi, a phenomenon typically associated with pathology and inflammation. Co-infected animals also had commensal bacteria inside their spleens, so it is possible that the shortened villi enabled translocation of the bacteria across the epithelial gut barrier, which normally restricts the entry of harmful substances by separating the intestinal organs from the externalenvironment.
The spleens and brains of Hpb/WNV co-infected mice also contained markedly reduced numbers of WNV-specific CD8+ T cells, which usually contribute to the clearance of WNV infection. The authors reasoned that the lack of CD8+ T cells was likely due to bacterial invasion, which may impact the activation of key immune cell types involved in triggering the differentiation of virus-specific CD8+ T cells. Remarkably, treatment of Hpb/WNV co-infected mice with antibiotics reversed these kinetics, leading to increased levels of WNV-specific CD8+ T cells, a result that correlated with diminished bacterial levels in the blood and spleen. This observation suggested that bacterial invasion of lymphoid tissues is largely responsible for impaired WNV-specific CD8+ T cell responses during co-infection withHpb and WNV.
The clearance of helminth infections is typically mediated by the activation of “type 2” immune responses, which are characterized by the production of various cytokines, including IL-4. Binding of IL-4 to its cognate cell surface receptor activates STAT6, a cytoplasmic transcription factor that ultimately signals the activation of macrophages and differentiation of T cells. To determine if these type 2 immune responses contribute to the lethality observed after co-infection with Hpb and WNV, the authors performed the next set of experiments on “STAT6 null” mice, which lack the STAT6 gene. Interestingly, STAT6 null mice co-infected with Hpb and WNV did not have any of the increased lethality observed in wild type mice. Hpb/WNV-co-infected STAT6 null mice also had reduced overall viral levels and no gut abnormalities characteristic of enhanced pathogenesis, suggesting that STAT6 signaling is needed for development of enhanced disease. To determine the relevance of IL-4 in the STAT6 signaling cascade, wild type mice were infected with WNV alone, followed by administration of IL-4. This regimen led to increased pathogenicity like that observed in Hpb/WNV co-infected mice, including decreased survival, weight loss, and higher WNV burden in the brain and gut. In contrast, the same WNV/IL-4 regimen given to STAT6 null mice did not produce the same pathogenicity, suggesting that the effects of IL-4 are dependent on the presence of STAT6. Type 2 immune responses in the gut are initiated by tuft cells, which are specialized cells of the intestinal epithelium that are capable of multiplying in response to the presence of certain parasites. To see whether tuft cells are needed for Hpb-mediated enhanced WNV disease, the authors infected “tuft null” mice (mice lacking tuft cells) with both Hpb and WNV. These mice did not develop any of the effects characteristic of enhanced pathogenesis, suggesting that tuft cells are needed for development of enhanced disease. Tuft cells selectively express a receptor for succinate, a metabolite needed for energy production. To see whether succinate sensing is involved in enhanced WNV disease, wild type mice were administered succinate and were then infected with WNV. All these mice developed enhanced disease, even in the absence of Hpb infection. However, the same succinate/WNV regimen in tuft null mice, or in mice expressing tuft cells but lacking succinate receptors, did not lead to enhanced disease. These experiments further confirm that succinate receptor-expressing tuft cells are needed to initiate the signaling pathway leading to enhanced disease. Collectively, these results suggest that Hpb-mediated activation of type 2 immune responses in intestinal epithelial cells depends on tuft cells and might be initiated by succinate sensing. Similar enhanced disease characteristics were also observed after co-infection of mice with Hpb and Zika virus or Powassan virus, suggesting that co-infection with helminths may enhance the disease severity of multiple human flaviviruses. Although these parasitic worm/flavivirus co-infections are currently more common in tropical regions, their prevalence may spread with increasing global climate changes/warming. This study outlines a fascinating aspect of the interface between parasitic and viral infections that warrants furtherexploration.
T CELLS WILL SAVE US FROM COVID-19, PART TWO 27 May 2021 by Vincent Racaniello8 Comments
T cells are the other arm of the adaptive immune response (in addition to B cells) that are essential for clearing virus infections. Most studies of immunity to SARS-CoV-2 infection have focused on antibodies and their ability to neutralize virus infection. The observation that variants of concern are less effectively neutralized by antibodies against ancestral strains have led to predictions of vaccine failure and doom. This outlook is incorrect: amino acid changes in the spike protein of SARS-CoV-2 variants of concern do not impact T cell reactivity and are not likely to affect the ability of T cells to clear infection. This conclusion has been emphasized by the results of another study which show that SARS-CoV-2 variants of concern partially escape humoral but not T-cell responses in COVID-19 convalescent donors and vaccinees.
Cytotoxic T cells can sense that a cell is infected and kill it (illustrated). T cells sense infected cells by virtue of viral peptides that are presented by major histocompatibility molecules on the plasma membrane. Such T cell peptides may be produced from nearly any viral protein. In contrast, only certain viral proteins, like the spike of SARS-CoV-2, can give rise to antibodies that block infection. T cell epitopes are presented to T cells on the infected cell surface by MHC molecules, which are encoded by highly polymorphic genes. That means that your MHC is likely different from mine, and so will be the viral peptides displayed in them. So if a T cell epitope varies during your infection, it won’t matter to other people – their infected cells will be displaying different T cell peptides. A study of antibody and T cell responses to SARS-CoV-2 and variants of concern B.1.1.7 and B.1.351 was carried out in a cohort of health care workers vaccinated with BNT162B2 mRNA vaccine. Some of these individuals had recovered from COVID-19 and received a single vaccine dose, while others had not been infected and received two vaccinedoses.
Plaque assays were used to show that vaccine-induced antibodies neutralized the infectivity of B.1.1.7 virus as well as ancestral SARS-CoV-2. However, neutralization titers against the B.1.135 variant were about 4-fold lower. To examine T cell responses to vaccination, blood mononuclear cells (PBMC) were stimulated with peptides from the spike protein. PBMC from immunized patients were activated equally by peptides spanning the entire spike protein from the ancestral virus, or from peptide pools covering the regions of spike that are changed in the variant viruses. As shown previously, T cell epitopes in the spike protein of variants of concern do not functionally change. We can deduce the meaning of these findings for infection with variants of concern. In theory, should a variant fail to be efficiently neutralized by antibody in an individual previously infected with ancestral virus, or vaccinated (with ancestral spike protein), the T cells should still be able to prevent spread of infection and severe disease or death. This hypothesis is supported by the outcome of trials with the Johnson & Johnson Ad26.COV2-S vaccine, an adenovirus vectored spike vaccine. Sera from volunteers in South Africa, where B.1.351 circulates, had a tenfold reduced neutralization titer against that variant of concern. However, the vaccine was 100% effective in preventing hospitalization and death due to COVID-19 – likely a consequence of virus-specific cytotoxic T cells. The situation with other vaccines is less clear. The AZD1222 vaccine, which showed 70% efficacy in the UK, showed only 22% efficacy in South Africa against mild to moderate COVID-19. Whether or not this vaccine would prevent severe COVID-19 could not be assessed as there was no serious disease observed during this trial. The B.1.1.7 variant has the N501Y change in the spike protein, while B.1.351 and P.1 (Brazil) have in addition the amino acid changes K417N/T and E484K. Variant B.1.617 (India) has E484Q and L452R; the latter is also present in CAL variants. Given that none of these changes alter T cell reactivity it is likely that spike vaccines will protect against serious disease and death caused by these variants. Reports of reinfection with such variants in previously vaccinated individuals that leads to serious disease should be taken with a largegrain of salt.
NOVEL HUMAN CORONAVIRUSES FROM PIGS AND DOGS 20 May 2021 by Vincent Racaniello3 Comments
The seven human coronaviruses have all originated from spillover events from a variety of nonhuman animals, including bats, rodents, and camels. Recently isolated coronaviruses from humans appear to have originated in pigs and dogs. Three of 369 plasma samples collected between May 2014 and December 2015 in two schools in Haiti were found to be positive for coronavirus. All
three children had fever, and one reported cough and abdominal pain. Whole genome sequence analysis of all three isolates revealed them to be porcine deltacoronaviruses (PDCoV). The human coronaviruses known to date are alpha- and betacoronaviruses. PDCoV was first identified in 2012 in Hong Kong and then in 2014 in the Americas. The virus infects epithelial cells in the jejunum and ileum and the large intestine, leading to gastrointestinal symptoms. No PDCoV infections have been reported in Haitian domestic pigs. The PDCoVs isolated four months apart from two children attending the same school are closely related to a virus isolated from pigs a year later in China. The other Haitian child was infected with PDCoV that is more closely related to an isolate from pigs in Arkansas from 2015. The implication of sequence analysis is that two separate zoonotic transmissions took place. How the viruses traveled from the US and China to Haiti is not clear. All three PDCoV human isolates share a signature of amino acid changes in the viral ORF1a/b and spike proteins that is not seen in other PDCoV isolates. These changes might have been selected during reproduction in human hosts. In a separate study, 8 of 301 nasopharyngeal swabs from patients hospitalized between 2017-2018 with pneumonia in Malaysia were shown to harbor canine coronavirus (CCoV), an alpha coronavirus. Close analysis of the genome sequence revealed that the virus is a recombinant, with most of the genome originating from CCoV and part of the spike from feline coronavirus. Canine and feline coronaviruses cause moderate to severe intestinal disease in dogs and cats. The viruses have a worldwide distribution and given the prevalence of these animals as pets, it is not surprising that human infections may occur, albeit rarely. The eight patients who harbored this novel CoV were children living in areas where exposure to domestic animal and jungle wildlife would be expected, possibly explaining how the infections were acquired. These human infections with porcine and canine coronaviruses appear to be isolated incidents which did not lead to extensive human transmission. Nevertheless the findings emphasize the public health threat of animal coronaviruses and the need for improving our surveillance for these viruses. TRIAL BY ERROR: JOURNAL EDITORIAL CALLS FOR CAUTION IN EXERCISE-BASED REHAB PROGRAMS FOR LONG COVID 15 May 2021 by David Tuller24 Comments
By David Tuller, DrPH The _Journal of Orthopaedic & Sports Physical Therapy_ recently published an editorial called _“Humility and Acceptance: Working Within Our Limits With Long COVID and Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome.”_ The editorial
emerged from a collaboration between rehabilitation specialists and patients, mostly from Canada. It confronts the conundrum of whether those experiencing what is called Long COVID should be advised to exercise, explicitly linking the issue to the history of misguided interventions for ME/CFS and the symptom of post-exertional malaise. about Trial By Error: Journal Editorial Calls for Caution in Exercise-Based Rehab Programs for Long COVID A GENETICALLY STABLE ATTENUATED POLIOVIRUS VACCINE 13 May 2021 by Vincent Racaniello3 Comments
Eradication of poliomyelitis appears to be on track: types 2 and 3 polioviruses have been declared eradicated, and in the past 12 months there have been just 338 cases of type 1 polio in Afghanistan and Pakistan. But there have also been 491 cases of polio caused by the type 2 Sabin vaccine. The development of a modified version of the type 2 vaccine component could improve this situation. The oral poliovirus vaccines (OPV) developed by Albert Sabin have played a huge role in reducing cases of polio globally from 400,000 a year in 1980 to the current numbers. Their success, however, comes with a cost: they may in rare cases cause the disease they are designed to prevent. The three serotypes of OPV are taken orally and then reproduce in the intestines where they confer effective immunity to polio. During reproduction of the viruses in the intestine, the mutations originally selected by Sabin to eliminate the neurovirulence of the viruses are lost. Most immunized children shed vaccine revertants, and about 1 in 1.4 million vaccine recipients contractpolio.
These vaccine revertants also circulate extensively throughout the human population, and may cause outbreaks of polio in areas where vaccine coverage drops. To address this problem, in 2016 WHO removed the type 2 component of poliovirus from OPV, which is responsible for most of the vaccine-associated cases. However vaccine-derived type 2 polioviruses continue to circulate even after this vaccine withdrawal and have caused a number of outbreaks. The response to control these outbreaks is to conduct mass immunizations with OPV type 2 – which re-introduces vaccine-derived polioviruses into the environment. The solution might be to develop a more genetically stable strain of type 2 OPV. Such strains have been developed by leveraging advances in basic research on polioviruses that have been carried out since the 1980s. A new OPV2 strain (nOPV2) was developed by introducing three different types of changes in the OPV2 genome. First, mutations were introduced in the 5’-noncoding region of the viral RNA in the area of a single base that is a major attenuating mutation in OPV. These changes were designed to stabilize this region against reversion. Second, an RNA stem loop structure called the _cre_ element, which is essential for viral RNA synthesis, was relocated from its original position in the genome to the 5’-noncoding region. This alteration should prevent RNA recombination that would replace the viral 5’-end with that of other enteroviruses, thereby removing the stabilizing changes. Finally, the RNA polymerase was modified so that it made fewer copying errors and had reduced recombinationfrequency.
The resulting nOPV2 was tested extensively in cells in culture and in experimental animals to demonstrate that the virus did not revert within the 5’-noncoding region, did not recombine with other enteroviruses, and maintained an attenuation phenotype in animals. Based on these findings nOPV2 and another redesigned strain produced by codon-deoptimization were tested in a phase I trial.
The adult volunteers, previously immunized with poliovirus vaccine, were housed in a containment facility to prevent environmental release of nOPV2. After oral administration of either vaccine, adults were monitored for symptoms, induction of immunity, and reversion of the virus to neurovirulence. The results indicated that the nOPV2s are safe, immunogenic, and do not revert to neurovirulence, while maintaining a stable 5’-noncoding region. Pending ongoing phase 2 trials, nOPV2 is likely to be licensed for use in quelling outbreaks of type 2 vaccine-derived polio. It cannot be tested for efficacy because there are insufficient cases of polio anywhere to allow such a study. It is hoped that the excreted vaccines will not revert to neurovirulence and will circulate for a limited time in humans, as suggested by the preclinical data, thereby eliminating type 2 vaccine-induced polio. However, the numbers of subjects in the clinical trial have been small, and the selection pressure imposed by thousands of human guts might change this outcome. Viruses have been known before to defy our expectations. TRIAL BY ERROR: MORE LETTERS ABOUT PROFESSOR ANTHONY DAVID’S MIS-CITATIONS OF KEY STUDY ON COSTS OF MUS 11 May 2021 by David Tuller 8Comments
By David Tuller, DrPH I have been in correspondence with the journal _Psychological Medicine_ in my efforts to get it to correct an undisputed factual era related to the cost of so-called “medically unexplained symptoms” (MUS). After three weeks, the journal’s co-editor-in-chief, Professor Robin Murray, finally alerted me on May 4th that the authors “have agreed” to a correction–as if they were making a concession to me rather than ensuring the accuracy of the medicalliterature.
about Trial By Error: More Letters about Professor Anthony David’s Mis-Citations of Key Study on Costs of MUS TRIAL BY ERROR: MY LETTERS TO PSYCHOSOMATICS JOURNAL ABOUT PROF WHITE’S MISLEADING GETSET PAPER 6 May 2021 by David Tuller By David Tuller, DrPH In early April, I wrote about a study published in the _Journal of Psychosomatic Research_—a one-year follow-up of the GETSET trial of self-help graded exercise therapy for ME/CFS. The investigators had previously reported short-term benefits for the intervention. In this new paper, despite no benefits of the intervention over regular care, the team reported success because the intervention arm did not score worse than it had at 12 weeks. Needless to say, this is not the proper way to report clinical trial results. about Trial By Error: My Letters to Psychosomatics Journal About Prof White’s Misleading GETSET Paper EARLY IMMUNE RESPONSES TO HERPES SIMPLEX VIRUS TYPE I INFECTION 6 May 2021 by Gertrud U. Reyby Gertrud U. Rey
Herpes simplex viruses infect cells of the skin and mucous membranes, where they establish a lifelong persistent infection in sensory neurons. Sporadic reactivation and viral shedding may lead to painful oral and genital disease and a three to five-fold increased risk of HIV transmission. There is currently no vaccine to prevent infection with herpes simplex virus type 1 or type 2 (HSV-1 or HSV-2). Until recently it was thought that initial interactions of HSV-1 with the immune system only involve Langerhans cells. Langerhans cells are skin-resident sentinel macrophages that detect microbial antigens, and they engulf, process, and present these antigens to T cells for downstream immune functions. However, a recent study suggests that early during infection, HSV-1 also interacts with a newly identified immune cell known as an epidermal conventional dendritic cell type 2 (Epi-cDC2). Like Langerhans cells, dendritic cells can swallow microbe-infected cells and present the microbial antigens to T helper cells, ultimately triggering the actions of cytotoxic T cells, which directly killinfected cells.
The study aimed to better define the role of Epi-cDC2s in early HSV-1 infection using _ex vivo_ explants as a model system. The explants consisted of pieces of human inner foreskin that were mounted on specialized gelatin scaffolds to mimic the _in vivo_ environment encountered by HSV-1 during infection. The authors exposed the explants to an HSV-1 virus in which a viral membrane protein was fused to a green fluorescent protein (GFP), allowing them to visually track a resulting infection using a fluorescence microscope. This method revealed that at 24 hours after exposure to the GFP-tagged HSV-1, both Langerhans cells and Epi-cDC2s contained the virus in their cytoplasm, suggesting that these cells either engulfed HSV-1-infected skin cells and/or were themselves infected by HSV-1. To determine whether the presence of HSV-1 in the cytoplasm of Epi-cDC2s resulted from infection and replication and not just from engulfing infected skin cells, the authors first did the following. They exposed cell cultures of Epi-cDC2s to HSV-1. After six hours of this exposure, Epi-cDC2s contained about as much virus as did control Langerhans cells, which are known to be infected by HSV-1. However, at 18 hours, Epi-cDC2s contained significantly higher HSV-1 levels than Langerhans cells, suggesting increased entry/uptake of virus into Epi-cDC2s compared to Langerhans cells. Next, to assess whether HSV-1 was also replicating in the Epi-cDC2 cells, not just entering them, the authors treated the cells with a fluorescent antibody that binds ICP27, a viral protein needed for replication. A significantly greater portion of Epi-cDC2s than Langerhans cells expressed ICP27, suggesting that HSV-1 was replicating, and doing so more efficiently inEpi-cDC2s.
Viruses may enter a host cell by a variety of mechanisms. One common mechanism, called receptor-mediated endocytosis, involves the formation of cell membrane-derived vesicles. In one version of this process, which requires a low pH, viral binding to a cell surface receptor triggers the cellular membrane to fold inward and form a slightly acidic “endosome” around the virus. Another version of receptor-mediated endocytosis is not dependent on a low pH, but requires cholesterol molecules and the motor protein actin to form cell surface protrusions called “ruffles.” When the ruffles become large enough, they collapse back onto the membrane and form large fluid-filled vesicles encasing the virus. In both of these versions of receptor-mediated endocytosis, the resulting vesicles enter the cytoplasm, where they eventually release their contents. In yet another mechanism of entry, also independent of acidic pH, viruses may simply fuse with the plasma membrane and deliver their contents intothe cytoplasm.
Although HSV-1 can enter cells by any of these pathways, its entry mechanism differs in different types of cells. To determine which pathway HSV-1 uses to enter Langerhans cells and Epi-cDC2s, the authors treated both types of cells with a drug that prevents acidification of endosomes. They then infected the cells with the GFP-tagged HSV-1 and measured infection by quantitating GFP with a fluorescence microscope. Increasing doses of the drug led to increased inhibition of infection of Langerhans cells, suggesting that these cells are infected with HSV-1 via a pH-dependent mechanism. In contrast, the drug did not affect infection of Epi-cDC2s, suggesting that HSV-1 does not require an acidic pH for entering Epi-cDC2s. To determine whether HSV-1 entry into Epi-cDC2s occurred via actin and cholesterol-dependent endocytosis, the authors treated Epi-cDC2s with inhibitors of actin or cholesterol prior to infection. Both treatments led to significant reduction in GFP fluorescence inside the cells, suggesting that cholesterol and actin are both important mediators of HSV-1 entry into Epi-cDC2s. Langerhans cells express a cell surface receptor called langerin, which mediates entry of HIV and influenza A. To see whether this receptor is also required for entry of HSV-1, the authors infected Langerhans cells with HSV-1 in the presence of an antibody that neutralizes langerin. This inhibition of langerin expression led to diminished infection of Langerhans cells, suggesting that langerin is required for HSV-1 entry into them. In contrast, inhibition of langerin on Epi-cDC2s had no effect on HSV-1 infection efficiency, suggesting that, even though Epi-cDC2s do express some langerin, this receptor is not required for HSV-1 entry of these cells. HSV-1 and HSV-2 are of high public health concern, and a vaccine to prevent infection with these viruses is urgently needed. Immune control of HSV-1/-2 infection and resolution of genital herpes lesions requires the collective action of various types of T cells, which are likely primed by different dendritic cell subsets. Understanding the dynamics of the initial interactions of HSV-1 and HSV-2 with cells of the immune system may result in better strategies for HSV-1/-2 vaccines. The pathways described here have important implications in vaccine design and prevention of persistent infection of neuronalcells.
TRIAL BY ERROR: IN GUARDIAN COLUMN, PROFESSOR PARIANTE PARROTS STANDARD BIOPSYCHOSOCIAL NONSENSE 1 May 2021 by David Tuller By David Tuller, DrPH On Tuesday (four days ago), The Guardian published an opinion piece from Professor Carmine Pariante titled “Long Covid is very far from ‘all in the mind’–but psychology can still help us to treat it.” The article is the latest from a member of the biopsychosocial ideological brigades to demonstrate what has long been apparent—those who proclaim that others are falling into an unhelpful mind-body dichotomy are using this argument to deflect attention from the failings of research into their favored interventions. Professor Pariante is a psychiatrist based at King’s College London, the home of Professor Trudie Chalder, Professor Sir Simon Wessely, and other leading lights of the biopsychosocial firmament, so he is likely steeped constantly in a brew of self-reaffirming but unwarranted assertions. about Trial By Error: In Guardian Column, Professor Pariante Parrots Standard Biopsychosocial Nonsense DEFECTIVE GENOMES MODULATE RESPIRATORY SYNCYTIAL VIRUS PATHOGENESIS 29 April 2021 by Vincent Racaniello During viral replication, defective genomes may arise that lack essential sequences. These so-called defective genomes cannot replicate unless they are in the same cell as a helper virus. Defective genomes play a role in modulating pathogenesis of respiratory syncytial virus in humans.
Copy-back defective viral genomes (cbDVGs) of RSV arise when the viral RNA polymerase halts and then turns around and begins copying the nascent strand (illustrated below – image credit). Because the
cbDVGs have strands of both (+) and (-) polarity it is possible to design primers to amplify them by RT-PCR. It has been suspected that defective viral genomes might modulate viral pathogenesis because they are efficient inducers of interferon. In a study of 122 hospitalized pediatric patients with RSV infection, the presence of cbDVGs was associated with higher viral loads and longer hospitalizations. Furthermore, patients harboring cbDVGs had higher expression of pro-inflammatory cytokine genes. Unexpectedly, non-hospitalized patients with confirmed RSV infection also had high levels of cbDVGs and high viral loads. Analysis of the kinetics of cbDVG production revealed that when cbDVGs arise early in infection, less severe symptoms present. In contrast, when cbDVGs arise later in infection, higher viral loads and more severe disease occur. The latter patients also produce higher levels of pro-inflammatory cytokines which likely cause immunopathogenesis. An interpretation of these findings is that when cbDVGs arise early in infection, they induce antiviral immune responses that limit viral replication and disease. When cbDVGs arise later, the virus has already reproduced to high levels, leading to more severe disease. The factors that regulate cbDVGs production are not known, but could involve sex, age, immune status, and the levels of the defective genomes in the virus inoculum. These results are of interest because it has not been possible to predict which RSV infected patients will develop severe disease. It might be possible to use levels of cbDVGs to forecast clinicaloutcome.
When defective viral particles were discovered many years ago, Alice Huang proposed that they might modulate viral pathogenesis. It was not until the 1990s that the technology became available to test this hypothesis. The results with RSV suggest that whether cbDVGs are beneficial or detrimental depends on when they arise in infection.Next Page »
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BY VINCENT RACANIELLO Earth's virology Professor Questions? virology@virology.ws With David Tuller andGertrud U. Rey
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